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One morning in 2005, Shelley Beverley woke up to find that she had gone deaf. She was 21, and living in Johannesburg with her older brother Neil. I was very scared, she says. It was just so sudden. She struggled through the rest of the day, hoping that her hearing would come back, but it didnt. In one sense, her hearing loss wasnt entirely a surprise: Beverleys grandmother had been deaf, Neil had lost his hearing when he was 13, and her mum, Mary, had lost hers when she was 32. We knew it ran in the family, she says, but I thought Id been lucky and not inherited it.

Beverley, 35, lives in Margate, a semi-rural district south of Hobart, with her husband James. The couple migrated to Australia from South Africa in 2010, looking for space, buying 2 hectares of lush green grass at the foot of a forested ridge near the mouth of the Derwent River. We love the wildlife here, says James, looking out the living room window. Weve seen pademelons, echidnas, quolls, blue-tongue lizards, even a Tassie devil. At dusk, hundreds of kangaroos emerge from the forest to gorge on the grass. Its very peaceful, says James. Its really helped us after everything thats happened.

Apart from their deafness, Beverleys family had largely enjoyed good health. Then, in September 2015, her mother, Mary, then 62, started experiencing fatigue and stomach pain. Doctors in Durban ordered a colonoscopy, but the procedure made her worse. Her feet became swollen and purple. Because of their hearing problems, Shelley and Mary had communicated mainly in text messages. But soon I began noticing that her wording got a bit funny, says Beverley. It didnt always make sense.

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Beverley flew to Durban in February 2016, but by that time her mother could no longer talk or walk. She was so weak that she couldnt move her hands or lift her neck. Two days after Beverley arrived in Durban, her mother caught a virus that caused fluid to build up on her lungs. The doctors tried unsuccessfully to drain it. Shortly afterwards, she died. She weighed just 36 kilograms. It was so fast, Beverley says. And we were still in the dark about what she had.

Shortly before Marys death, Neil had also fallen ill. He developed a number of mysterious symptoms, including facial twitches and seizures. He kept falling over and tripping, and experienced vomiting and headaches so severe he lost his vision for weeks at a time. His behaviour became strange showering with his clothes on, and hallucinating.

One day, Dad was driving him around and Neil started talking to all these little people he thought were around his feet, says Beverley. Doctors in Durban had trouble diagnosing him, so they sent a biopsy to London, where he was found to have a type of mitochondrial cytopathy one of a large family of chronic and progressive diseases that affect the muscles, brain and nervous system. As the family soon learnt, the condition has no cure and no effective therapies. One of the common early symptoms is hearing loss.

Neil died in June 2017, aged 34, by which time Beverley had discovered she also had the condition. It was fear, so much fear, she says. She began experiencing symptoms, including migraines and vision loss. She has since developed diabetes, hypertension, gastro-paresis (when your stomach muscles dont work), and pharyngeal dysphagia (difficulty swallowing). Every time I get sick now, the flu or something, I think, When am I going to need a wheelchair or a feeding tube? When will my legs stop working?

Mito has taken everything from me, she says. If I die, at least James will still have a part of me.

Beverley has bright blue eyes and long, straight, ash-brown hair. Shes got a lazy left eye and uncommonly pale skin, which she attributes to her condition. Oh, and I had bunions out in 2010, she says, laughing wryly.

She doesnt know how long shes got left, but she is determined to make it count. She has joined mito awareness groups, and is an active member of the Mito Foundation, which supports sufferers, and funds research. She has exhaustively researched the condition and takes every opportunity to educate doctors. Youd be surprised by how little they know about it, she says.

But her overriding focus has been on a cutting-edge, and currently illegal, procedure called mitochondrial donation, a form of IVF which would allow those with the condition to have children, safe in the knowledge they would not be passing it on. Mito has taken everything from me, she says. If I die, at least James will still have a part of me. I would like him to look at our child, and say, You have your mums smile or your mums eyes.

An IVF treatment known as mitochondrial donation could potentially save up to 60 Australian children a year from being born with the condition. Credit:

Mitochondrial donation has been labelled immoral and unethical, a slippery slope to designer babies, not to mention potentially unsafe. The only country in the world to have legalised it is the UK. A report by medical experts into the technologys potential application in Australia is due to be delivered to Health Minister Greg Hunt this month.

This fight is really personal to me, Beverley says. Short of a cure, people with mito should at least have the option of having healthy children.

Mitochondria are microscopic structures in human cells that provide the body with energy. For this reason, they are often described as the cells powerhouse. They are crucially important: if your mitochondria fail or mutate, your body will be starved of energy, causing multiple organ failure and premature death.

A stylised representation of a mitochondrion, which provides the body with energy. Malfunction can lead to organ failure and death.Credit:Josh Robenstone

Mito, which is maternally inherited, usually affects the muscles and major organs such as the brain, heart, liver, inner ears, and eyes. But it can cause any symptom in any organ, at any age. Indeed, the term mito includes more than 200 disorders, the symptoms of which are maddeningly varied and seemingly unrelated, leading to delayed diagnoses or incorrect diagnoses or, indeed, no diagnosis.

Many of these people have been fobbed off by doctors or laughed off by people who think they are hypochondriacs, says Dr David Thorburn, a mitochondrial researcher at the Murdoch Childrens Research Institute, in Melbourne, who has diagnosed some 700 cases over the past 28 years. Most people are relieved to finally know what it is, because that is the end of that part of their journey.

Its sometimes said babies produced as a result of mitochondrial donation would have three parents the mother, the father, and the donor.

Up to two million people worldwide have some form of mito. - Others, like Beverley, who have a less severe type of the disease, will get adult onset, and can expect to become ill in their 30s, 40s or 50s.

According to Thorburn, One of the things that most dismays families with mito is the lack of control they have over passing the condition down to future generations of their family.

Remaining childless is one way to stop the condition from being passed down, as is adopting, but as Thorburn acknowledges, There is an innate desire in many individuals to have their own children. For these people, mito donation offers the very real prospect that the condition is eliminated from future generations.

Mitochondrial replacement is a highly specialised procedure, requiring a level of manual dexterity sufficient to manipulate a womans egg, which is roughly the width of a human hair. Within that egg is a nucleus, where a persons genes are located, and the cytoplasm, the jelly-like substance that surrounds it. Mitochondria are found in the cytoplasm.

Mitochondrial replacement involves taking a donor females healthy egg, removing its nucleus and replacing it with the nucleus of the woman affected by mitochondrial disease, but whose nucleus is healthy. The egg is then fertilised using her partners sperm. (Another option is to fertilise the egg first, and then swap the nucleus.) The resulting embryo is then implanted into the mother.

Researcher David Thorburn: "Mito donation offers the very real prospect that the condition is eliminated from future generations."Credit:Josh Robenstone

Since more than 99.9 per cent of our genes are found in the eggs nucleus, which remains unaffected, the procedure will have no impact on the childs height, hair colour or mannerisms. Despite that, its sometimes said that babies produced as a result of mitochondrial donation would have three parents the mother, the father, and the donor.

The technology has been tested in mice for more than 30 years, but only since 2009 has research been done on human embryos, mainly in the UK. Almost from the start, the research was subject to sensational headlines about scientists playing God, and the possibility of genetic engineering, with much of the hysteria being fuelled by anti-abortion groups. The Catholic Church described it as a further step in commodification of the human embryo and a failure to respect new individual human lives.

In 2012, the Human Genetics Alert, an independent watchdog group in London, wrote a paper comparing any baby produced with mitochondrial replacement to Frankensteins creation, since they would be produced by sticking together bits from many different bodies. According to the Conservative British MP Jacob Rees-Mogg, the procedure was not a cure for disease, it is the creating of a different person.

Regulators subjected the technology to four separate scientific reviews, together with rounds of ethical debate and community consultation. In 2015, the UK Parliament voted to legalise the technology for use in humans, on the proviso that it only be available to those women at high risk of passing on the disease. Since then, 13 couples in the UK have received the go-ahead to undergo the procedure.

Its unclear how many children, if any, have been born: the parents have asked that details not be published. Meanwhile, scientists like Thorburn wait eagerly for news of any developments. I know the UK researchers well and have asked several of them, and they are keeping completely quiet about it in respecting the families wishes, he says.

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If there have been babies born in the UK using the procedure, they arent the first. In April 2016, a child was born using the technique in Mexico, to a Jordanian mother who carried a fatal mitochondrial condition known as Leigh syndrome. The doctor in charge, an American fertility specialist called Dr John Zhang, later admitted that he had gone to Mexico because the procedure is illegal in America. In Mexico, he admitted, There are no rules.

Even those who want mitochondrial donation legalised in Australia concede that much remains unknown about the procedure. Its long-term risks can only be understood through lifelong health check-ups, but this is impossible until any children conceived via this procedure become adults. Implications for subsequent generations also remain unclear.

No medical procedure is 100 per cent safe, says Sean Murray, CEO of the Mito Foundation. But we think we are at the stage now where the benefits of the technology are greater than the risks.

One of the issues around safety concerns the compatibility of the donors mitochondria with the recipients nuclear genes. A 2016 study in mice suggested that mismatched mitochondria affected their metabolism and shortened their lives. Another concern is known as carryover, whereby a tiny amount of mutant mitochondria is inevitably transferred from the affected mothers egg into the donor egg during the procedure.

Instead of it being wiped out, the mutation might then reappear in the descendants of any girls born as a result. For this reason, some people have proposed that the procedure be restricted to male embryos only, but this raises all kinds of ethical issues around selective breeding and sex selection.

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Indeed, it often seems as if the term ethical minefield was coined especially with mitochondrial donation in mind.

My primary ethical concern has to do with the sanctity of human life, says Father Kevin McGovern, a Catholic priest and member of the National Health and Medical Research Councils Mitochondrial Donation Expert Working Committee.

If mitochondrial donation is permitted here, the technique most likely to be used is pronuclear transfer, which requires that both the donors egg and the affected mothers egg be fertilised. [This is to ensure that both eggs are at the same developmental stage.] But once the nucleus is removed from the donors fertilised egg, it is discarded. For people who believe that life begins at conception, this is akin to murder. You are creating two lives and destroying one for spare parts.

The Catholic Church has consistently opposed mitochondrial donation. In a Senate inquiry into the technology in 2018, Dr Bernadette Tobin, director of the Plunkett Centre for Ethics at the Australian Catholic University, suggested the process was intrinsically evil.

The inquiry also heard from Father Anthony Fisher, Catholic Archbishop of Sydney, who raised concerns about the moral right of the child to know how he or she was conceived the problem of what he called genealogical bewilderment and the donors right to remain anonymous. He also worried that women might effectively become egg vending machines: The availability of human ova is often assumed when people talk about reproductive technology as if they were somehow there in a cupboard to be used. In fact, it means women have to be used to obtain these eggs. They are extracted by invasive procedures that do carry some risk.

A report by medical experts into mitochondrial donation and its potential application in Australia is due to be delivered to Health Minister Greg Hunt this month. Credit:Alex Ellinghausen

Equally troubling for the Australian Catholic Bishops Conference, the peak national body for the churchs bishops, was the fact that mitochondrial donation involved conceiving babies not by marital intercourse [but by] a technical procedure.

Most of these concerns are redundant, argues the Mito Foundations Sean Murray. We already have a well defined regulatory framework for dealing with all this, he says. As far as the donors right to remain anonymous, we would defer to the appropriate federal or state and territory regulations that apply for sperm or egg donations. In regard to a kids right to know they had a mitochondrial donor, societally there seems to be a preference to inform kids. Its important for them to understand their genetic lineage.

Then theres the matter of consent. The parents can wrestle with the ethical issues and weigh up all the risks, but the only person who cant consent to the procedure is the unborn child. Well, says Murray, they cant consent to being born with mito, either.

The Mito Foundations Sean Murray: "In regard to a kids right to know they had a mitochondrial donor, societally there seems to be a preference to inform kids."Credit:Joshua Morris

Murray, 47, is one of the founding directors of the Mito Foundation, which was established in Sydney in 2009. Mito runs in my family, he says. My older brother, Peter, died of it in 2009 at 45, and my mum passed away in 2011, at 70. What people often dont understand is that even in families that have mito, each member can have different mutational loads basically, different amounts of bad mitochondria. Peter got a high load, but I didnt. Thats why Im still here.

A computer scientist by training, Murray now works full-time on the foundation. Much of his job involves travelling around the country, explaining mito to politicians, journalists and philanthropists, raising funds for research and, most crucially, advocating for a change to the laws.

Mitochondrial donation falls foul of two pieces of legislation: the Research Involving Human Embryos Act 2002, and the Prohibition of Human Cloning for Reproduction Act 2002. The laws prohibit the implantation of a human embryo that contains more than two peoples genetic material. The laws were subject to a mandatory review in 2010, but the then Labor government recommended they remain the same.

In 2013, the Mito Foundation urged the government to revisit its decision. Two years later, it began lobbying in earnest. What we tried to get across was that the science around mito donation has come a long way since 2010, says Murray. Also, the process that the UK went through to legalise it really reassured us that the procedure is safe and effective.

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In the past five years, Murray and his colleagues have consulted with more than 100 MPs and senators. Only one of them, according to Murray, said I dont like this. They have also talked to dozens of industry experts, including academics and medical and research bodies, about the benefits of mitochondrial donation. Most of them get it straight away, he says. We are talking about a technique that will prevent the chance of having a morbidly ill child.

Now, a breakthrough appears imminent. In February 2019, Health Minister Greg Hunt asked the National Health and Medical Research Council to look into the matter, review the science and conduct public consultation. The NHMRC is due to hand its report to Hunt this month. The expectation among the mito community is that he will recommend the laws be changed. Any proposals would then need to be debated in Parliament, where issues around reproductive medicine have, in the past, been hotly contested.

Murray expects some opposition from more conservative MPs, but nothing like the rancour seen in the NSW Parliament during last years debate over legalising abortion. Shadow health minister Chris Bowen has, for his part, said that Labor will support changing the laws.

Mitochondrial sufferer Shelley Beverley at home in Tasmania. This fight is really personal to me. Credit:Peter Mathew

Whether this will help people like Shelley Beverley is unclear. If Hunt gives it the green light, it will take two years at least for mitochondrial donation to become available to prospective parents, given the time involved in drafting and passing legislation, establishing a regulatory regime and getting doctors up to speed with the technology.

This will probably be too late for Beverley. I really only have about a year left to give it a go, she tells me. After that, my symptoms may progress and biologically things get worse after 35. She says she would consider going to the UK for the treatment, but that at present they are not accepting international patients.

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In the meantime, she watches TV, and reads a little, but not too much. (It puts me to sleep.) She gardens: she has a bed of huge white and pink roses out the back of her house, as a memorial to her mother and brother. And she eats. James cooks for me. He lets me choose the best meat and potatoes! Ive put on weight since I met him. She describes James as something close to an angel. He will listen to every problem I have or feeling I experience. He will always put me first.

Beverley started going out with James when she was 21, right around the time she first went deaf. I was so scared that he wouldnt like me as much. I remember calling him and saying I was scared he would leave me. But James is still here. Im very lucky to have him, she says. If I go, I want him to have a part of me.

To read more from Good Weekend magazine, visit our page at The Sydney Morning Herald, The Age and Brisbane Times.

Tim Elliott is a senior writer with Good Weekend.

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How far should genetic engineering go to allow this couple to have a healthy baby? - Brisbane Times

Even at their most effective and draconian containment strategies have only slowed the spread of the respiratory disease Covid-19. With the World Health Organization finally declaring a pandemic, all eyes have turned to the prospect of a vaccine, because only a vaccine can prevent people from getting sick.

About 35 companies and academic institutions are racing to create such a vaccine, at least four of which already have candidates they have been testing in animals. The first of these produced by Boston-based biotech firm Moderna will enter human trials imminently.

This unprecedented speed is thanks in large part to early Chinese efforts to sequence the genetic material of Sars-CoV-2, the virus that causes Covid-19. China shared that sequence in early January, allowing research groups around the world to grow the live virus and study how it invades human cells and makes people sick.

But there is another reason for the head start. Though nobody could have predicted that the next infectious disease to threaten the globe would be caused by a coronavirus flu is generally considered to pose the greatest pandemic risk vaccinologists had hedged their bets by working on prototype pathogens. The speed with which we have [produced these candidates] builds very much on the investment in understanding how to develop vaccines for other coronaviruses, says Richard Hatchett, CEO of the Oslo-based nonprofit the Coalition for Epidemic Preparedness Innovations (Cepi), which is leading efforts to finance and coordinate Covid-19 vaccine development.

Coronaviruses have caused two other recent epidemics severe acute respiratory syndrome (Sars) in China in 2002-04, and Middle East respiratory syndrome (Mers), which started in Saudi Arabia in 2012. In both cases, work began on vaccines that were later shelved when the outbreaks were contained. One company, Maryland-based Novavax, has now repurposed those vaccines for Sars-CoV-2, and says it has several candidates ready to enter human trials this spring. Moderna, meanwhile, built on earlier work on the Mers virus conducted at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

Sars-CoV-2 shares between 80% and 90% of its genetic material with the virus that caused Sars hence its name. Both consist of a strip of ribonucleic acid (RNA) inside a spherical protein capsule that is covered in spikes. The spikes lock on to receptors on the surface of cells lining the human lung the same type of receptor in both cases allowing the virus to break into the cell. Once inside, it hijacks the cells reproductive machinery to produce more copies of itself, before breaking out of the cell again and killing it in the process.

All vaccines work according to the same basic principle. They present part or all of the pathogen to the human immune system, usually in the form of an injection and at a low dose, to prompt the system to produce antibodies to the pathogen. Antibodies are a kind of immune memory which, having been elicited once, can be quickly mobilised again if the person is exposed to the virus in its natural form.

Traditionally, immunisation has been achieved using live, weakened forms of the virus, or part or whole of the virus once it has been inactivated by heat or chemicals. These methods have drawbacks. The live form can continue to evolve in the host, for example, potentially recapturing some of its virulence and making the recipient sick, while higher or repeat doses of the inactivated virus are required to achieve the necessary degree of protection. Some of the Covid-19 vaccine projects are using these tried-and-tested approaches, but others are using newer technology. One more recent strategy the one that Novavax is using, for example constructs a recombinant vaccine. This involves extracting the genetic code for the protein spike on the surface of Sars-CoV-2, which is the part of the virus most likely to provoke an immune reaction in humans, and pasting it into the genome of a bacterium or yeast forcing these microorganisms to churn out large quantities of the protein. Other approaches, even newer, bypass the protein and build vaccines from the genetic instruction itself. This is the case for Moderna and another Boston company, CureVac, both of which are building Covid-19 vaccines out of messenger RNA.

Cepis original portfolio of four funded Covid-19 vaccine projects was heavily skewed towards these more innovative technologies, and last week it announced $4.4m (3.4m) of partnership funding with Novavax and with a University of Oxford vectored vaccine project. Our experience with vaccine development is that you cant anticipate where youre going to stumble, says Hatchett, meaning that diversity is key. And the stage where any approach is most likely to stumble is clinical or human trials, which, for some of the candidates, are about to get under way.

Clinical trials, an essential precursor to regulatory approval, usually take place in three phases. The first, involving a few dozen healthy volunteers, tests the vaccine for safety, monitoring for adverse effects. The second, involving several hundred people, usually in a part of the world affected by the disease, looks at how effective the vaccine is, and the third does the same in several thousand people. But theres a high level of attrition as experimental vaccines pass through these phases. Not all horses that leave the starting gate will finish the race, says Bruce Gellin, who runs the global immunisation programme for the Washington DC-based nonprofit, the Sabin Vaccine Institute.

There are good reasons for that. Either the candidates are unsafe, or theyre ineffective, or both. Screening out duds is essential, which is why clinical trials cant be skipped or hurried. Approval can be accelerated if regulators have approved similar products before. The annual flu vaccine, for example, is the product of a well-honed assembly line in which only one or a few modules have to be updated each year. In contrast, Sars-CoV-2 is a novel pathogen in humans, and many of the technologies being used to build vaccines are relatively untested too. No vaccine made from genetic material RNA or DNA has been approved to date, for example. So the Covid-19 vaccine candidates have to be treated as brand new vaccines, and as Gellin says: While there is a push to do things as fast as possible, its really important not to take shortcuts.

An illustration of that is a vaccine that was produced in the 1960s against respiratory syncytial virus, a common virus that causes cold-like symptoms in children. In clinical trials, this vaccine was found to aggravate those symptoms in infants who went on to catch the virus. A similar effect was observed in animals given an early experimental Sars vaccine. It was later modified to eliminate that problem but, now that it has been repurposed for Sars-CoV-2, it will need to be put through especially stringent safety testing to rule out the risk of enhanced disease.

Its for these reasons that taking a vaccine candidate all the way to regulatory approval typically takes a decade or more, and why President Trump sowed confusion when, at a meeting at the White House on 2 March, he pressed for a vaccine to be ready by the US elections in November an impossible deadline. Like most vaccinologists, I dont think this vaccine will be ready before 18 months, says Annelies Wilder-Smith, professor of emerging infectious diseases at the London School of Hygiene and Tropical Medicine. Thats already extremely fast, and it assumes there will be no hitches.

In the meantime, there is another potential problem. As soon as a vaccine is approved, its going to be needed in vast quantities and many of the organisations in the Covid-19 vaccine race simply dont have the necessary production capacity. Vaccine development is already a risky affair, in business terms, because so few candidates get anywhere near the clinic. Production facilities tend to be tailored to specific vaccines, and scaling these up when you dont yet know if your product will succeed is not commercially feasible. Cepi and similar organisations exist to shoulder some of the risk, keeping companies incentivised to develop much-needed vaccines. Cepi plans to invest in developing a Covid-19 vaccine and boosting manufacturing capacity in parallel, and earlier this month it put out a call for $2bn to allow it to do so.

Once a Covid-19 vaccine has been approved, a further set of challenges will present itself. Getting a vaccine thats proven to be safe and effective in humans takes one at best about a third of the way to whats needed for a global immunisation programme, says global health expert Jonathan Quick of Duke University in North Carolina, author of The End of Epidemics (2018). Virus biology and vaccines technology could be the limiting factors, but politics and economics are far more likely to be the barrier to immunisation.

The problem is making sure the vaccine gets to all those who need it. This is a challenge even within countries, and some have worked out guidelines. In the scenario of a flu pandemic, for example, the UK would prioritise vaccinating healthcare and social care workers, along with those considered at highest medical risk including children and pregnant women with the overall goal of keeping sickness and death ra tes as low as possible. But in a pandemic, countries also have to compete with each other for medicines.

Because pandemics tend to hit hardest those countries that have the most fragile and underfunded healthcare systems, there is an inherent imbalance between need and purchasing power when it comes to vaccines. During the 2009 H1N1 flu pandemic, for example, vaccine supplies were snapped up by nations that could afford them, leaving poorer ones short. But you could also imagine a scenario where, say, India a major supplier of vaccines to the developing world not unreasonably decides to use its vaccine production to protect its own 1.3 billion-strong population first, before exporting any.

Outside of pandemics, the WHO brings governments, charitable foundations and vaccine-makers together to agree an equitable global distribution strategy, and organisations like Gavi, the vaccine alliance, have come up with innovative funding mechanisms to raise money on the markets for ensuring supply to poorer countries. But each pandemic is different, and no country is bound by any arrangement the WHO proposes leaving many unknowns. As Seth Berkley, CEO of Gavi, points out: The question is, what will happen in a situation where youve got national emergencies going on?

This is being debated, but it will be a while before we see how it plays out. The pandemic, says Wilder-Smith, will probably have peaked and declined before a vaccine is available. A vaccine could still save many lives, especially if the virus becomes endemic or perennially circulating like flu and there are further, possibly seasonal, outbreaks. But until then, our best hope is to contain the disease as far as possible. To repeat the sage advice: wash your hands.

This article was amended on 19 March 2020. An earlier version incorrectly stated that the Sabin Vaccine Institute was collaborating with the Coalition for Epidemic Preparedness Innovations (Cepi) on a Covid-19 vaccine.

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When will a coronavirus vaccine be ready? - The Guardian

The news last week that NBA player Rudy Gobert, a Frenchman of Caribbean heritage, had tested positive for the coronavirus shattered a myth that some of the world's more conspiracy-minded had circulated online through jokes, news stories and social media posts.

Black people are not, in fact, immune to the coronavirus.

On Tuesday, the Afro-British actor Idris Elba, who lives part time in the United States and tested positive for COVID-19 this week, posted on social media about his early lack of symptoms and subsequent changes, how he managed to be tested, the dangers of the disease and the myth of black immunity.

"Something that is scaring me, when I read the comments and some of the reactions, my people, black people, please, please understand that coronavirus is ... you can get it," Elba said. "There are so many stupid, ridiculous conspiracy theories about black people not being able to get it. ...That is the quickest way to get more black people killed. And I'm talking about the whole world, wherever we are. ... Just know you have to be just as vigilant as every other race."

Variations on the immunity myth claims that black worshipers can't be infected at church where a pastor refused to cancel in-person services and false assertions that there are zero COVID-19 infections in Africa to name a few remain on the internet along with other fantastical ideas. The myth of group immunity may, public health, disease control and bioethicists say, provide some people with a bit of levity or sense of control in a seemingly dire time. But the risk of false information circulating in any form far outweighs the value of a few chuckles or nerve-calming denial.

What's more, fictional claims about black immunity from a potentially deadly viral infection are connected with a long history of contradictory but uniformly racist ideas serving the social or political needs of the moment, experts say.

"I want to be very clear there is, despite many claims to the contrary, no truth, no fact at all in claims of genetic differences, immunity or susceptibility, to disease based on race," said Otis Brawley, a professor of epidemiology and oncology at the Johns Hopkins University Bloomberg School of Public Health.

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The list of health conditions linked to genetic variations found more often in specific geographic regions is a short one. Even health conditions that appear disproportionately in some populations, such as sickle cell disease, fall in this category, Brawley said. As a result there are people classified in the United States as both white and black who have sickle cell disease or the genetic trait. But, this pattern is, too often, wrongly conflated with race, he said.

"Race medicine is almost always bad medicine," said Brawley. "So I do not have and, to my knowledge, no one else has, any data demonstrating either racial or geographic immunity from coronaviruses."

While the false notion of black immunity to coronavirus has, to some degree, faded in the days since the Gobert news which was followed by several other black NBA players testing positive as well other absurd notions, conspiracy theories and lies have rippled through many social media feeds.

"There are a whole range of crazy notions gaining traction," said Gail Christopher, executive director of the National Collaborative for Health Equity. "We all would like to have hope right now to counter the anxiety that the bulk of the news is giving us. So anybody is possibly vulnerable to misinformation. We do, all have, naturally, a psychological propensity to cling to hope, but that is also part of what makes this so dangerous."

Jokes may help some deal with the fear of a disease creating massive, disempowering social upheaval, Christopher said. Conspiracy theories may do the same. And the effort to rebrand the virus as the fault of the Chinese (or vice versa), is nothing more than a flagrant attempt to shift blame and deflect attention from a disjointed and inadequate official response, she said. What's more, black Americans are overrepresented among those living with some of the underlying health conditions asthma, diabetes, high blood pressure, heart disease that can put a person at risk of becoming seriously ill or dying due to the coronavirus, Christopher said. Global differences in health care access and quality compound this problem.

Representatives from the World Health Organization have met with many of the nation's major technology companies, and the organization is working with Google to curb the spread of misinformation online.

"The COVID-19 outbreak and response has been accompanied by a massive 'infodemic,'" the organization said in a statement to NBC News last week.

The WHO is also working with social media companies and influencers to detect misinformation and limit its spread, the agency added

"These myths have a track record not just of shaping attitudes but of shaping policy and practice in public and private spaces, in hospitals and in schools, in workplaces, too," said Dorothy Roberts, a University of Pennsylvania bioethicist, lawyer and sociologist who researches race in medicine. "It's not farfetched to fear that now."

Over the course of 100 years, the false belief spread that people of African descent had inferior or weak lungs ideas championed by no less than Thomas Jefferson and Samuel Cartwright, a respected doctor and professor at the school that would become Tulane University, according to Roberts, author of "Fatal Invention: How Science, Politics and Big Business Re-Create Race in the Twenty-First Century." The lungs of black people were so in need of constant exertion, the men argued, that forced unpaid labor slavery was a form of treatment.

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In the 1790s, nearly two decades after he signed the Declaration of Independence, Dr. Benjamin Rush, a respected white Philadelphia physician, and others advanced the idea that black people were somehow biologically immune to yellow fever. Rush did so during a massive outbreak in that city. Black people, Rush and others said, were uniquely positioned to care for the sick, dig graves, and cart away and bury bodies. In the end, 4,000 to 5,000 people died, including an estimated 240 black residents.

Given that history, this month, The Philadelphia Inquirer published a column refuting false claims that black Americans are immune to coronavirus. The city is more than 42 percent black. But the problem of racial myths in medicine remains a part of modern thinking well beyond Philadelphia, Roberts said.

In 2016, a survey of 222 medical students and residents found that half believed at least one of several myths about biological differences between black and white people that shaped their approach to treating pain. As a result, the medical professionals were overwhelmingly less willing to regard or treat the pain of black patients the same as white patients.

And the problems do not end there. To this day, most of the nation's medical facilities use different standards for measuring lung and kidney function for black patients versus others, Roberts said. This, in turn, means that black patients must register more significant breathing difficulties or kidney dysfunction before the most serious medical interventions are offered.

"Any way you look at it, I see no benefit to any of the myths about black physical peculiarity," Roberts said. "They have all been dangerous to black people's health and welfare in America, supportive of white supremacy and promoted low levels of care and concern about black people's health.

"So I think it's a mistake to even joke about it. I just don't find it funny at all."

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Coronavirus outbreak revives dangerous race myths and pseudoscience - NBC News

PARIS & LEIDEN, Netherlands--(BUSINESS WIRE)--HORAMA SA, a French biotechnology company focusing on gene therapy for the treatment of rare genetic diseases in ophthalmology, announced today an exclusive licensing agreement with the Leiden University Medical Center (LUMC) for global rights to a gene therapy program to treat the Inherited Retinal Dystrophy associated with pathogenic CRB1 gene mutations, a rare but devastating ophthalmic condition leading to blindness

"We are excited to enter into this agreement with the LUMC, a leading academic institution with highly recognised scientific leaders in the field of gene therapy such as Jan Wijnholds, to expand our leadership in gene therapy. This collaboration enables us to expand our pipeline of gene therapy treatments for ophthalmic conditions for which there is a high unmet medical need, commented Christine Placet, CEO of HORAMA.

Our studies in the last 20 years resulted in the development of a platform for candidate gene therapy medicines for children with pathogenic CRB1 mutations. The main obstacle to test our novel innovative medicine gene therapy products in clinical studies was the high costs of the clinical development phase. We are, therefore, excited about this research agreement with HORAMA team, which is a global expert in this field, commented Jan Wijnholds, LUMC.

Under the agreement, HORAMA will receive an exclusive worldwide license to certain patent rights and know-how for the drug candidate (referenced as HORA-001). In return for these rights, LUMC will receive an undisclosed upfront payment, milestone payments and royalties on net sales of products. HORAMA shall be responsible to bring the gene therapy to market with completion of the non-clinical and clinical studies. Based on current timelines, and subject to regulatory review, HORAMA expects initiating a Phase I/II clinical study with HORA-001 in 2023.

Per the agreement, the parties have entered into a non-clinical development agreement with Leiden University Medical Center (LUMC), led by Dr. Jan Wijnholds, Team Leader and permanent staff member at the LUMC Department of Ophthalmology.

About HORAMA

At HORAMA, we believe in gene therapy to treat a broad range of inherited disorders.

Our focus is on Inherited Retinal Dystrophies with our lead clinical program targeting patients with PDE6B gene mutations, a condition which leads to progressive vision loss in children and adults ultimately leading to legal blindness.

Our team is pushing the boundaries of gene therapy by advancing next generation delivery platforms that will improve effectiveness and coverage of gene transfer to address multiple diseases. For more information, please go to: http://www.horama.fr.

Gene therapy market (source: FiorMarkets and Grand View Research, Inc)

Gene therapy is being developed with an aim to treat rare conditions with limited or no treatment options.

Genetic disorders occur due to gene mutations, which can result in incorrect protein synthesis. Gene therapy is used to introduce a healthy gene into cells to allow the synthesis of a functional protein. Growing awareness and acceptance of gene therapy for various disease treatments are favouring market growth.

The global gene therapy market is estimated to reach $5.5 billion by 2026, while the global ophthalmology market is projected to grow to $43 billion by 2026 (April 2019 report issued by Grand View Research, Inc.).

Inherited Retinal Dystrophies

Inherited Retinal Dystrophies (IRD) represent a diverse group of progressive visually debilitating diseases that can lead to blindness. In patients with an IRD, mutations in genes, which are critical to retinal function, lead to progressive, direct or indirect photoreceptor cell death and associated visual function losses.

IRDs are a genetically heterogeneous group of diseases, with over 260 genes identified to date, IRDs associated with pathogenic CRB1 gene mutations are among this heterogeneous group, similar to the autosomal recessive IRD associated with pathogenic PDE6B gene mutations.

About CRB1

CRB1 gene mutations are a major cause of early onset and delayed onset IRD. Proteins such as CRB1 and CRB2 are essential in the retina to maintain adhesion between photoreceptors and Mller glial cells. Loss of CRB function results in loss of photoreceptors and causes blindness.

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HORAMA Signs Exclusive License Agreement with Leiden University Medical Center Targeting CRB1 Gene Mutations to Treat Inherited Retinal Dystrophies -...

In the months since the novel coronavirus rose from a regional crisis to a global threat, drug makers large and small have scrambled to advance their best ideas for thwarting a pandemic.

Some are taking a cue from older antivirals. Some are tapping tried-and-true technologies, and others are pressing forward with futuristic approaches to human medicine.

Heres a guide to some of the most talked-about efforts to treat or prevent coronavirus infection, with details on the science, history, and timeline for each endeavor.Were looking at novel medicines, not repurposed drugs. (For more on some of the efforts to repurpose drugs, read this.) The below therapies and vaccines are sorted in order of how close they could be to approval, starting with a treatment in Phase 3 trials, followed by others in Phase 1 studies and then preclinical development. Approval, of course, would only come if they are proven safe and effective.

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Gilead SciencesApproach: TreatmentStage: Phase 3

Gileads remdesivir is being studied in five clinical trials around the world. In China, Gilead is recruiting about 1,000 patients diagnosed with the coronavirus to determine whether multiple doses of remdesivir can reverse the infection. The primary goals are reducing fever and helping patients get out of the hospital within two weeks. The drug, which previously failed in a study on Ebola virus, is administered intravenously. More on the drug here.

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Ascletis PharmaApproach: TreatmentStage: Phase 1

Chinese drug maker Ascletis Pharma is testing a combination of antivirals, one approved for HIV and one approved for hepatitis C, that might treat coronavirus infection. Last month, the company enrolled 11 patients with coronavirus-caused pneumonia and administered a cocktail of danoprevir and ritonavir. All 11 were eventually discharged, according to Ascletis. The company hasnt disclosed plans for a larger study.

Moderna TherapeuticsApproach: VaccineStage: Phase 1Moderna set a drug industry record with mRNA-1273, a vaccine candidate identified just 42 days after the novel coronavirus was sequenced. The company is working with the National Institutes of Health on a healthy-volunteer study that began earlier this month. If mRNA-1273 proves itself to be safe, Moderna will enroll hundreds more patients to determine whether the vaccine protects against infection. Modernas product is a synthetic strand of messenger RNA, or mRNA, designed to convince bodily cells to produce antibodies against the virus. The company, founded in 2010, is yet to win Food and Drug Administration approval for any of its mRNA medicines. More on the vaccine candidate here.

CanSino BiologicsApproach: VaccineStage: Phase 1

CanSino Biologics, headquartered in Tianjin, is close to testing its novel coronavirus vaccine in a clinical trial in China. CanSinos approach involves taking a snippet of coronavirus genetic code and entwining it with a harmless virus, thereby exposing healthy volunteers to the novel infection and spurring the production of antibodies. The company said this week that Chinese authorities approved its planned trial, which will begin as soon as possible. CanSino markets a vaccine for Ebola virus in China.

Arcturus TherapeuticsApproach: VaccineStage: Preclinical

Arcturus Therapeutics is pressing forward with a vaccine that relies on engineering RNA. The company plans to take an RNA virus that has been edited to encode for proteins that will protect against infection and load it into a liquid nanoparticle. The resulting vaccine, being developed in partnership with Duke University, promises a better immune response at a lower dose than competing mRNA approaches, according to the company. The vaccine remains in preclinical development, and Arcturus has promised to start a human trial as quickly as possible.

BioNTechApproach: VaccineStage: PreclinicalGermanys BioNTech is working on an mRNA vaccine for the novel coronavirus with plans to enter clinical testing in April. Like its competitors, the company uses strands of mRNA to spur the production of protective antibodies. Earlier this month, Shanghais Fosun Pharma signed a deal to market BioNTechs vaccine in China if its eventually approved. Pfizer has agreed to co-develop the vaccine in the rest of the world.

CureVacApproach: VaccineStage: Preclinical

Like Moderna, CureVac uses man-made mRNA to spur the production of proteins. And, like Moderna, it got a grant from the nonprofit Coalition for Epidemic Preparedness Innovations to apply its technology to coronavirus. CureVac has said it expects to have a candidate ready for animal testing by April, aiming to start a clinical study this summer. The company is also working with CEPI on a mobile mRNA manufacturing technology, one that would theoretically allow health care workers to rapidly produce vaccines to respond at the site of an outbreak.

Eli LillyApproach: TreatmentStage: Preclinical

Eli Lilly has partnered with a Canadian firm called AbCellera to develop antibody treatments for coronavirus infection. Using a blood sample from a coronavirus survivor, AbCellera identified more than 500 antibodies that might protect against the virus. Now its working with Lilly to identify which are most potent. The two companies aim to have a treatment ready for human trials within the next four months.

GlaxoSmithKlineApproach: VaccineStage: Preclinical

GlaxoSmithKline, one of the worlds largest vaccine manufacturers, is lending its technology to a Chinese biotech firm at work on a coronavirus vaccine. Under an agreement signed last month, GSK is providing its proprietary adjuvants compounds that enhance the effectiveness of vaccines to Clover Biopharmaceuticals, a privately held company based in Chengdu. Clovers approach involves injecting proteins that spur an immune response, thereby priming the body to resist infection. GSK struck a similar deal with the University of Queensland in Australia, which is also working on a protein vaccine.The company has not said when it expects to advance either into human testing. GSK is also lending its scientific expertise to CEPI.

Inovio PharmaceuticalsApproach: VaccineStage: Preclinical

Inovio has spent the last four decades working to turn DNA into medicine, and the company believes its technology could quickly generate a vaccine for the novel coronavirus. Working with CEPI grant money, Inovio has come up with a DNA vaccine it believes can generate protective antibodies and keep patients from infection. The company has partnered with a Chinese manufacturer, Beijing Advaccine Biotechnology, and is working through preclinical development with a candidate called INO-4800. The company expects to progress into clinical trials in April and has promised to manufacture 1 million doses of its candidate this year.

Johnson & JohnsonApproach: Vaccine and treatmentStage: Preclinical

Johnson & Johnson, which has in the past responded to outbreaks of the Ebola and Zika viruses, is taking a multipronged approach to the coronavirus. The company is in the early days of developing a vaccine that would introduce patients to a deactivated version of the virus, triggering an immune response without causing infection. Human trials could begin by November. At the same time, J&J is working with the federal Biomedical Advanced Research and Development Authority on potential treatments for patients who are already infected, a process that includes investigating whether any of its older medicines might work against the coronavirus.

PfizerApproach: Vaccine and treatmentStage: Preclinical

Outside of its vaccine work with BioNTech, Pfizer has put out a five-point plan to address the outbreak, which includes making its technology, scientists, expertise, and manufacturing available to outside institutions. The company has also promised to create a rapid-response program to make it easier to respond to future pandemics.

Regeneron PharmaceuticalsApproach: TreatmentStage: Preclinical

Regeneron has grown into a $50 billion business based on its ability to craft human antibodies out of genetically engineered mice. Now its tapping that technology in hopes of treating coronavirus. The company immunized its proprietary antibody-generating mice with a harmless analog of the novel coronavirus, generating potential treatments for the infection. Regeneron plans to select the two most potent antibodies and advance the cocktail into human studies by early summer. The last time Regeneron embarked on this process, during the Ebola outbreak of 2015, it came up with an antibody cocktail that roughly doubled survival rates for treated patients. More on Regenerons treatment here.

SanofiApproach: Vaccine and treatmentStage: Preclinical

Sanofi, which has successfully developed vaccines for yellow fever and diphtheria, is working with BARDA on an answer to the coronavirus. Sanofis approach involves taking some of the coronaviruss DNA and mixing it with genetic material from a harmless virus, creating a chimera that can prime the immune system without making patients sick. Sanofi expects to have a vaccine candidate to test in the lab within six months and could be ready to test a vaccine in people within a year to 18 months. Approval would likely be at least three years away, the company said. Outside of vaccines, Sanofi and Regeneron have started a clinical trial to test whether Kevzara, an approved anti-inflammatory drug, can help with the symptoms of Covid-19.

TakedaApproach: TreatmentStage: Preclinical

Japanese pharma giant Takeda is at work on a treatment derived from the blood of people who have already been infected by the coronavirus. The company is drawing blood from coronavirus survivors, harvesting the plasma, and then isolating the protective antibodies that kept those patients alive. Its not a new idea. Blood transfusions have been used to combat viral outbreaks since at least the Spanish Flu pandemic of 1918. But Takedas take on it could prove to be faster in development than other therapeutic approaches. According to the company, the therapy could be available to patients in 12 to 18 months.

Vir BiotechnologyApproach: TreatmentStage: Preclinical

Vir Biotechnology, a company focused on infectious disease, has isolated antibodies from people who survived SARS, a viral relative of the novel coronavirus, and is working to determine whether they might treat the infection. Teaming up with Chinese pharma contractor WuXi Biologics, the San Francisco-based Vir is in the early stages of development and hasnt specified when it expects to have products ready for human testing. The company has also aligned with Alnylam Pharmaceuticals to work on treatments that might halt viral replication by interfering with RNA signaling. Virs CEO, Biogen veteran George Scangos, is also coordinating the trade group BIOs response to the coronavirus outbreak.

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An updated guide to the coronavirus drugs and vaccines in development - STAT

The ability to detect electrical activity in the brain through the scalp, and to control it, will soon transform medicine and change society in profound ways. Patterns of electrical activity in the brain can reveal a persons cognitionnormal and abnormal. New methods to stimulate specific brain circuits can treat neurological and mental illnesses and control behavior. In crossing this threshold of great promise, difficult ethical quandaries confront us.

Mind reading

The ability to interrogate and manipulate electrical activity in the human brain promises to do for the brain what biochemistry did for the body. Likewise, in experimental research destined to soon enter medical practice, just a few minutes of monitoring electrical activity in your brain using EEG and other methods can reveal not only neurological illness but also mental conditions like ADHD and schizophrenia.

Against the historical backdrop of ethical lapses and concerns that curtailed brain stimulation research for mental illnesses decades ago, we are reaching a point where it will become unethical to deny people suffering from severe mental or neurological illness treatments by optogenetic or electrical stimulation of their brain, or to withhold diagnosing their conditions objectively by reading their brains electrical activity. But the genie is out of the bottle. We better get to know her.

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'The genie is out of the bottle': How 'mind reading' will transform medical care - Genetic Literacy Project

Mar 12th 2020

NEENA NIZAR is 42 years old, a professor of business studies and just 122cm tall. The ends of her bones are soft and pliable: on an x-ray they look frayed, like old paintbrushes. During her childhood and adolescence in Dubai she was operated on 30 times. The source of her problem remained a mystery. In 2010, after three decades of wondering, she finally received a diagnosis: Jansens Metaphyseal Chondrodysplasia, a condition first recognised in the 1930s. Her problems stem from a broken copy of just one of her 20,000 genes.

Dr Nizar is in some ways very unusual. Fewer than one in 200m people have the mutation to the PTH1R gene that causes Jansens disease. In other ways she is like everyone else. Although few people have a defect as debilitating, everyones health, and ill-health, is tied to the contents of their genomes. All genomes contain arrangements of genes that make psychological disorders, cancers, dementias or circulatory diseases either more of a problem or less of one. Everyone has genes that make them better or worse at metabolising drugs, more or less likely to benefit from specific forms of exercise, better able to digest some foods than others.

The same arrangement will never be seen twice. Though for identical twins the differences are the height of subtlety, each of the 7.5bn human genomes sharing the planet is unique. That irreducible diversity represents a challenge to many of the 20th centurys greatest medical advances, which were based on a one-size-fits-all approach. Personalising medicine is an enticing opportunity for improvement.

Good doctors have always treated their patients as individuals. In the 20th century blood tests, X-rays, body scans and other diagnostic tools made the specifics of each patients particular problems ever more visible. A spectacular reduction in the cost of reading, or sequencing, the DNA bases that make up human genetic information is adding a new level of individuality. It is now possible to inspect genetic differences with an ease previously unimaginable, and thus to know something about propensities to disease well before any symptoms show up.

Nobody knows exactly how many human genomes have been fully sequenced, and different sequencing procedures read the genome to different degreesthere are quick skims and painstaking philological studies. But the number is in the millions (see chart). By the 2030s genome sequencing is likely to be as routine in some places as taking a pin-prick of blood from a babys heel is todayit may even be part of the same procedure. Genome science is becoming a matter of practical medicine. New therapies that make it possible to adjust or edit this genetic inheritance are coming to market.

This flood of data is allowing medicine to become more precise and more personalin many ways, the p-words are two sides of the same coin. Previously recognised genetic diseases, such as Jansens, have been traced to specific genes and can be connected to defects in the proteins they create (almost all genes describe proteins, and proteins do almost all the bodys chemical work). Most of these diseases are rare, in that they typically affect no more than one person in 2,000 in the general population. But with over 6,000 such rare diseases now recognised, this means they are common in the aggregate. In Britain one in 17 people can expect to suffer from a rare disease at some point.

Studies of genetic diseases are not just a worthwhile end in themselves. Understanding what goes wrong when a specific protein is out of whack can reveal basic information about the bodys workings that may be helpful for treating other ailments. And the growing understanding of how large sets of genes may contribute to disease is making it possible to pick out the patients most at risk from common diseases like diabetes, heart conditions and cancer. That will help doctors personalise their interventions. In theory, the rise in access to personal genetic information allows individuals to better calculate these risks and to take pre-emptive action. In practice, so far, few people seem to do so.

Genomics is not the only source of new personal-health data. Just as all genomes are unique, so are the lives that all those genome-carriers lead. The increase in other forms of data about individuals, whether in other molecular information from medical tests, electronic health records, or digital data recorded by cheap, ubiquitous sensors, makes what goes on in those lives ever easier to capture. The rise of artificial intelligence and cloud computing is making it possible to analyse this torrent of data.

Almost 4bn people carry smartphones that can monitor physical activity. It is estimated that by 2022, 1bn people may be wearing a device such as a smart watch that can monitor their heart rate. The data-driven giants and startups of Silicon Valley are eager to help. Consumers no longer need to go to a doctor for a genome scan or to engage with a wide range of opinion about what ails them, or will ail them. The pharmaceutical companies used to dominating medicine are working hard to keep up. So are doctors, hospitals and health systems.

These possibilities are not without their risks, drawbacks and potential for disappointment. The ability to pinpoint what has gone wrong in a genome does not make it easy to fix. Moreover, as technology helps people monitor themselves in more ways, the number of the worried well will swell and unnecessary care will grow. Many could be done real harm by an algorithmic mirage.

Beyond this, the move fast and break things attitude common in tech companies sits uneasily with first, do no harm. And the untrammelled, unsupervised and unaccountable means of data accrual seen in other industries which have undergone digital transformations sits uneasily with concerns over medical privacy.

The very nature of medicine, though, means that the future will not just be a matter of business goals, research cultures, technological prowess, wise practice and well-crafted regulations. It will also be subject to the driving interests of particular individuals in ways never seen before. The development of gene-based medical research in Britain was deeply affected by the short, difficult life of Ivan Cameron, whose father, David Cameron, did much to build up genomics when he was prime minister. Many of those working in this field are impelled by personal loss.

And then there are those whose interests stem from the way in which their own genes shape their lives. People like Dr Nizar, who is now crafting a new research agenda for Jansens disease. There may only be 30 people in the world who suffer from it. But two of them are her children, and they are in ceaseless pain. Science knows why; medicine cannot yet help. We believe in miracles, she says. She is also working to make one happen.

This article appeared in the Technology Quarterly section of the print edition under the headline "Populations of one"

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Medicine is getting to grips with individuality - The Economist

Mar 12th 2020

THE INTERCONNECTEDNESS of the modern world has been a boon for SARS-CoV-2. Without planes, trains and automobiles the virus would never have got this far, this fast. Just a few months ago it took its first steps into a human host somewhere in or around Wuhan, in the Chinese province of Hubei. As of this week it had caused over 120,000 diagnosed cases of covid-19, from Troms to Buenos Aires, Alberta to Auckland, with most infections continuing to go undiagnosed (see article).

But interconnectedness may be its downfall, too. Scientists around the world are focusing their attention on its genome and the 27 proteins that it is known to produce, seeking to deepen their understanding and find ways to stop it in its tracks. The resulting plethora of activity has resulted in the posting of over 300 papers on MedRXiv, a repository for medical-research work that has not yet been formally peer-reviewed and published, since February 1st, and the depositing of hundreds of genome sequences in public databases. (For more coverage of covid-19 see our coronavirus hub.)

The assault on the vaccine is not just taking place in the lab. As of February 28th Chinas Clinical Trial Registry listed 105 trials of drugs and vaccines intended to combat SARS-CoV-2 either already recruiting patients or proposing to do so. As of March 11th its American equivalent, the National Library of Medicine, listed 84. This might seem premature, considering how recently the virus became known to science; is not drug development notoriously slow? But the reasonably well-understood basic biology of the virus makes it possible to work out which existing drugs have some chance of success, and that provides the basis for at least a little hope.

Even if a drug were only able to reduce mortality or sickness by a modest amount, it could make a great difference to the course of the disease. As Wuhan learned, and parts of Italy are now learning, treating the severely ill in numbers for which no hospitals were designed puts an unbearable burden on health systems. As Jeremy Farrar, the director of the Wellcome Trust, which funds research, puts it: If you had a drug which reduced your time in hospital from 20 days to 15 days, thats huge.

Little noticed by doctors, let alone the public, until the outbreak of SARS (severe acute respiratory syndrome) that began in Guangdong in 2002, the coronavirus family was first recognised by science in the 1960s. Its members got their name because, under the early electron microscopes of the period, their shape seemed reminiscent of a monarchs crown. (It is actually, modern methods show, more like that of an old-fashioned naval mine.) There are now more than 40 recognised members of the family, infecting a range of mammals and birds, including blackbirds, bats and cats. Veterinary virologists know them well because of the diseases they cause in pigs, cattle and poultry.

Virologists who concentrate on human disease used to pay less attention. Although two long-established coronaviruses cause between 15% and 30% of the symptoms referred to as the common cold, they did not cause serious diseases in people. Then, in 2002, the virus now known as SARS-CoV jumped from a horseshoe bat to a person (possibly by way of some intermediary). The subsequent outbreak went on to kill almost 800 people around the world.

Some of the studies which followed that outbreak highlighted the fact that related coronaviruses could easily follow SARS-CoV across the species barrier into humans. Unfortunately, this risk did not lead to the development of specific drugs aimed at such viruses. When SARS-CoV-2similarly named because of its very similar genomeduly arrived, there were no dedicated anti-coronavirus drugs around to meet it.

A SARS-CoV-2 virus particle, known technically as a virion, is about 90 nanometres (billionths of a metre) acrossaround a millionth the volume of the sort of cells it infects in the human lung. It contains four different proteins and a strand of RNAa molecule which, like DNA, can store genetic information as a sequence of chemical letters called nucleotides. In this case, that information includes how to make all the other proteins that the virus needs in order to make copies of itself, but which it does not carry along from cell to cell.

The outer proteins sit athwart a membrane provided by the cell in which the virion was created. This membrane, made of lipids, breaks up when it encounters soap and water, which is why hand-washing is such a valuable barrier to infection.

The most prominent protein, the one which gives the virions their crown- or mine-like appearance by standing proud of the membrane, is called spike. Two other proteins, envelope protein and membrane protein, sit in the membrane between these spikes, providing structural integrity. Inside the membrane a fourth protein, nucleocapsid, acts as a scaffold around which the virus wraps the 29,900nucleotides of RNA which make up its genome.

Though they store their genes in DNA, living cells use RNA for a range of other activities, such as taking the instructions written in the cells genome to the machinery which turns those instructions into proteins. Various sorts of virus, though, store their genes on RNA. Viruses like HIV, which causes AIDS, make DNA copies of their RNA genome once they get into a cell. This allows them to get into the nucleus and stay around for years. Coronaviruses take a simpler approach. Their RNA is formatted to look like the messenger RNA which tells cells what proteins to make. As soon as that RNA gets into the cell, flummoxed protein-making machinery starts reading the viral genes and making the proteins they describe.

First contact between a virion and a cell is made by the spike protein. There is a region on this protein that fits hand-in-glove with ACE2, a protein found on the surface of some human cells, particularly those in the respiratory tract.

ACE2 has a role in controlling blood pressure, and preliminary data from a hospital in Wuhan suggest that high blood pressure increases the risks of someone who has contracted the illness dying of it (so do diabetes and heart disease). Whether this has anything to do with the fact that the viruss entry point is linked to blood-pressure regulation remains to be seen.

Once a virion has attached itself to an ACE2 molecule, it bends a second protein on the exterior of the cell to its will. This is TMPRSS2, a protease. Proteases exist to cleave other proteins asunder, and the virus depends on TMPRSS2 obligingly cutting open the spike protein, exposing a stump called a fusion peptide. This lets the virion into the cell, where it is soon able to open up and release its RNA (see diagram).

Coronaviruses have genomes bigger than those seen in any other RNA virusesabout three times longer than HIVs, twice as long as the influenza viruss, and half as long again as the Ebola viruss. At one end are the genes for the four structural proteins and eight genes for small accessory proteins that seem to inhibit the hosts defences (see diagram). Together these account for just a third of the genome. The rest is the province of a complex gene called replicase. Cells have no interest in making RNA copies of RNA molecules, and so they have no machinery for the task that the virus can hijack. This means the virus has to bring the genes with which to make its own. The replicase gene creates two big polyproteins that cut themselves up into 15, or just possibly 16, short non-structural proteins (NSPs). These make up the machinery for copying and proofreading the genomethough some of them may have other roles, too.

Once the cell is making both structural proteins and RNA, it is time to start churning out new virions. Some of the RNA molecules get wrapped up with copies of the nucleocapsid proteins. They are then provided with bits of membrane which are rich in the three outer proteins. The envelope and membrane proteins play a large role in this assembly process, which takes place in a cellular workshop called the Golgi apparatus. A cell may make between 100 and 1,000 virions in this way, according to Stanley Perlman of the University of Iowa. Most of them are capable of taking over a new celleither nearby or in another bodyand starting the process off again.

Not all the RNA that has been created ends up packed into virions; leftovers escape into wider circulation. The coronavirus tests now in use pick up and amplify SARS-CoV-2-specific RNA sequences found in the sputum of infected patients.

Because a viral genome has no room for free riders, it is a fair bet that all of the proteins that SARS-CoV-2 makes when it gets into a cell are of vital importance. That makes each of them a potential target for drug designers. In the grip of a pandemic, though, the emphasis is on the targets that might be hit by drugs already at hand.

The obvious target is the replicase system. Because uninfected cells do not make RNA copies of RNA molecules, drugs which mess that process up can be lethal to the virus while not necessarily interfering with the normal functioning of the body. Similar thinking led to the first generation of anti-HIV drugs, which targeted the process that the virus uses to transcribe its RNA genome into DNAanother thing that healthy cells just do not do.

Like those first HIV drugs, some of the most promising SARS-CoV-2 treatments are molecules known as nucleotide analogues. They look like the letters of which RNA or DNA sequences are made up; but when a virus tries to use them for that purpose they mess things up in various ways.

The nucleotide-analogue drug that has gained the most attention for fighting SARS-CoV-2 is remdesivir. It was originally developed by Gilead Sciences, an American biotechnology firm, for use against Ebola fever. That work got as far as indicating that the drug was safe in humans, but because antibody therapy proved a better way of treating Ebola, remdesivir was put to one side. Laboratory tests, though, showed that it worked against a range of other RNA-based viruses, including SARS-CoV, and the same tests now show that it can block the replication of SARS-CoV-2, too.

There are now various trials of remdesivirs efficacy in covid-19 patients. Gilead is organising two in Asia that will, together, involve 1,000 infected people. They are expected to yield results in mid- to late-April. Other nucleotide analogues are also under investigation. When they screened seven drugs approved for other purposes for evidence of activity against SARS-CoV-2, a group of researchers at the State Key Laboratory of Virology in Wuhan saw some potential in ribavirin, an antiviral drug used in the treatment of, among other things, hepatitis C, that is already on the list of essential medicines promulgated by the World Health Organisation (WHO).

Nucleotide analogues are not the only antiviral drugs. The second generation of anti-HIV drugs were the protease inhibitors which, used along with the original nucleotide analogues, revolutionised the treatment of the disease. They targeted an enzyme with which HIV cuts big proteins into smaller ones, rather as one of SARS-CoV-2s NSPs cuts its big polyproteins into more little NSPs. Though the two viral enzymes do a similar job, they are not remotely relatedHIV and SARS-CoV-2 have about as much in common as a human and a satsuma. Nevertheless, when Kaletra, a mixture of two protease inhibitors, ritonavir and lopinavir, was tried in SARS patients in 2003 it seemed to offer some benefit.

Another drug which was developed to deal with other RNA-based virusesin particular, influenzais Favipiravir (favilavir). It appears to interfere with one of the NSPs involved in making new RNA. But existing drugs that might have an effect on SARS-CoV-2 are not limited to those originally designed as antivirals. Chloroquine, a drug mostly used against malaria, was shown in the 2000s to have some effect on SARS-CoV; in cell-culture studies it both reduces the viruss ability to get into cells and its ability to reproduce once inside them, possibly by altering the acidity of the Golgi apparatus. Camostat mesylate, which is used in cancer treatment, blocks the action of proteases similar to TMPRSS2, the protein in the cell membrane that activates the spike protein.

Not all drugs need to target the virus. Some could work by helping the immune system. Interferons promote a widespread antiviral reaction in infected cells which includes shutting down protein production and switching on RNA-destroying enzymes, both of which stop viral replication. Studies on the original SARS virus suggested that interferons might be a useful tool for stopping its progress, probably best used in conjunction with other drugs

Conversely, parts of the immune system are too active in covid-19. The virus kills not by destroying cells until none are left, but by overstimulating the immune systems inflammatory response. Part of that response is mediated by a molecule called interleukin-6one of a number of immune-system modulators that biotechnology has targeted because of their roles in autoimmune disease.

Actemra (tocilizumab) is an antibody that targets the interleukin-6 receptors on cell surfaces, gumming them up so that the interleukin-6 can no longer get to them. It was developed for use in rheumatoid arthritis. China has just approved it for use against covid-19. There are anecdotal reports of it being associated with clinical improvements in Italy.

While many trials are under way in China, the decline in the case rate there means that setting up new trials is now difficult. In Italy, where the epidemic is raging, organising trials is a luxury the health system cannot afford. So scientists are dashing to set up protocols for further clinical trials in countries expecting a rush of new cases. Dr Farrar said on March 9th that Britain must have its trials programme agreed within the week.

International trials are also a high priority. Soumya Swaminathan, chief scientist at the WHO, says that it is trying to finalise a master protocol for trials to which many countries could contribute. By pooling patients from around the world, using standardised criteria such as whom to include and how to measure outcomes, it should be possible to create trials of thousands of patients. Working on such a large scale makes it possible to pick up small, but still significant, benefits. Some treatments, for example, might help younger patients but not older ones; since younger patients are less common, such an effect could easily be missed in a small trial.

The caseload of the pandemic is hard to predict, and it might be that even a useful drug is not suitable in all cases. But there are already concerns that, should one of the promising drugs prove to be useful, supplies will not be adequate. To address these, the WHO has had discussions with manufacturers about whether they would be able to produce drugs in large enough quantities. Generic drug makers have assured the organisation that they can scale up to millions of doses of ritonavir and lopinavir while still supplying the HIV-positive patients who rely on the drugs. Gilead, meanwhile, has enough remdesivir to support clinical trials and, thus far, compassionate use. The firm says it is working to make more available as rapidly as possible, even in the absence of evidence that it works safely.

In the lab, SARS-CoV-2 will continue being dissected and mulled over. Details of its tricksiness will be puzzled out, and the best bits of proteins to turn into vaccines argued over. But that is all for tomorrow. For today doctors can only hope that a combination of new understanding and not-so-new drugs will do some good.

Dig deeper:

This article appeared in the Briefing section of the print edition under the headline "Anatomy of a killer"

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Understanding SARS-CoV-2 and the drugs that might lessen its power - The Economist

Shinya Yamanaka's 2006 discovery of induced pluripotent stem cells (iPSCs) ignited a revolution in the field of stem cell biology (1). For the first time, nearly all human somatic tissues could be produced from iPSCs reprogrammed from blood or skin cells, in a process that took only weeks. This advance was particularly crucial for obtaining surrogate tissues from cell types that are otherwise difficult to procure and do not readily expand in vitro, such as cardiac or neural cells. Additionally, many ethical concerns are avoided, because this technology uses a patient's own genetic material to create iPSCs rather than relying on embryonic stem cells. In the aftermath of Yamanaka's discovery, entire biomedical industries have developed around the promise of using human iPSCs (hiPSCs) and their derivatives for in vitro disease modeling, drug screening, and cell therapy (2).

The hiPSC technology has had a particularly notable impact in cardiac regenerative medicine, a field where scientists and clinicians have been working to devise new methods to better understand how cardiovascular disease manifests and how to restore cardiovascular function after disease strikes (3). The heart is limited in its ability to regenerate lost cardiomyocytes (beating heart muscle cells), following an adverse event such as a heart attack (4). Cardiomyocytes derived from hiPSCs (hiPSC-CMs) may represent a potential replacement option for dead cells in such a scenario. However, certain issues remain to be addressed, such as whether hiPSC-CMs can integrate with host myocardial tissue in the long term (5).

While using hiPSC-CMs for in vivo cell therapy may become practical in the future, employing hiPSC-CMs for high-throughput drug discovery and screening is becoming a reality in the present (6). Cardiovascular diseases can be recapitulated in a dish with patient-specific hiPSC-CMs. For example, if a patient exhibits a cardiac arrhythmia caused by a genetic abnormality in a sarcomeric protein or ion channel, that same rhythm problem can be recapitulated in vitro (7). Thanks to advances in hiPSC differentiation protocols, hiPSC-CMs can now be mass-produced to study cardiovascular disease mechanisms in vitro (8).

My graduate thesis in the laboratories of Joseph Wu and Sean Wu at Stanford University focused on in vitro applications of hiPSC-CMs for cardiovascular disease modeling and for high-throughput screening of chemotherapeutic compounds to predict cardiotoxicity. I initially embarked on a project using hiPSC-CMs to model viral myocarditis, a viral infection of the heart, caused by the B3 strain of coxsackievirus (9). I began by demonstrating that hiPSC-CMs express the receptors necessary for viral internalization and subsequently found that hiPSC-CMs were highly susceptible to coxsackievirus infection, exhibiting viral cytopathic effect within hours of infection. I also identified compounds that could alleviate coxsackievirus infection on hiPSC-CMs, a translationally relevant finding, as there remains a shortage of treatments for viral myocarditis.

Using a genetically modified variant of coxsackievirus B3 expressing luciferase, I developed a screening platform for assessing the efficacy of antiviral compounds. Pretreatment with interferon-, ribavirin, or pyrrolidine dithiocarbamate markedly suppressed viral replication on hiPSC-CMs by activating intracellular antiviral response and viral protein clearance pathways. These compounds alleviated viral replication in a dose-dependent fashion at low concentrations without causing cellular toxicity.

I next sought to use hiPSC-CMs to screen anticancer chemotherapeutic compounds for their off-target cardiovascular toxicities (10). Cardiotoxicity represents a major cause of drug withdrawal from the pharmaceutical market, and several chemotherapeutic agents can cause unintended cardiovascular damage (11). Using cultured hiPSC-CMs, I evaluated 21 U.S. Food and Drug Administrationapproved tyrosine kinase inhibitors (TKIs), commonly prescribed anticancer compounds, for their cardiotoxic potential. HiPSC-CMs express the major tyrosine kinase receptor proteins such as the insulin, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors, lending validity to this cellular model.

Initially, human induced pluripotent stem cells (hiPSCs) can be produced by reprogramming skin or blood cells by nonviral or viral reprogramming methods. Cardiac differentiation protocols allow for the creation of cardiomyocytes derived from hiPSCs (hiPSC-CMs) for downstream applications, including in vitro disease modeling, drug screening, and regenerative cell therapy.

With data from a battery of cellular apoptosis, contractility, electrophysiology, and signaling assays, I generated a cardiac safety index to help align in vitro toxicity data to clinical drug safety guidelines (12). From the safety index, I determined that a subclass of VEGF receptor 2/PDGF receptorinhibiting tyrosine kinase inhibitors, some of which exhibit toxicity clinically, also elicited cardiotoxicities in hiPSC-CMs. These manifested as substantial alterations in cellular electrophysiology, contractility, and viability when administered at clinically relevant concentrations. I also discovered that cotreatment with either IGF or insulin partially rescued TKI-induced toxicity by up-regulating antiapoptotic signaling pathways. This work could prove useful for groups aiming to develop effective screening platforms to assess new chemotherapeutic compounds for cardiotoxic side effects.

I also collaborated with the Center for the Advancement of Science in Space (CASIS) to send a sample of hiPSC-CMs to the International Space Station. As humankind ventures beyond our home planet, it is imperative that we better understand how the heart functions for long periods of time in microgravity. Analysis of these hiPSC-CMs revealed microgravity-induced alterations in metabolic gene expression and calcium handling (13).

In recent years, the stem cell field has experienced an explosion of studies using hiPSC-CMs as a model cellular system to study cardiovascular biology. As improvements in hiPSC-CM mass production continue, we will see a rise in studies using these cells for disease modeling and drug screening. Thus, although hiPSC-CM technology is in its infancy, it holds great potential to improve cardiovascular health.

PHOTO: COURTESY OF A. SHARMA

FINALIST

Arun Sharma

Arun Sharma received his undergraduate degree from Duke University and a Ph.D. from Stanford University. Having completed a postdoctoral fellowship at the Harvard Medical School, Sharma is now a senior research fellow jointly appointed at the Smidt Heart Institute and Board of Governors Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles. His research seeks to develop in vitro platforms for cardiovascular disease modeling and drug cardiotoxicity assessment. http://www.sciencemag.org/content/367/6483/1206.1

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Stem cells to help the heart - Science Magazine

LONDON, March 13, 2020 (GLOBE NEWSWIRE) -- GW Pharmaceuticals plc (NASDAQ:GWPH) ("GW", "the Company" or "the Group"), a world leader in discovering, developing and commercialising cannabinoid prescription medicines, today announces the submission of a Type II Variation Application to the European Medicines Agency (EMA) seeking approval of EPIDYOLEX, (cannabidiol) oral solution, for the treatment of seizures associated with Tuberous Sclerosis Complex (TSC), a rare genetic condition and a leading cause of genetic epilepsy. If approved, this will be the third licensed indication for GW's cannabidiol oral solution in Europe.

"This submission to the EMA is an important step for GW and furthers GW's mission to bring innovative cannabinoid medicines to patients with high unmet need," said Chris Tovey, GW's Chief Operating Officer. "We look forward to working with the EMA to demonstrate GW's cannabidiol oral solution's potential in this new indication and hope to make this rigorously tested cannabis-based medicine available to a new group of patients through a potential approval in due course."

TSC is a condition that causes mostly benign tumours to grow in vital organs of the body including the brain, skin, heart, eyes, kidneys and lungs, and in which epilepsy is the most common neurological feature. TSC is typically diagnosed in childhood.1

The Type II Variation Application is based on data from a positive Phase 3 safety and efficacy study. The study met its primary endpoint with patients treated with GW's cannabidiol oral solution 25 mg/kg/day experiencing a significantly greater reduction from baseline in TSC-associated seizures compared to placebo (49% vs 27%; p=0.0009). Results for the 50 mg/kg/day dose group were similar, with seizure reductions of 48% from baseline vs 26.5% for placebo (p=0.0018). All key secondary endpoints were supportive of the effects on the primary endpoint. The safety profile observed was consistent with findings from previous studies, with no new safety risks identified.

ADDITIONAL INFORMATION

About Tuberous Sclerosis Complex (TSC)Tuberous Sclerosis Complex (TSC) is a rare genetic condition that has an estimated prevalence in the EU of 10 in 100,000.2 The condition causes mostly benign tumours to grow in vital organs of the body including the brain, skin, heart, eyes, kidneys and lungs and is a leading cause of genetic epilepsy.1,3 TSC often occurs in the first year of life with patients suffering from either focal seizures or infantile spasms. It is associated with an increased risk of autism and intellectual disability.1 The severity of the condition can vary widely. In some children the disease is very mild, while others may experience life-threatening complications.4

About EPIDIOLEX/EPIDYOLEX (cannabidiol) oral solutionEPIDIOLEX/EPIDYOLEX (cannabidiol) oral solution, the first prescription, plant-derived cannabis-based medicine approved by the U.S. Food and Drug Administration (FDA) for use in the U.S. and the European Medicines Agency's (EMA) for use in Europe, is an oral solution which contains highly purified cannabidiol (CBD). EPIDYOLEX received approval in Europe in September 2019 for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in patients two years of age or older in conjunction with clobazam. In the U.S., EPIDIOLEX was approved in June 2018 by the FDA and is indicated for the treatment of seizures associated with LGS or Dravet syndrome in patients two years of age or older. A supplemental New Drug Application (sNDA) was submitted to the FDA in early 2020 for the treatment of seizures associated with Tuberous Sclerosis Complex (TSC). GW's cannabidiol oral solution has received Orphan Drug Designation from the FDA and the EMA for the treatment of seizures associated with Dravet syndrome, LGS and TSC, each of which are severe childhood-onset, drug-resistant syndromes.

About GW Pharmaceuticals plc Founded in 1998, GW is a biopharmaceutical company focused on discovering, developing and commercialising novel therapeutics from its proprietary cannabinoid product platform in a broad range of disease areas. The Company's lead product, EPIDIOLEX/EPIDYOLEX (cannabidiol) oral solution is commercialised in Europe by GW, and in the U.S. by the Company's subsidiary, Greenwich Biosciences. The Company has a strong pipeline of additional cannabinoid product candidates, with late-stage clinical trials in autism, schizophrenia, post-traumatic stress disorder (PTSD) and spasticity associated with multiple sclerosis (MS) and spinal cord injury. For further information, please visit http://www.gwpharm.com.

1 NIH Tuberous Sclerosis Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet. 2 Prevalence and incidence or rare diseases: Bibliographic data.https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf3 TS Alliance Website. https://www.tsalliance.org/. Accessed November 19, 2019.4 de Vries PJ, Belousova E, Benedik MP, et al. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis. 2018;13(1):157.5 Kwan P., Brodie M.J. Early identification of refractory epilepsy. N. Engl. J. Med. 2000;342(5):314319.6 French JA. Refractory epilepsy: clinical overview. Epilepsia. 2007;48 Suppl 1:3-7.

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GW Pharmaceuticals submits Type II Variation Application to the European Medicines Agency (EMA) to expand the use of EPIDYOLEX, (cannabidiol) oral...

The young mothers didnt tell their children they had the coronavirus. Mama was working hard, they said, to save sick people.

Instead, Deng Danjing and Xia Sisi were fighting for their lives in the same hospitals where they worked, weak from fever and gasping for breath. Within a matter of weeks, they had gone from healthy medical professionals on the front lines of the epidemic in Wuhan, China, to coronavirus patients in critical condition.

The world is still struggling to fully understand the new virus, its symptoms, spread and sources. For some, it can feel like a common cold. For others, it is a deadly infection that ravages the lungs and pushes the immune system into overdrive, destroying even healthy cells. The difference between life and death can depend on the patients health, age and access to care although not always.

The virus has infected more than 132,000 globally. The vast majority of cases have been mild, with limited symptoms. But the viruss progression can be quick, at which point the chances of survival plummet. Around 68,000 people have recovered, while nearly 5,000 have died.

The fates of Ms. Deng and Dr. Xia reflect the unpredictable nature of a virus that affects everyone differently, at times defying statistical averages and scientific research.

As the new year opened in China, the women were leading remarkably similar lives. Both were 29 years old. Both were married, each with a young child on whom she doted.

Ms. Deng, a nurse, had worked for three years at Wuhan No. 7 Hospital, in the city where she grew up and where the coronavirus pandemic began. Her mother was a nurse there, too, and in their free time they watched movies or shopped together. Ms. Dengs favorite activity was playing with her two pet kittens, Fat Tiger and Little White, the second of which she had rescued just three months before falling sick.

Before the epidemic, Ms. Deng had promised to take her 5-year-old daughter to the aquarium.

Dr. Xia, a gastroenterologist, also came from a family of medical professionals. As a young child, she had accompanied her mother, a nurse, to work. She joined the Union Jiangbei Hospital of Wuhan in 2015 and was the youngest doctor in her department. Her colleagues called her Little Sisi or Little Sweetie because she always had a smile for them. She loved Sichuan hot pot, a dish famous for its numbingly spicy broth.

Dr. Xia loved traveling with her family. She had recently visited Wuzhizhou Island, a resort destination off the southern coast of China.

When a mysterious new virus struck the city, the women began working long hours, treating a seemingly endless flood of patients. They took precautions to protect themselves. But they succumbed to the infection, the highly contagious virus burrowing deep into their lungs, causing fever and pneumonia. In the hospital, each took a turn for the worse.

One recovered. One did not.

Onset of virus & hospitalization

Ms. Deng, a Wuhan native who liked makeup and hanging out with her friends at Starbucks, had worked for eight years as a nurse, following her mothers career path. Dr. Xia, who was a favorite among elderly patients, spent long hours at the hospital helping to treat people suspected of having the virus.

The symptoms came on suddenly.

Dr. Xia had ended her night shift on Jan. 14 when she was called back to attend to a patient a 76-year-old man with suspected coronavirus. She dropped in frequently to check in on him.

Five days later, she started feeling unwell. Exhausted, she took a two-hour nap at home, then checked her temperature: It was 102 degrees. Her chest felt tight.

A few weeks later, in early February, Ms. Deng, the nurse, was preparing to eat dinner at the hospital office, when the sight of food left her nauseated. She brushed the feeling aside, figuring she was worn out by work. She had spent the beginning of the outbreak visiting the families of confirmed patients and teaching them to disinfect their homes.

After forcing down some food, Ms. Deng went home to shower, and then, feeling groggy, took a nap. When she woke up, her temperature was 100 degrees.

Fever is the most common symptom of the coronavirus, seen in nearly 90 percent of patients. About a fifth of people experience shortness of breath, often including a cough and congestion. Many also feel fatigued.

Both women rushed to see doctors. Chest scans showed damage to their lungs, a tell-tale sign of the coronavirus that is present in at least 85 percent of patients, according to one study.

In particular, Ms. Dengs CT scan showed what the doctor called ground-glass opacities on her lower right lung hazy spots that indicated fluid or inflammation around her airways.

The hospital had no space, so Ms. Deng checked into a hotel to avoid infecting her husband and 5-year-old daughter. She sweated through the night. At one point, her calf twitched. In the morning, she was admitted to the hospital. Her throat was swabbed for a genetic test, which confirmed she had the coronavirus.

Her room in a newly opened staff ward was small, with two cots and a number assigned to each one. Ms. Deng was in bed 28. Her roommate was a colleague who had also been diagnosed with the virus.

At Jiangbei Hospital, 18 miles away, Dr. Xia was struggling to breathe. She was placed in an isolation ward, treated by doctors and nurses who wore protective suits and safety goggles. The room was cold.

Day 1, hospitalization begins

After Ms. Deng was admitted to the hospital, she told her husband to take care of himself, reminding him of the 14-day incubation period for the virus. He assured her his temperature was normal. Dr. Xia asked her husband about the possibility of getting off oxygen therapy soon. He responded optimistically.

When Ms. Deng checked into the hospital, she tried to stay upbeat. She texted her husband, urging him to wear a mask even at home, and to clean all their bowls and chopsticks with boiling water or throw them out.

Her husband sent a photograph of one of their cats at home. Waiting for you to come back, he said.

I think itll take 10 days, half a month, she replied. Take care of yourself.

There is no known cure for Covid-19, the official name for the disease caused by the new coronavirus. So doctors rely on a cocktail of other medicines, mostly antiviral drugs, to alleviate the symptoms.

Ms. Dengs doctor prescribed a regimen of arbidol, an antiviral medicine used to treat the flu in Russia and China; Tamiflu, another flu medicine more popular internationally; and Kaletra, an HIV medicine thought to block the replication of the virus. Ms. Deng was taking at least 12 pills a day, as well as traditional Chinese medicine.

Arbidol, an antiviral medication, was prescribed to help alleviate Ms. Dengs symptoms.

Despite her optimism, she grew weaker. Her mother delivered home-cooked food outside the ward, but she had no appetite. To feed her, a nurse had to come at 8:30 each morning to hook her up to an intravenous drip with nutrients. Another drip pumped antibodies into her bloodstream, and still another antiviral medicine.

Dr. Xia, too, was severely ill, but appeared to be slowly fighting the infection. Her fever had subsided after a few days, and she began to breathe more easily after being attached to a ventilator.

Her spirits lifted. On Jan. 25, she told her colleagues she was recovering.

I will return to the team soon, she texted them on WeChat.

We need you the most, one of her colleagues responded.

In early February, Dr. Xia asked her husband, Wu Shilei, also a doctor, whether he thought she could get off oxygen therapy soon.

Take it easy. Dont be too anxious, he replied on WeChat. He told her that the ventilator could possibly be removed by the following week.

I keep on thinking about getting better soon, Dr. Xia responded.

There was reason to believe she was on the mend. After all, most coronavirus patients recover.

Later, Dr. Xia tested negative twice for the coronavirus. She told her mother she expected to be discharged on Feb. 8.

Day 4 to 16 after hospitalization

In the hospital, Ms. Dengs only contacts were her roommate and the medical staff. She added a caption to a photo with her doctor, saying laughter would help chase the illness away. Two tests indicated that Dr. Xia was free of the virus, but her condition suddenly deteriorated.

By Ms. Dengs fourth day in the hospital, she could no longer pretend to be cheerful. She was vomiting, having diarrhea and relentlessly shivering.

Her fever jumped to 101.3 degrees. Early in the morning on Feb. 5, she woke from a fitful sleep to find the medicine had done nothing to lower her temperature. She cried. She said she was classified as critically ill.

The next day, she threw up three times, until she was left spitting white bubbles. She felt she was hallucinating. She could not smell or taste, and her heart rate slowed to about 50 beats per minute.

On a phone call, Ms. Dengs mother tried to reassure her that she was young and otherwise healthy, and that the virus would pass like a bad cold. But Ms. Deng feared otherwise. I felt like I was walking on the edge of death, she wrote in a social media post from her hospital bed the next day.

China defines a critically ill patient as someone with respiratory failure, shock or organ failure. Around 5 percent of infected patients became critical in China, according to one of the largest studies to date of coronavirus cases. Of those, 49 percent died. (Those rates may eventually change once more cases are examined around the world.)

While Dr. Xia appeared to be recovering, she was still terrified of dying. Testing can be faulty, and negative results dont necessarily mean patients are in the clear.

She asked her mother for a promise: Could her parents look after her 2-year-old son if she didnt make it?

Hoping to dispel her anxiety with humor, her mother, Jiang Wenyan, chided her: Hes your own son. Dont you want to raise him yourself?

Dr. Xia also worried about her husband. Over video chat, she urged him to put on protective equipment at the hospital where he worked. She said she would wait for me to return safely, he said, and go to the frontline again with me when she recovered.

Then came the call. Dr. Xias condition had suddenly deteriorated. In the early hours of Feb. 7, her husband rushed to the emergency room.

Her heart had stopped.

Day 17 after hospitalization

After being discharged, Ms. Deng briefly got to see her mother, who had been working at the hospital during her illness. She then went home to isolate herself for two weeks.

In most cases, the body repairs itself. The immune system produces enough antibodies to clear the virus, and the patient recovers.

By the end of Ms. Dengs first week in the hospital, her fever had receded. She could eat the food her mother delivered. On Feb. 10, as her appetite returned, she looked up photos of meat skewers online and posted them wishfully to social media.

On Feb. 15, her throat swab came back negative for the virus. Three days later, she tested negative again. She could go home.

Ms. Deng met her mother briefly at the hospitals entrance. Then, because Wuhan remained locked down, without taxis or public transportation, she walked home alone.

I felt like a little bird, she recalled. My freedom had been returned to me.

She had to isolate at home for 14 days. Her husband and daughter stayed with her parents.

At home, she threw out her clothing, which she had been wearing for her entire time in the hospital.

Since then, she has passed the time by playing with her cats and watching television. She jokes that she is getting an early taste of retirement. She does daily deep breathing exercises to strengthen her lungs, and her cough has faded.

The Chinese government has urged recovered patients to donate plasma, which experts say contains antibodies that could be used to treat the sick. Ms. Deng contacted a local blood bank soon after getting home.

She plans to go back to work as soon as the hospital allows it.

It was the nation that saved me, she said. And I think I can pay it back to the nation.

Day 35 after hospitalization

On Dr. Xias desk at work, her colleagues left 1,000 paper cranes a Chinese symbol of hope and blessings. Written on the wings was a message: Rest in peace, we will use our lives to continue this relay race and prevail over this epidemic.

It was sometime after 3 a.m. on Feb. 7 when Dr. Xia was rushed to intensive care. Doctors first intubated her. Then, the president of the hospital frantically summoned several experts from around the city, including Dr. Peng Zhiyong, head of the department of critical care at Zhongnan Hospital.

They called every major hospital in Wuhan to borrow an extracorporeal membrane oxygenation, or Ecmo, machine to do the work of her heart and lungs.

Dr. Xias heart started beating again. But the infection in her lungs was too severe, and they failed. Her brain was starved of oxygen, causing irreversible damage. Soon, her kidneys shut down and doctors had to put her on round-the-clock dialysis.

The brain acts as the control center, Dr. Peng said. She couldnt command her other organs, so those organs would fail. It was only a matter of time.

Dr. Xia slipped into a coma. She died on Feb. 23.

Dr. Peng remains baffled about why Dr. Xia died after she had seemed to improve. Her immune system, like that of many health workers, may have been compromised by constant exposure to sickness. Perhaps she suffered from what experts call a cytokine storm, in which the immune systems reaction to a new virus engulfs the lungs with white blood cells and fluid. Perhaps she died because her organs were starved of oxygen.

Back at Dr. Xias home, her son, Jiabao which means priceless treasure still thinks his mother is working. When the phone rings, he tries to grab it from his grandmothers hands, shouting: Mama, mama.

Her husband, Dr. Wu, doesnt know what to tell Jiabao. He hasnt come to terms with her death himself. They had met in medical school and were each others first loves. They had planned to grow old together.

I loved her very much, he said. Shes gone now. I dont know what to do in the future, I can only hold on.

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Two Women Fell Sick From the Coronavirus. One Survived. - The New York Times

A central promise of regenerative medicine is the ability to repair aged or diseased organs using stem cells (SCs). This approach will likely become an effective strategy for organ rejuvenation, holding the potential to increase human health by delaying age-related diseases (1). The successful translation of this scientific knowledge into clinical practice will require a better understanding of the basic mechanisms of aging, along with an integrated view of the process of tissue repair (1).

The advent of SC therapies, now progressing into clinical trials, has made clear the many challenges limiting the application of SCs to treat disease. Our duty, as scientists, is to anticipate such limitations and propose solutions to effectively deliver on the promise of regenerative medicine.

Degenerating tissues have difficulty engaging a regulated repair response that can support efficient cell engraftment and restoration of tissue function (2). This problem, which I encountered when trying to apply SC-based interventions to treat retinal disease, will likely be an important roadblock to the clinical application of regenerative medicine approaches in elderly patients, those most likely to benefit from such interventions. I therefore hypothesized that the inflammatory environment present in aged and diseased tissues would be a major roadblock for efficient repair and that finding immune modulators with the ability to resolve chronic inflammation and promote a prorepair environment would be an efficient approach to improve the success of SC-based therapies (2, 3).

Immune cells, as sources and targets of inflammatory signals, emerged naturally as an ideal target for intervention. I chose to focus on macrophages, which are immune cells of myeloid origin that exist in virtually every tissue of the human body and which are able to reversibly polarize into specific phenotypes, a property that is essential to coordinate tissue repair (3, 4).

If there is an integral immune modulatory component to the process of tissue repair that has evolved to support the healing of damaged tissues, then it should be possible to find strategies to harness this endogenous mechanism and improve regenerative therapies. Anchored in the idea that tissue damage responses are evolutionarily conserved (5), I started my research on this topic using the fruit fly Drosophila as a discovery system.

The fruit fly is equipped with an innate immune system, which is an important player in the process of tissue repair. Using a well-established model of tissue damage, I sought to determine which genes in immune cells are responsible for their prorepair activity. MANF (mesencephalic astrocyte-derived neurotrophic factor), a poorly characterized protein initially identified as a neurotrophic factor, emerged as a potential candidate (6). A series of genetic manipulations involving the silencing and overexpression of MANF and known interacting partners led me to the surprising discovery that, instead of behaving as a neurotrophic factor, MANF was operating as an autocrine immune modulator and that this activity was essential for its prorepair effects (2). Using a model of acute retinal damage in mice and in vitro models, I went on to show that this was an evolutionarily conserved mechanism and that MANF function could be harnessed to limit retinal damage elicited by multiple triggers, highlighting its potential for clinical application in the treatment of retinal disease (2).

Having discovered a new immune modulator that sustained endogenous tissue repair, I set out to test my initial hypothesis that this factor might be used to improve the success of SC-based therapies applied to a degenerating retina. Indeed, the low integration efficiency of replacement photoreceptors transplanted into congenitally blind mice could be fully restored to match the efficiency obtained in nondiseased mice by supplying MANF as a co-adjuvant with the transplants (2). This intervention improved restoration of visual function in treated mice, supporting the utility of this approach in the clinic (7).

Next, my colleagues and I decided to address the question of whether the immune modulatory mechanism described above was relevant for aging biology and whether we could harness its potential to extend health span. We found that MANF levels are systemically decreased in aged flies, mice, and humans. Genetic manipulation of MANF expression in flies and mice revealed that MANF is necessary to limit age-related inflammation and maintain tissue homeostasis in young organisms. Using heterochronic parabiosis, an experimental paradigm that involves the surgical joining of the circulatory systems of young and old mice, we established that MANF is one of the circulatory factors responsible for the rejuvenating effects of young blood. Finally, we showed that pharmacologic interventions involving systemic delivery of MANF protein to old mice are effective therapeutic approaches to reverse several hallmarks of tissue aging (8).

A confocal fluorescence microscope image of a giant macrophage shows MANF (mesencephalic astrocyte-derived neurotrophic factor) expression in red.

The biological process of aging is multifactorial, necessitating combined and integrated interventions that can simultaneously target several of the underlying problems (9). The potential of immune modulatory interventions as rejuvenating strategies is emerging and requires a deeper understanding of its underlying molecular and cellular mechanisms.

One expected outcome of reestablishing a regulated inflammatory response is the optimization of tissue repair capacity that naturally decreases during aging (3). Combining these interventions with SCbased therapeutics holds potential to deliver on the promise of regenerative medicine as a path to rejuvenation (1).

PHOTO: COURTESY OF J. NEVES

GRAND PRIZE WINNER

Joana Neves

Joana Neves received undergraduate degrees from NOVA University in Lisbon and a Ph.D. from the Pompeu Fabra University in Barcelona. After completing her postdoctoral fellowship at the Buck Institute for Research on Aging in California, Neves started her lab in the Instituto de Medicina Molecular (iMM) at the Faculty of Medicine, University of Lisbon in 2019. Her research uses fly and mouse models to understand the immune modulatory component of tissue repair and develop stem cellbased therapies for age-related disease.

PHOTO: COURTESY OF A. SHARMA

FINALIST

Arun Sharma

Arun Sharma received his undergraduate degree from Duke University and a Ph.D. from Stanford University. Having completed a postdoctoral fellowship at the Harvard Medical School, Sharma is now a senior research fellow jointly appointed at the Smidt Heart Institute and Board of Governors Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles. His research seeks to develop in vitro platforms for cardiovascular disease modeling and drug cardiotoxicity assessment. http://www.sciencemag.org/content/367/6483/1206.1

FINALIST

Adam C. Wilkinson

Adam C. Wilkinson received his undergraduate degree from the University of Oxford and a Ph.D. from the University of Cambridge. He is currently completing his postdoctoral fellowship at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, where he is studying normal and malignant hematopoietic stem cell biology with the aim of identifying new biological mechanisms underlying hematological diseases and improving the diagnosis and treatment of these disorders. http://www.sciencemag.org/content/367/6483/1206.2

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Aging eyes and the immune system - Science Magazine

March 13, 2020 -Once people are aware of the issues surrounding genomic data sharing, collection, and security, individuals are more concerned with how their information will be used and expect to receive compensation for providing it, according to a survey published in PLOS One.

As the potential for personalized therapies continues to grow and genetic testing becomes more widely available, genomics entities have to find ways to advance the field while still protecting peoples genetic data.

The use of human genomic data collections is expanding, fueled by declining technological costs and enthusiasm for the promise of precision medicine, researchers said.

Accordingly, various organizations responsible for managing enormous genomic biobanks are developing and refining their governance systemsi.e., the organizational structures and policies that shape data collection, data integrity, data end uses, transparency, stakeholder input processes, and data securityseeking to balance the benefits of broad data use with the need to mitigate risk and meet societal responsibilities.

It's essential to measure the publics expectations surrounding the collection and use of genomic data, the research team stated. Prior research in this area has focused on the context of research biobanks owned by academic institutions, the group said, and has highlighted the idea that individuals providing their data are acting as altruistic donors.

READ MORE: Data Sharing Standards Needed to Address Patients SDOH

Findings in this context suggest that most participants, within the sole context of non-profit research biobanks, are generally willing to donate their data, are comfortable with indefinite use of their data, and are reassured by moderate privacy protections, the team said.

Yet the context of previous research presents an incomplete profile of public expectations for genetic database governance. We note that governance expectations for genetic databases in the future will be informed by two developing social phenomena: growing awareness of both the commercial value of genomic data and the emerging privacy risks for individuals providing data.

Researchers set out to assess individuals willingness to contribute genomic data to both nonprofit and for-profit organizations, as well as respondents views on genomic governance policies. The team provided 2,020 survey participants with a three-minute video created from mainstream coverage of genomic databases.

The group then asked participants questions about how governance policies or the ways genomic data is used, secured, and regulated would impact respondents willingness to provide data and the compensation they expect to receive.

The results showed that just 11.7 percent of respondents were willing to provide their data as an altruistic donation, while 50.6 percent said they would be willing to provide it if compensated with a payment of some amount. Nearly 38 percent said they were unwilling to provide it even if payment was available.

READ MORE: Can Healthcare Overcome Its Past Pitfalls to Leverage Genomic Data?

The researchers noted that these results contrast with previous surveys that focused on donating genomic data to academic research biobanks, which consistently report rates of willingness above 50 percent.

When people were more informed, they were a lot more interested in requiring greater security for their data, and they were a little bit more hesitant to give it up, said Ifeoma Ajunwa, assistant professor of labor relations, law and history at Cornell University and co-author of the study.

The team also evaluated the dollar amounts that people were seeking in exchange for their data. The median reported value among individuals was $130, which mirrors the amount paid per genome in a recent commercial transaction summarized in the video shown to participants.

This finding suggests that the pre-survey video influenced perceptions and responses, reflecting what could happen as individuals encounter real-life information alerting them to the value of genetic data.

In addition to compensation, the survey asked participants how 12 specific policies would impact their willingness to provide genomic data. The three policies that made them most willing to provide it were the ability to request their data to be deleted; assurance that their data wouldnt be sold or shared; and requiring specific permissions to use the data.

READ MORE: FDA Recognizes Genomic Database to Advance Precision Medicine

The three policies that decreased willingness the most were selling database access to pharmaceutical firms; providing data to the federal government; and retaining the data indefinitely without a specified date for destruction.

These results demonstrate the importance individuals place on control when it comes to data sharing.

A common denominator across these governance policy findings is a preference for restrictions on sharing or reuse, unless permission is specifically granted by the individual, researchers said.

These preferences appear to pose a challenge for the goals and business models of many database-owning organizations, which often envision that their databases will serve multiple, not-necessarily-specified scientific and commercial purposes, through access arrangements with multiple outside partners. This tension appears to hold equally for commercial as well as public organizations.

The group concluded that based on these findings, a one-size-fits-all approach wont meet public expectations for genomic data governance. Future research will need to continually evaluate evolving attitudes about genomic databases.

People need to know the full worth of their genetic data in order to make an informed consent, Ajunwa said. How much is the data worth, what kinds of safeguarding are necessary, is it OK to have something in digital form and therefore more vulnerable? There are all of these outstanding questions to be answered.

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More Than 50% of People Expect Compensation for Genomic Data Sharing - HealthITAnalytics.com

Researchers from the University of Exeter have found that increased levels of the stress hormone cortisol in babies and small children when separated from their parents, especially their mothers, may have a long term genetic impact on future generations.

In a commentary published by the Journal of the Royal Society of Medicine, the authors say that several studies show that small children cared for outside the home, especially in poor quality care and for 30 or more hours per week, have higher levels of cortisol than children who are cared for at home.

While cortisol release is a normal response to stress in mammals facing an emergency, sustained cortisol release over hours or days can be harmful, Professor Sir Denis Pereira Gray, Emeritus Professor of General Practice at the University of Exeter, who wrote the paper with two colleagues, said.

Raised cortisol levels are a sign of stress, something which Professor Gray said has been associated with children, particularly boys, acting aggressively. Not all children are affected, he said, but an important minority are.

Raised cortisol levels are associated with reduced antibody levels and changes in those parts of the brain which are associated with emotional stability.

Environmental factors interact with genes, so that genes can be altered, and once altered by adverse childhood experiences, can pass to future generations. Such epigenetic effects need urgent study, the authors said.

Professor Gray would like to see future researchers explore the links between the care of small children in different settings, their cortisol levels, DNA, and behaviour.

The research, and associated commentary, may be viewed here.

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Research International Poor quality care and long hours may alter children's genetic maps , researchers find Researchers - The Sector

Above: A researcher works in a lab that is developing testing for the COVID-19 coronavirus at Hackensack Meridian Health Center for Discovery and Innovation on February 28, 2020 in Nutley, New Jersey. (Photo by Kena Betancur/Getty Images)

There's a massive shortage of COVID-19 (Coronavirus) test kits in the U.S., as cases continue to skyrocket in places like Seattle and New York City. This is largely due to the failure of the Centers for Disease Control and Prevention (CDC) to distribute the tests in a timely fashion.

But it didn't have to be this way. Back in January and Februarywhen cases of the deadly disease began aggressively circulating outside of Chinadiagnostics already existed in places like Wuhan, where the pandemic began. Those tests followed World Health Organization (WHO) test guidelines, which the U.S. decided to eschew.

Instead, the CDC created its own in-depth diagnostics that could identify not only COVID-19, but a host of SARS-like coronaviruses. Then, disaster struck: When the CDC sent tests to labs during the first week of February, those labs discovered that while the kits did detect COVID-19, they also produced false positives when checking for other viruses. As the CDC went back to the drawing board to develop yet more tests, precious time ticked away.

"I think that we should have had testing more widely available about a month earlier," Dr. Carl Fichtenbaum, professor of clinical medicine at the University of Cincinnati's School of Medicine, tells Popular Mechanics. "That would have been more appropriate so that we could have identified people earlier on and used some of the mitigating strategies that were using now."

As the spread of Coronavirus continues to escalate in the U.S., private institutions like academic research hospitals are scrambling in a mad dash to come up with more test kits. And there is hope: The Cleveland Clinic says it has developed a diagnostic test that can deliver results in just hours, as opposed to the time it takes the existing CDC tests, which can take days.

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Testing for COVID-19 comes in two primary forms: You'll either have your throat swabbed if you're in the U.S., or perhaps have your blood drawn if you're in another country, like China. The different approaches ultimately come down to how scientists have developed the lab tests.

In the U.S., the CDC's diagnostic tool relies on polymerase chain reaction testing (PCR), which detects genetic material found in the virus's DNA. Unlike in other methods, the virus doesn't have to be alive for its presence to be detected.

"We take parts of the virus and we [test] whats called the conserved parts of the virus, parts that dont change a lot," Dr. Fichtenbaum explains. "There are always mutations. Were looking at the genetic code and we take a sequence of what we call primers, or things that will match up with that genetic code, and we put them through a series of steps where the primers will match the genetic code if [the virus] is present."

PCR testing is generally too advanced to be done at a hospital, and is more in the wheelhouse of clinical laboratory settings. There, researchers extract the sample's nucleic acidone of the four bases found in DNA sequencesto study the virus genome. They can amplify portions of that genome through a special process called reverse transcription polymerase chain reaction. That way, scientists can compare the sample to SARS-CoV-2, the virus that causes the novel coronavirus.

SARS-CoV-2 has almost 30,000 nucleotides in total, which make up its DNA. The University of Washington School of Medicine's PCR test hones in on about 100 of those that are known to be unique to the virus.

The researchers are looking for two genes in particular, and if they find both, the test is considered positive. If they only find one, the test is inconclusive. However, the CDC notes, "it is possible the virus will not be detected" in the early stages of the viral infection.

In some cases, Dr. Fichtenbaum says, it's possible to quantify the number of copies of the viral gene present. It could be one, 10, or 10 million, he says, and the higher that amount is, the more contagious you may be, or the further along you may be in the illness.

U.S. Centers for Disease Control and Prevention

As of press time, the CDC has directly examined some 3,791 specimens in Atlanta, according to data produced on Thursday afternoon, while public health laboratories across the country have tested another 7,288. Notably, some data after March 6 is still pending.

Regardless, with about 1,000 confirmed cases in the U.S., those figures suggest roughly one in 11 people tested have actually contracted the novel Coronavirus. Surely, if more tests were available, those numbers would be higher, Dr. Fichtenbaum says. Because of the CDC snafu and an initial muted reaction to the outbreak from President Trump's administration, we're about a month behind on the diagnostics front, he adds.

Piling onto other reasons, Dr. Karen C. Carrolldirector of the Division of Medical Microbiology at Johns Hopkins University School of Medicinebelieves that the test shortage is "complicated" by the fact that no one expected COVID-19 to spread so quickly in the U.S.

Not to mention, manufacturers are now low on supplies that academic labs, like hers, require to develop and distribute test kits, she tells Popular Mechanics.

During a Congressional hearing on Wednesday, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the public health care system is failing to make tests available to people who may have contracted COVID-19.

"The idea of anybody getting [the test] easily the way people in other countries are doing it, we're not set up for that. Do I think we should be? Yes, but we're not," he said.

The silver lining: The CDC is now working in tandem with private labs to make more tests available. The concern then becomes how many tests these labs can actually perform each day. Experts estimate that most labs will have the capacity to complete about 100 tests per day, which just isn't good enough to contain COVID-19 at this point.

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Just because your doctor may have ordered you a COVID-19 test, that doesn't mean you'll actually receive one.

According to CDC guidelines, there are three general classes of patients who seek the diagnostic test, and it's up to the discretion of the health care systems to administer them. With limited supply, those are tough decisions. The classes are:

Testing can be quite restrictive, and people who aren't in a high risk category, or who have traveled to a country where there are cases of COVID-19but had no known exposure to the virusare turned away.

"Once we relax the standards for testing so that we can test on anyone we think appropriate, and its not as complicated, we'll be able to reduce the spread," Dr. Fichtenbaum says.

Right now in Ohio, where Dr. Fichtenbaum is based, doctors must fill out a four-page form and conduct in-depth tracing of a patient's movements before they can administer a test, he says. Not only is it time-consuming, but it may result in the patient not receiving a test at alland could have contracted the virus.

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To expedite the availability of diagnostics, the U.S. Food and Drug Administration (FDA) announced in late February that academic hospital systems had the green light to develop their own test kits.

The move allows these institutions to rely on their own internal validation upfront, rather than wait on the time-consuming FDA approvals process before using the tests. While FDA approval is still ultimately required under this policy, once the hospitals themselves have determined the tests are accurate and safe, they can begin using them.

Dr. Carroll of Johns Hopkins says that her lab went live with their own test yesterday. "Now, we have 15 days to send [the FDA] our validation package," she says. Her lab can now use the test to check for COVID-19 in patients that come to the medical center, but a few more things must also happen in tandem to satisfy the FDA's requirements.

Once a private lab sends in their validation package, which includes data collected during the test development, the FDA may call back with questions about the kit or ask for clarification. If the labs get radio silence for a while, that's normal, according to Dr. Carroll, but eventually, they must be granted what is known as an Emergency Use Authorization.

Under section 564 of the Federal Food, Drug, and Cosmetic Act, the FDA Commissioner may allow unapproved medical productslike privately developed COVID-19 teststo be used in an emergency for diagnosis, treatment or prevention when there are no better alternatives.

"I dont know how quickly they will get back to laboratories, they havent told us that," Dr. Carroll says.

Labs must also have close communication with their state health department laboratory, which is essentially the top lab in the state, she added. The FDA is requiring private institutions to send their first five negative and first five positive testing results to their state lab to ensure uniformity and effectiveness.

"A public health laboratory monitors certain communicable diseases," Dr. Carroll explains. "Some even offer testing for the community, like STDs such as Gonorrhea."

Other hospitals across the U.S. are making strides in test development, too. In Washington, where the CDC's faulty tests stymied the progress of testing, potentially aiding the community spread seen there, the University of Washington Medical Center has developed a COVID-19 test based on WHO recommendations, unlike the CDC. The hospital system has the capacity to conduct about 1,000 tests per day, and is working to ramp that up to 4,000 or 5,000 daily tests.

The Cleveland Clinic's test, meanwhile, should only take about eight hours to turn around a positive or negative result and should be ready by the end of March.

In a statement provided Thursday to Popular Mechanics, the Cleveland Clinic says it will soon have the capabilities to conduct on-site testing. "We are in the process of validating our testing capabilities and will soon send out more information."

Moving forward, Dr. Fichtenbaum expects the FDA to soon approve what's known as multiplex testing, which will allow labs to run 96 tests at once, rather than work with one specimen at a time.

"They need to approve that at each lab and theyre slow," says Dr. Fichtenbaum. But he anticipates the FDA will give the all-clear in the next few days. Then, it's just a matter of manufacturing the tests, which should happen rapidly.

In the meantime, community spread continues, despite self-quarantine measures, countless canceled events, and sweeping work-from-home policies. The number of positive cases is probably significantly higher than the data shows, says Dr. Fichtenbaum, which only worsens the contagion.

"I think that COVID-19 is probably more prevalent in our communities than we think," he says.

And the clinical microbiologists working tirelessly at the front lines in hospitals fully expect to meet demand. Dr. Heba Mostafa, assistant professor of pathology at Johns Hopkins University, tells Popular Mechanics that she expects to see testing ramp up and really meet demand over the course of the next four to eight weeks.

And Dr. Carroll says that the spirit of collaboration between academic medical centers has been refreshing. The University of Texas and the University of Washington have each helped out the Johns Hopkins effort, she says. They helped supply the genetic material necessary to complete their test's validation. Still, it's grueling.

"Our hospital is very happy that we went live yesterday, but of course now theyre interested in how many tests we can do," Carroll said with a laugh. "I sometimes feel that clinical microbiologists are the unsung heroes."

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Why There Aren't Enough Coronavirus Tests in the U.S. - Popular Mechanics

Mar 12th 2020

BEING ABLE to see all the details of the genome at once necessarily makes medicine personal. It can also make it precise. Examining illness molecule by molecule allows pharmaceutical researchers to understand the pathways through which cells act according to the dictates of genes and environment, thus seeing deep into the mechanisms by which diseases cause harm, and finding new workings to target. The flip side of this deeper understanding is that precision brings complexity. This is seen most clearly in cancer. Once, cancers were identified by cell and tissue type. Now they are increasingly distinguished by their specific genotype that reveals which of the panoply of genes that can make a cell cancerous have gone wrong in this one. As drugs targeted against those different mutations have multiplied, so have the options for oncologists to combine them to fit their patients needs.

Cancer treatment has been the most obvious beneficiary of the genomic revolution but other diseases, including many in neurology, are set to benefit, too. Some scientists now think there are five different types of diabetes rather than two. There is an active debate about whether Parkinsons is one disease that varies a lot, or four. Understanding this molecular variation is vital when developing treatments. A drug that works well on one subtype of a disease might fail in a trial that includes patients with another subtype against which it does not work at all.

Thus how a doctor treats a disease depends increasingly on which version of the disease the patient has. The Personalised Medicine Coalition, a non-profit advocacy group, examines new drugs approved in America to see whether they require such insights in order to be used. In 2014, it found that so-called personalised medicines made up 21% of the drugs newly approved for use by Americas Food and Drug Administration (FDA). In 2018 the proportion was twice that.

Two of those cited were particularly interesting: Vitrakvi (larotrectinib), developed by Loxo Oncology, a biotech firm, and Onpattro (patisiran), developed by Alnylam Pharmaceuticals. Vitrakvi is the first to be approved from the start as tumour agnostic: it can be used against any cancer that displays the mutant protein it targets. Onpattro, which is used to treat peripheral-nerve damage, is the first of a new class of drugssmall interfering RNAs, or siRNAsto be approved. Like antisense oligonucleotides (ASOs), siRNAs are little stretches of nucleic acid that stop proteins from being made, though they use a different mechanism.

Again like ASOs, siRNAs allow you to target aspects of a disease that are beyond the reach of customary drugs. Until recently, drugs were either small molecules made with industrial chemistry or bigger ones made with biologynormally with genetically engineered cells. If they had any high level of specificity, it was against the actions of a particular protein, or class of proteins. Like other new techniques, including gene therapies and anti-sense drugs, siRNAs allow the problem to be tackled further upstream, before there is any protein to cause a problem.

Take the drugs that target the liver enzyme PCSK9. This has a role in maintaining levels of bad cholesterol in the blood; it is the protein that was discovered through studies of families in which congenitally high cholesterol levels led to lots of heart attacks. The first generation of such drugs were antibodies that stuck to the enzyme and stopped it working. However, the Medicines Company, a biotech firm recently acquired by Novartis, won approval last year for an siRNA called inclisiran that interferes with the expression of the gene PCSK9thus stopping the pesky protein from being made in the first place. Inclisiran needs to be injected only twice a year, rather than once a month, as antibodies do.

New biological insights, new ways of analysing patients and their disease and new forms of drug are thus opening up a wide range of therapeutic possibilities. Unfortunately, that does not equate to a range of new profitable opportunities.

Thanks in part to ever better diagnosis, there are now 7,000 conditions recognised as rare diseases in America, meaning that the number of potential patients is less than 200,000. More than 90% of these diseases have no approved treatment. These are the diseases that personalised, precision medicine most often goes after. Nearly 60% of the personalised medicines approved by the FDA in 2018 were for rare diseases.

Zolgensma is the most expensive drug ever brought to market.

That might be fine, were the number of diseases stable. But precision in diagnosis is increasingly turning what used to be single diseases into sets of similar-looking ones brought about by distinctly different mechanisms, and thus needing different treatment. And new diseases are still being discovered. Medical progress could, in short, produce more new diseases than new drugs, increasing unmet need.

Some of it will, eventually, be met. For one thing, there are government incentives in America and Europe for the development of drugs for rare diseases. And, especially in America, drugs for rare diseases have long been able to command premium prices. Were this not the case, Novartis would not have paid $8.7bn last year to buy AveXis, a small biotech firm, thereby acquiring Zolgensma, a gene therapy for spinal muscular atrophy (SMA). Most people with SMA lack a working copy of a gene, SMN1, which the nerve cells that control the bodys muscles need to survive. Zolgensma uses an empty virus-like particle that recognises nerve cells to deliver working copies of the gene to where it is needed. Priced at $2.1m per patient, it is the most expensive drug ever brought to market. That dubious accolade might not last long. BioMarin, another biotech firm, is considering charging as much as $3m for a forthcoming gene therapy for haemophilia.

Drug firms say such treatments are economically worthwhile over the lifetime of the patient. Four-fifths of children with the worst form of SMA die before they are four. If, as is hoped, Zolgensma is a lasting cure, then its high cost should be set against a half-century or more of life. About 200 patients had been treated in America by the end of 2019.

But if some treatments for rare diseases may turn a profit, not all will. There are some 6,000 children with SMA in America. There are fewer than ten with Jansens disease. When Dr Nizar asked companies to help develop a treatment for it, she says she was told your disease is not impactful. She wrote down the negative responses to motivate herself: Every day I need to remind myself that this is bullshit.

A world in which markets shrink, drug development gets costlier and new unmet needs are ceaselessly discovered is a long way from the utopian future envisaged by the governments and charities that paid for the sequencing of all those genomes and the establishment of the worlds biobanks. As Peter Bach, director of the Centre for Health Policy and Outcomes, an academic centre in New York, puts it with a degree of understatement: if the world needs to spend as much to develop a drug for 2,000 people as it used to spend developing one for 100,000, the population-level returns from medical research are sharply diminishing.

And it is not as if the costs of drug development have been constant. They have gone up. What Jack Scannell, a consultant and former pharmaceutical analyst at UBS, a bank, has dubbed Erooms lawEroom being Moore, backwardsshows the number of drugs developed for a given amount of R&D spending has fallen inexorably, even as the amount of biological research skyrocketed. Each generation assumes that advances in science will make drugs easier to discover; each generation duly advances science; each generation learns it was wrong.

For evidence, look at the way the arrival of genomics in the 1990s lowered productivity in drug discovery. A paper in Nature Reviews Drug Discovery by Sarah Duggers from Columbia University and colleagues argues that it brought a wealth of new leads that were difficult to prioritise. Spending rose to accommodate this boom; attrition rates for drugs in development subsequently rose because the candidates were not, in general, all that good.

Today, enthused by their big-science experience with the genome and enabled by new tools, biomedical researchers are working on exhaustive studies of all sorts of other omes, including proteomesall the proteins in a cell or body; microbiomesthe non-pathogenic bacteria living in the mouth, gut, skin and such; metabolomessnapshots of all the small molecules being built up and broken down in the body; and connectomes, which list all the links in a nervous system. The patterns they find will doubtless produce new discoveries. But they will not necessarily, in the short term, produce the sort of clear mechanistic understanding which helps create great new drugs. As Dr Scannell puts it: We have treated the diseases with good experimental models. Whats left are diseases where experiments dont replicate people. Data alone canot solve the problem.

Daphne Koller, boss of Insitro, a biotech company based in San Francisco, shares Dr Scannells scepticism about the way drug discovery has been done. A lot of candidate drugs fail, she says, because they aim for targets that are not actually relevant to the biology of the condition involved. Instead researchers make decisions based on accepted rules of thumb, gut instincts or a ridiculous mouse model that has nothing to do with what is actually going on in the relevant human diseaseeven if it makes a mouse look poorly in a similar sort of way.

But she also thinks that is changing. Among the things precision biology has improved over the past five to 10 years have been the scientists own tools. Gene-editing technologies allow genes to be changed in various ways, including letter by letter; single-cell analysis allows the results to be looked at as they unfold. These edited cells may be much more predictive of the effects of drugs than previous surrogates. Organoidsself-organised, three-dimensional tissue cultures grown from human stem cellsoffer simplified but replicable versions of the brain, pancreas, lung and other parts of the body in which to model diseases and their cures.

Insitro is editing changes into stem cellswhich can grow into any other tissueand tracking the tissues they grow into. By measuring differences in the development of very well characterised cells which differ in precisely known ways the company hopes to build more accurate models of disease in living cells. All this work is automated, and carried out on such a large scale that Dr Koller anticipates collecting many petabytes of data before using machine learning to make sense of it. She hopes to create what Dr Scannell complains biology lacks and what drug designers need: predictive models of how genetic changes drive functional changes.

There are also reasons to hope that the new upstream drugsASOs, siRNAs, perhaps even some gene therapiesmight have advantages over todays therapies when it comes to small-batch manufacture. It may also prove possible to streamline much of the testing that such drugs go through. Virus-based gene-therapy vectors and antisense drugs are basically platforms from which to deliver little bits of sequence data. Within some constraints, a platform already approved for carrying one message might be fast-tracked through various safety tests when it carries another.

One more reason for optimism is that drugs developed around a known molecule that marks out a diseasea molecular markerappear to be more successful in trials. The approval process for cancer therapies aimed at the markers of specific mutations is often much shorter now than it used to be. Tagrisso (osimertinib), an incredibly specialised drug, targets a mutation known to occur only in patients already treated for lung cancer with an older drug. Being able to specify the patients who stand to benefit with this degree of accuracy allows trials to be smaller and quicker. Tagrisso was approved less than two years and nine months after the first dose was given to a patient.

With efforts to improve the validity of models of disease and validate drug targets accurately gaining ground, Dr Scannell says he is sympathetic to the proposal that, this time, scientific innovation might improve productivity. Recent years have seen hints that Erooms law is being bent, if not yet broken.

If pharmaceutical companies do not make good on the promise of these new approaches then charities are likely to step in, as they have with various ASO treatments for inherited diseases. And they will not be shackled to business models that see the purpose of medicine as making drugs. The Gates Foundation and Americas National Institutes of Health are investing $200m towards developing treatments based on rewriting genes that could be used to tackle sickle-cell disease and HIVtreatments that have to meet the proviso of being useful in poor-country clinics. Therapies in which cells are taken out of the body, treated in some way and returned might be the basis of a new sort of business, one based around the ability to make small machines that treat individuals by the bedside rather than factories which produce drugs in bulk.

There is room in all this for individuals with vision; there is also room for luck: Dr Nizar has both. Her problem lies in PTH1R, a hormone receptor; her PTH1R gene makes a form of it which is jammed in the on position. This means her cells are constantly doing what they would normally do only if told to by the relevant hormone. A few years ago she learned that a drug which might turn the mutant receptor off (or at least down a bit) had already been characterisedbut had not seemed worth developing.

The rabbit, it is said, outruns the fox because the fox is merely running for its dinner, while the rabbit is running for its life. Dr Nizars incentives outstrip those of drug companies in a similar way. By working with the FDA, the NIH and Massachusetts General Hospital, Dr Nizar helped get a grant to make enough of the drug for toxicology studies. She will take it herself, in the first human trial, in about a years time. After that, if things go well, her childrens pain may finally be eased.

This article appeared in the Technology Quarterly section of the print edition under the headline "Kill or cure?"

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New drugs are costly and unmet need is growing - The Economist

The clinic helps children at risk of developing heart disease in the future due to high cholesterol.

They can now attend a ground-breaking clinic run by the familial hypercholesterolemia (FH) service at York Teaching Hospital NHS Foundation Trust.

FH is an inherited condition which can lead to extremely high cholesterol levels and is passed down through families in the genes.

The FH service, led by Dr Chandrajay, Consultant in Chemical Pathology and Metabolic Medicine, and Claire Tuson, Familial Hypercholesterolaemia Specialist Nurse, has recently extended their service to include children and adolescents.

Claire explained: Research has shown that children with FH start to develop a build-up of fatty plaque in their arteries before the age of 10. Once diagnosed, FH is easy to treat so it makes sense to work with families as soon as possible.

Last year, with the support of Consultant Paediatrician Dr Dominic Smith, we extended gene testing to all children aged 10 years old and over, who have a parent affected with FH. Testing children for FH could prevent a potentially fatal heart attack or stroke.

The first six children from York and Scarborough that were identified with FH have recently attended our new Yorkshire and Humber joint paediatric clinic for children and their families, which launched at the end of January.

FH is estimated to affect 1 in 250 people in the UK, including over 56,000 children.

It is an inherited disorder of cholesterol and lipid metabolism, caused by an alteration in a single gene where people have higher levels of bad cholesterol levels from birth. If left undetected and untreated FH can lead to the early development of heart and circulatory problems.

Kiera Pickering, aged 12, and her brother Connor, aged 11, from Scarborough, were two of the first children to attend the clinic.

Claire added: Its a real breakthrough to be able to identify and treat children with FH so early. Alongside dietary and lifestyle advice to maintain a healthy body weight, children can be considered for statin therapy from as young as 10 years old.

"Statin treatment can not only prevent, but potentially reverse, the build-up of cholesterol and allow children and young people to live a perfectly healthy life.

Despite the availability of genetic testing, more than 85 percent of people with FH in the UK are undiagnosed.

The British Heart Foundation estimates that currently only around 600 children in the UK have been diagnosed with FH, meaning that thousands more are not on treatment and remain unaware of their future risk of heart disease.

For more information about the FH clinics contact claire.tuson@york.nhs.uk

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Scarborough brother and sister, aged 11 and 12, with the genetic cholesterol condition FH are helped by new clinic - Whitby Gazette

Familialhypercholesterolemia (FH) is one of the most clinically relevant monogenicdisorders contributing to the development of atherosclerotic cardiovasculardisease (ASCVD). The prevalence of FH was estimated to be 1 in 200 to 1 in 250 individualsin studies in which genetic testing was conducted on large community populationsamples.1 However, the disease often remains undetected and thusuntreated, with only 10% of individuals with FH receiving adequate diagnosisand treatment.2

Notingthe recent accumulation of studies on FH, the authors of a Nature ReviewsCardiology article sought tosummarize the key elements of a model of care for the condition that canbe adapted as new evidence emerges.1 Selected points are highlightedbelow.

Screening and detection. A combination of selective, opportunistic (eg, genetic screening of blood donors), systematic, and universal screening approaches is recommended to improve the detection of FH. Universal screening of children and childparent (reverse) cascade testing is potentially a highly effective method for detecting patients with FH at a young age, before they develop ASCVD32 [and] might be particularly relevant to communities with gene founder effects, noted the review authors. All children with FH should ideally be detected from the age of 5 years or earlier if homozygous FH (hoFH) is suspected.

Diagnosis. In the United States, elevated levels of low-density lipoprotein cholesterol (LDL-C) and a family history of FH are the main phenotypic criteria for FH diagnosis in children. Patients with hoFH, heterozygous FH (heFH), and polygenic hypercholesterolemia may also present with overlapping LDL-C levels, posing a challenge for the development of a standardized diagnostic tool for FH.

Genetic testing. Aninternational expert panel recently endorsed genetic testing in the care ofpatients with FH as it would [allow] a definitive diagnosis, improve[e] riskstratification, address the increasing need for more potent therapies, improve[e]adherence to treatments, and increase[e] the precision and cost- effectivenessof cascade testing.1,3 However, genetic testing remains underuseddue to issues such as cost, low access to genetic counseling, and lack ofclinician knowledge in this area.

Clinical risk assessment.Cumulative lifetime exposure to elevated LDL-C is the key factor driving ASCVDrisk in asymptomatic patients with FH, further underscoring the need for timelydiagnosis and risk stratification. In addition to phenotypic and geneticfactors, imaging of subclinical atherosclerosis, might be the most usefulclinical tool for assessing risk in FH.1 For example, imaging ofcoronary artery calcium can be used to predict coronary events in asymptomaticmiddle-aged patients with FH taking statins, and computed tomography coronaryangiography can be used to assess plaque burden and to intensify therapy.

Care of adults.Emerging evidence continues to support aggressive cholesterol-lowering therapyand lifestyle management in patients with FH from as young as 8 years tomaximally mitigate the cumulative cholesterol burden of risk. The review authorsemphasize the importance of patient-centered care and shared decision making,although health literacy is a challenge that may need to be addressed with somepatients.

Whilethere is insufficient evidence to develop strictly defined LDL-C treatmenttargets, current evidence-based recommendations stipulate that in adultpatients with FH, statin therapy and diet should initially be targeted toachieve a 50% reduction in LDL-cholesterol level and an LDL-cholesterol level<1.8 mmol/l (70 mg/dl) or <2.6 mmol/l (100 mg/dl) for primaryprevention, and <1.4 mmol/l (55 mg/dl) or <1.8 mmol/l (70 mg/dl) forsecondary prevention or for patients at very high risk.1

The addition of ezetimibe is indicated in patients who do not achieve the recommended LDL-C levels with statins alone. The use of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor as a third-line therapy is recommended in those patients or in patients who are intolerant to statins. The addition of a PCSK9 inhibitor in patients with heFH can further reduce LDL-C levels by approximately 60% and lead to recommended treatment targets in more than 80% of patients. However, these agents should not be used during pregnancy, as they cross the placenta and their impact on fetal development has not yet been determined.

Care of children. Extensive evidence supports the treatment of FH starting in childhood, as [m]odest and sustained reductions in LDL- cholesterol levels from early life can have a major effect on reducing mortality associated with ASCVD. Initial therapy is based on lifestyle management in early childhood, with the addition of statins by age 10 years in children with HeFH and upon diagnosis in children with hoFH. Ongoing research is investigating the efficacy and safety of PCSK9 inhibitors in children with heFH or hoFH.4,5

Radical therapies and novel approaches. Lipoprotein apheresis may be required insevere cases of FH, including in pregnant women, and liver transplantationremains the only curative therapy for patients with severe hoFH.

In ongoing studies, an array of novel treatment approaches are being examined, including functional LDL receptor gene transfer therapy in patients with hoFH and targeted RNA-based therapies to lower elevated lipoporotein(a) levels.6-8

Reviewauthors also emphasized the importance of clinical registries, patient supportgroups and networks, and the need for structured research programs that areunderpinned by actionable dissemination and implementation strategies,research skills and training among service providers, and sustainable fundingmodels. They stated that a major challenge is translating new evidence intohealth policy and routine care. Systems approaches for supporting healthorganizations and providers in addressing these gaps in care and serviceprovision are essential.

We spoke with Seth Shay Martin, MD, MHS, associate professor ofmedicine at the Johns Hopkins University School of Medicine in Baltimore,Maryland, and director of the Advanced Lipid Disorders Program of the Ciccarone Center atJohns Hopkins.

Cardiology Advisor: What are examplesof the latest advances in knowledge or practice pertaining to FH?

Dr Martin: A big advance inpractice has been the introduction of PCSK9 inhibitors. When added to statinsand ezetimibe, this class of medications can lower LDL-C by 60% sometimes the reduction can be lower, but inmy experience the effect is commonly approximately 60%. This leads to patientscoming back to clinic really satisfied.

Cardiology Advisor: What is the optimalapproach for the treatment of these patients, and what are some of the toptreatment challenges?

Dr Martin: The optimal approach is to follow the 2018 American Heart Association/American College of Cardiology multi-society guidelines, which recommend a combination approach of lifestyle modification with first-line maximal statin therapy, followed by the addition of ezetimibe and PCSK9 inhibitors. The LDL-C threshold at which additional therapy should be considered is70 mg/dL in high-riskpatients with ASCVD and FH. In patients with isolated FH (termed severe hypercholesterolemia by the guidelines,based on LDL-C levels 190 mg/dL), the LDL-C threshold is 100 mg/dL.

Cardiology Advisor: What are otherrelevant treatment implications for clinicians who treat these patients?

Dr Martin: One of the joys intaking care of a patient with FH is taking care of a family. It is a geneticdisorder with a 50% chance of being passed from parent to child. It is key toperform cascade testing to identify other members of the family; family visitsto the clinic can be beneficial for all.

Cardiology Advisor: What are remaining needs in thisarea?

Dr Martin: There is a great need for increasing awareness and diagnosis rates for FH. This is what our center is working to do as partners of the FH Foundation and as a CASCADE FH Registry site.

References

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Reviewing Evidence on the Screening, Diagnosis, and Care of Familial Hypercholesterolemia - The Cardiology Advisor

DetailsCategory: DNA RNA and CellsPublished on Friday, 13 March 2020 09:52Hits: 132

HAIFA, Israel I March 12, 2020 I HAIFA, Israel, March 12, 2020 - Pluristem Therapeutics Inc. (Nasdaq:PSTI) (TASE:PSTI), a leading regenerative medicine company developing a platform of novel biological products, today announced it has signed a collaborative agreement with the BIH Center for Regenerative Therapy (BCRT) and the Berlin Center for Advanced Therapies (BeCAT) at Charite University of Medicine Berlin to expand its existing framework and research agreement and conduct a joint project evaluating the therapeutic effects of Pluristems patented PLX cell product candidates for potential treatment of the respiratory and inflammatory complications associated with the COVID-19 coronavirus.

PLX cells are allogeneic mesenchymal-like cells that have immunomodulatory properties that induce the immune systems natural regulatory T cells and M2 macrophages, and thus may prevent or reverse the dangerous overactivation of the immune system. Accordingly, PLX cells may potentially reduce the fatal symptoms of COVID-19 induced pneumonia and pneumonitis. Previous pre-clinical findings of PLX cells revealed significant therapeutic effects in animal studies of pulmonary hypertension, lung fibrosis, acute kidney injury and gastrointestinal injury which are potential complications of the severe COVID-19 infection. Clinical data using PLX cells demonstrated the strong immunomodulatory potency of PLX cells in patients post major surgery. Taken together, PLX cells potential capabilities with the safety profile observed from clinical trials involving hundreds of patients worldwide potentially position them as a therapy for mitigating the tissue-damaging effects of COVID-19.

The collaboration with Charit researchers will allow us to expedite our program to potentially enable the use of PLX cells to treat patients infected with COVID-19 that have respiratory and immunological complications. The fact that PLX is available off-the-shelf, combined with our ability to manufacture large scale quantities, is a key advantage in case a large number of patients may need respiratory support. The primary target is to prevent the deterioration of patients towards Acute Respiratory Distress Syndrome (ARDS) and sepsis. We intend to start the joint collaboration immediately, with an aim to bringing much needed treatment to a rapidly expanding global health threat, stated Yaky Yanay, Pluristem President and CEO.

Prof. Hans-Dieter Volk, Director of the BCRT at Charite University Medicine Berlin, commented, Through our long-term collaboration with Pluristem, we have a thorough understanding of PLX cells and their mechanism of action. Charites unique knowledge, which includes research and clinical expertise in the immunopathogenesis of viral infections and critically ill patients, provides us an accelerated framework in which we believe PLX cells can be explored as a potential therapy for patients infected with COVID-19.

About BIH Center for Regenerative TherapiesThe BIH Center for Regenerative Therapies (BCRT) is a cooperative translational research institution of the Charit University Hospital in Berlin and the Berlin Institute of Health (BIH). The mission of the BCRT is to develop a translational platform for Regenerative Therapies from bench-to-bedside. The clinical platforms -- Immune, muskuloskleletal, and cardiovascular system -- are cross-linked by cross-field clinical fields (cachexia/sarcopenia, genetic diseases) and technology and translation support platforms. There are extended experiences in clinical trials with cell therapy, including phase 1-3 trials with PLX cells.

About Berlin Center for Advanced Therapies (BeCAT)The Berlin Center for Advanced Therapies is a spin-off of the BCRT focusing on translation of cell and gene therapies in the major research fields of regenerative medicine and cancer. It consists of four research fields (endogenous regeneration, tissue engineering, anti-cancer immunotherapy, and rare diseases) and three technology platforms (manufacturing, product characteristics and biomarker, and clinical development and regulatory affairs.

About Pluristem TherapeuticsPluristem Therapeutics Inc. is a leading regenerative medicine company developing novel placenta-based cell therapy product candidates. The Company has reported robust clinical trial data in multiple indications for its patented PLX cell product candidates and is currently conducting late stage clinical trials in several indications. PLX cell product candidates are believed to release a range of therapeutic proteins in response to inflammation, ischemia, muscle trauma, hematological disorders and radiation damage. The cells are grown using the Company's proprietary three-dimensional expansion technology and can be administered to patients off-the-shelf, without tissue matching. Pluristem has a strong intellectual property position; a Company-owned and operated GMP-certified manufacturing and research facility; strategic relationships with major research institutions; and a seasoned management team.

SOURCE: Pluristem Therapeutics

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Pluristem and Charit University of Medicine Berlin Join Forces Targeting Potential Treatment for Respiratory and Inflammatory Intratissue...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Flagship Pioneering, a life sciences innovation enterprise, announced the launch of Repertoire Immune Medicines, a clinical-stage biotechnology company tapping the curative powers of our immune system to prevent, treat and cure cancer, autoimmune disorders and infectious diseases.

Repertoire Immune Medicines was formed by combining two Flagship companies the innovative and proprietary immune decoding platforms of Cogen Immune Medicines and the immuno-oncology platforms of Torque Therapeutics to create a fully integrated Immune Medicines company. At the helm is Chief Executive Officer John Cox, who most recently led the spin-off of Bioverativ (BIIV) from Biogen (BIIB), and its growth and successful acquisition by Sanofi (SNY).

During the last 4 years, these two Flagship Pioneering originated companies each advanced novel and complementary platforms protected by over 30 patent families. Through their combination, Repertoire Immune Medicines now has the unique capability to decipher human subject-derived antigen-T cell receptor (TCR) codes from healthy or diseased tissues in the context of the major MHC (HLA) types. These complexes dictate T cell activation or exhaustion, and their immunological codes can be used to design and clinically test a multitude of unprecedented therapeutic products based on precedented and specific mechanisms of T cell killing of antigen presenting tumor cells or infected cells.

Repertoire is pioneering a new class of therapies based on high throughput, high content interrogation of the intrinsic ability of T cells to prevent, or cure diseases, said Noubar Afeyan, Ph.D., Chief Executive Officer of Flagship Pioneering and Co-Founder and Chairman of the Board of Repertoire Immune Medicine. He continued, our products will be designed to leverage the highly evolved, potent and clinically-validated mechanism of the natural immune synapse to provide immune security to patients. With these ambitious goals in mind, we are pleased to have a proven leader, John Cox, as CEO to realize our shared vision to dramatically improve outcomes for those in need or at risk.

Repertoire has developed a suite of DECODE technologies that allows in-depth characterization of the immune synapse with unprecedented precision. The company leverages its functional response technologies to thoroughly understand the presentation of antigens in disease, de-orphan T cell receptors in the context of single-cell phenotypes, and curate vast amounts of data to enable deep-learning computational prediction models. By coupling single cell technologies with cellular and acellular antigen libraries, the company decodes CD4+ and CD8+ TCR-antigen specificity across selected T cell subsets from patients and from healthy individuals.

I am pleased to work with the Flagship Pioneering team to integrate these two pioneering companies into a fully formed immune medicines business, said John Cox, Chief Executive Officer of Repertoire Immune Medicines. Advancing rationally designed immune medicines into the clinic and eventually to commercialization offers tremendous potential for patients and long-term value for our shareholders.

Three DECODE discovery technologies are at the core of the companys immune synapse deciphering platform:

Decoding immune synapses relevant to a particular disease allows Repertoire to deploy the molecular codes to rationally design new immune medicines as disease-fighting TCRs and disease-associated antigens in its therapeutic products.

Repertoires DEPLOY technologies form a product-based platform that includes:

Repertoire is currently engaged in its first dose escalation safety trial with an autologous T cell product TRQ15-01, which leverages its proprietary PRIME platform to prepare the patients T cells and its proprietary TETHER platform to link an IL-15 nanogel immune modulator to the T cells.

The journey for Repertoire Immune Medicines commenced when Flagship Labs scientists contemplated how to rationally and efficiently direct the power of our T cells for therapeutics and cures. One origination group, led by David Berry, M.D., Ph.D., General Partner of Flagship Pioneering, focused on systematically unlocking antigen specific immune control. In parallel, another Flagship origination group, led by Doug Cole, M.D., General Partner of Flagship Pioneering, and based on the cytokine binding work from Prof. Darrell Irvines lab at MIT, focused on using autologous T cells to direct potent immune modulators to the tumor microenvironment.

To date, the combined companies raised over $220M to create and develop the DECODE discovery platform and DEPLOY product platform, and to initiate its first clinical trial of PRIME & TETHER T cells in cancer. Repertoires rapid advancement reflects its creative, dedicated and diverse team of over 120 professionals possessing expertise in immunology, experimental medicine, physics, computational science, material sciences, process engineering, bioengineering, protein design and applied mathematics.

ABOUT REPERTOIRE IMMUNE MEDICINESRepertoire Immune Medicines, a Flagship Pioneering company, is a clinical stage biotechnology company working to unleash the remarkable power of the human immune system to prevent, treat or cure cancer, autoimmune conditions and infectious diseases. The company is founded on the premise that the repertoire of TCR-antigen codes that drive health and disease represents one of the greatest opportunities for innovation in medical science. The company harnesses and deploys the intrinsic ability of T cells to prevent and cure disease. Repertoire scientists created and developed a suite of technologies for its DECODE discovery and DEPLOY product platforms that allow in-depth characterization of the immune synapse and the ability to rationally design, and clinically develop, multi-clonal immune medicines. The company is currently conducting experimental medicine clinical trials using autologous T cells primed against cancer antigens and tethered to IL-15. To learn more about Repertoire Immune Medicine, please visit our website: http://www.repertoire.com.

ABOUT FLAGSHIP PIONEERINGFlagship Pioneering conceives, creates, resources, and develops first-in-category life sciences companies to transform human health and sustainability. Since its launch in 2000, the firm has applied a unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in over $30 billion in aggregate value. To date, Flagship is backed by more than $3.3 billion of aggregate capital commitments, of which over $1.7 billion has been deployed toward the founding and growth of its pioneering companies alongside more than $10 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 37 transformative companies, including: Axcella Health (NADAQ: AXLA), Denali Therapeutics (NASDAQ: DNLI), Evelo Biosciences (NASDAQ: EVLO), Foghorn Therapeutics, Indigo Agriculture, Kaleido Biosciences (NASDAQ: KLDO), Moderna (NASDAQ: MRNA), Rubius Therapeutics (NASDAQ: RUBY), Seres Therapeutics (NASDAQ: MCRB), and Syros Pharmaceuticals (NASDAQ: SYRS). To learn more about Flagship Pioneering, please visit our website: http://www.FlagshipPioneering.com.

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Flagship Pioneering Announces the Launch of Repertoire Immune Medicines with Industry Veteran John G. Cox as Chief Executive Officer - Business Wire