StemCell Therapy

In a talk at UAB on March 6, the NIH director shared his thoughts on exceptional opportunities for science and young scientists and highlighted several exciting UAB projects.

NIH Director Francis Collins, M.D., Ph.D., visited UAB on March 6. In addition to his public talk, Collins had breakfast with UAB medical students and met with groups of young researchers and other investigators across campus.Speaking to a packed University of Alabama at Birmingham audience March 6, Francis Collins, M.D., Ph.D., director of the National Institutes of Health, shared his picks of 10 areas of particular excitement and promise in biomedical research.

In nearly every area, UAB scientists are helping to lead the way as Collins himself noted in several cases. At the conclusion of his talk, Collins addedhis advice for young scientists. Here is Collins top 10 list, annotated with some of the UAB work ongoing in each area and ways that faculty, staff and students can get involved.

I am so jazzed with what has become possible with the ability to study single cells and see what they are doing, Collins said. They have been out of our reach now we have reached in. Whether you are studying rheumatoid arthritis, diabetes or the brain, you have the chance to ask each cell what it is doing.

Single-cell sequencing and UAB:Collins noted that Robert Carter, M.D., the acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, was a longtime faculty member at UAB (serving as director of the Division of Clinical Immunology and Rheumatology). For the past several years, UAB researchers have been studying gene expression in subpopulations of immune cells inpatients with rheumatoid arthritis.

Join in:Researchers can take advantage of the single-cell sequencing core facility in UABsComprehensive Flow Cytometry Core, directed by John Mountz, M.D., Ph.D., Goodwin-Blackburn Research Chair in Immunology and professor in the Department of Medicine Division of Clinical Immunology and Rheumatology.

Learn more:Mountz and other heavy users of single-cell sequencing explain how the techniqueslet them travel back in time and morein this UAB Reporter story.

The NIHsBRAIN Initiativeis making this the era where we are going to figure out how the brain works all 86 billion neurons between your ears, Collins said. The linchpin of this advance will be the development of tools to identify new brain cell types and circuits that will improve diagnosis, treatment and prevention of autism, schizophrenia, Parkinsons and other neurological conditions, he said.

Brain tech and UAB:Collins highlighted thework of BRAIN Initiative granteeHarrison Walker, M.D., an associate professor in the Department of Neurology, whose lab has been developing a more sophisticated way to understand the benefits of deep brain stimulation for people with Parkinsons and maybe other conditions, Collins said.

Join in:UABs planned new doctoral program in neuroengineering would be the first of its kind in the country.

Learn more:Find out why neuroengineering is asmart career choicein this UAB Reporter story.

Researchers can now take a blood cell or skin cell and, by adding four magic genes, Collins explained, induce the cells to become stem cells. These induced pluripotent stem (iPS) cells can then in turn be differentiated into any number of different cell types, including nerve cells, heart muscle cells or pancreatic beta cells. The NIH has invested in technology to put iPS-derived cells on specialized tissue chips. Youve got you on a chip, Collins explained. Some of us dream of a day where this might be the best way to figure out whether a drug intervention is going to work for you or youre going to be one of those people that has a bad consequence.

iPS cells at UAB:Collins displayed images of thecutting-edge cardiac tissue chipdeveloped by a UAB team led by Palaniappan Sethu, Ph.D., an associate professor in the Department of Biomedical Engineering and the Division of Cardiovascular Disease. The work allows the development of cardiomyocytes that can be used to study heart failure and other conditions, Collins said.

Join in:UABs biomedical engineering department, one of the leading recipients of NIH funding nationally, is a joint department of the School of Engineering and School of Medicine. Learn more about UABsundergraduate and graduate programs in biomedical engineering, and potential careers, here.

Learn more:See howthis novel bioprinterdeveloped by UAB biomedical researchers is speeding up tissue engineering in this story from UAB News.

We have kind of ignored the fact that we have all these microbes living on us and in us until fairly recently, Collins said. But now it is clear that we are not an organism we are a superorganism formed with the trillions of microbes present in and on our bodies, he said. This microbiome plays a significant role not just in skin and intestinal diseases but much more broadly.

Microbiome at UAB:Collins explained that work led by Casey Morrow, Ph.D., and Casey Weaver, M.D., co-directors of theMicrobiome/Gnotobiotics Shared Facility, has revealed intriguing information abouthow antibiotics affect the gut microbiome. Their approach has potential implications for understanding, preserving and improving health, Collins said.

Join in:Several ongoing clinical trials at UAB are studying the microbiome, including a studymodifying diet to improve gut microbiotaand an investigation of the microbiomes ofpostmenopausal women looking for outcomes and response to estrogen therapy.

Learn more:This UAB News storyexplains the UAB researchthat Collins highlighted.

Another deadly influenza outbreak is likely in the future, Collins said. What we need is not an influenza vaccine that you have to redesign every year, but something that would actually block influenza viruses, he said. Is that even possible? It just might be.

Influenza research at UAB:Were probably at least a decade away from a universal influenza vaccine. But work ongoing at UAB in the NIH-fundedAntiviral Drug Discovery and Development Center(AD3C), led by Distinguished Professor Richard Whitley, M.D., is focused on such an influenza breakthrough.

Join in:For now, the most important thing you can do to stop the flu is to get a flu vaccination. Employees can schedule afree flu vaccination here.

Learn more:Why get the flu shot? What is it like? How can you disinfect your home after the flu? Get all the information atthis comprehensive sitefrom UAB News.

The NIH has a role to play in tackling the crisis of opioid addiction and deaths, Collins said. The NIHs Helping to End Addiction Long-term (HEAL) initiative is an all-hands-on-deck effort, he said, involving almost every NIH institute and center, with the goal of uncovering new targets for preventing addiction and improving pain treatment by developing non-addictive pain medicines.

Addiction prevention at UAB:A big part of this initiative involves education to help professionals and the public understand what to do, Collins said. The NIH Centers of Excellence in Pain Education (CoEPE), including one at UAB, are hubs for the development, evaluation and distribution of pain-management curriculum resources to enhance pain education for health care professionals.

Join in:Find out how to tell if you or a loved one has a substance or alcohol use problem, connect with classes and resources or schedule an individualized assessment and treatment through theUAB Medicine Addiction Recovery Program.

Learn more:Discover some of the many ways that UAB faculty and staff aremaking an impact on the opioid crisisin this story from UAB News.

We are all pretty darn jazzed about whats happened in the past few years in terms of developing a new modality for treating cancer we had surgery, we had radiation, we had chemotherapy, but now weve got immunotherapy, Collins said.

Educating immune system cells to go after cancer in therapies such as CAR-T cell therapy is the hottest science in cancer, he said. I would argue this is a really exciting moment where the oncologists and the immunologists together are doing amazing things.

Immunotherapy at UAB:I had to say something about immunology since Im at UAB given that Max Cooper, whojust got the Lasker Awardfor [his] B and T cell discoveries, was here, Collins said. This is a place I would hope where lots of interesting ideas are going to continue to emerge.

Join in:The ONeal Comprehensive Cancer Center at UAB is participating in a number of clinical trials of immunotherapies.Search the latest trials at the Cancer Centerhere.

Learn more:Luciano Costa, M.D., Ph.D., medical director of clinical trials at the ONeal Cancer Center, discusses the promise ofCAR-T cell therapy in this UAB MedCast podcast.

Assistant Professor Ben Larimer, Ph.D., is pursuing a new kind of PET imaging test that could give clinicians afast, accurate picture of whether immunotherapy is workingfor a patient in this UAB Reporter article.

The All of Us Research Program from NIH aims to enroll a million Americans to move away from the one-size-fits-all approach to medicine and really understand individual differences, Collins said. The program, which launched in 2018 and is already one-third of the way to its enrollment goal, has a prevention rather than a disease treatment approach; it is collecting information on environmental exposures, health practices, diet, exercise and more, in addition to genetics, from those participants.

All of Us at UAB:UAB has been doing a fantastic job of enrolling participants, Collins noted. In fact, the Southern Network of the All of Us Research Program, led by UAB, has consistently been at the top in terms of nationwide enrollment, as School of Medicine Dean Selwyn Vickers, M.D., noted in introducing Collins.

Join in:Sign up forAll of Usat UAB today.

Learn more:UABs success in enrolling participants has led to anew pilot study aimed at increasing participant retention rates.

Rare Disease Day, on Feb. 29, brought together hundreds of rare disease research advocates at the NIH, Collins said. NIH needs to play a special role because many diseases are so rare that pharmaceutical companies will not focus on them, he said. We need to find answers that are scalable, so you dont have to come up with a strategy for all 6,500 rare diseases.

Rare diseases at UAB: The Undiagnosed Diseases Network, which includes aUAB siteled by Chief Genomics Officer Bruce Korf, M.D., Ph.D., is a national network that brings together experts in a wide range of conditions to help patients, Collins said.

Participants in theAlabama Genomic Health Initiative, also led by Korf, donate a small blood sample that is tested for the presence of specific genetic variants. Individuals with indications of genetic disease receive whole-genome sequencing. Collins noted that lessons from the AGHI helped guide development of the All of Us Research Program.

Collins also credited UABs Tim Townes, Ph.D., professor emeritus in the Department of Biochemistry and Molecular Genetics, for developing the most significantly accurate model of sickle cell disease in a mouse which has been a great service to the [research] community. UAB is now participating in anexciting clinical trial of a gene-editing technique to treat sickle cellalong with other new targeted therapies for the devastating blood disease.

Join in:In addition to UABs Undiagnosed Diseases Program (which requires a physician referral) and the AGHI, patients and providers can contact theUAB Precision Medicine Institute, led by Director Matt Might, Ph.D. The institute develops precisely targeted treatments based on a patients unique genetic makeup.

Learn more:Discover how UAB experts solved medical puzzles for patients by uncovering anever-before-described mutationandcracking a vomiting mysteryin these UAB News stories.

We know that science, like everything else, is more productive when teams are diverse than if they are all looking the same, Collins said. My number one priority as NIH director is to be sure we are doing everything we can to nurture and encourage the best and brightest to join this effort.

Research diversity at UAB:TheNeuroscience Roadmap Scholars Programat UAB, supported by an NIH R25 grant, is designed to enhance engagement and retention of under-represented graduate trainees in the neuroscience workforce. This is one of several UAB initiatives to increased under-represented groups and celebrate diversity. These include several programs from theMinority Health and Health Disparities Research Centerthat support minority students from the undergraduate level to postdocs; thePartnership Research Summer Training Program, which provides undergraduates and especially minority students with the opportunity to work in UAB cancer research labs; theDeans Excellence Award in Diversityin the School of Medicine; and the newly announcedUnderrepresented in Medicine Senior Scholarship Programfor fourth-year medical students.

Join in:The Roadmap program engages career coaches and peer-to-peer mentors to support scholars. To volunteer your expertise, contact Madison Bamman atmdbamman@uab.eduorvisit the program site.

Learn more:Farah Lubin, Ph.D., associate professor in the Department of Neurobiology and co-director of the Roadmap Scholars Program,shares the words and deeds that can save science careersin this Reporter story. In another story, Upender Manne, Ph.D., professor in the Department of Pathology and a senior scientist in the ONeal Comprehensive Cancer Center, explains how students in the Partnership Research Summer Training Program gethooked on cancer research.

In answer to a students question, Collins also shared his advice to young scientists. One suggestion: Every investigator needs to be pretty comfortable with some of the computational approaches to science, Collins said. Big data is here artificial intelligence, machine-learning. We can all get into that space. But its going to take some training, and it will be really helpful to have those skills.

Join in:UAB launched aMaster of Science in Data Scienceprogram in fall 2018.

Learn more:Discover how UAB researchers areusing machine-learning in their labsand toimprove cancer treatment. Those looking for a free introduction cantake advantage of the Data Science Clubfrom UAB IT Research Computing.

Read this article:
Looking to the future with Dr. Francis Collins - UAB News

In a laboratory in the depths of Imperial College London, all eyes are on a group of mice scurrying about their daily business. The rodents were injected a few weeks ago with a prototype vaccine which it is hoped will achieve what the world has so far singularly failed to do so far - stop the coronavirus Covid-19.

Progress, says Professor Robin Shattock of Imperials department of infectious disease, looks good. His team first started developingthe vaccine in mid-January and are working at record pace, taking just 14 days to get from the genetic sequencing of the virus to generating the trial vaccine in the laboratory. It relies upon a cutting-edge technique which injects new genetic code into the muscle, instructing it to make a protein found on the surface of coronavirus triggering a protective immune response. Should the mice trial prove a success then Prof Shattock hopes to be experimenting on humans in the summer and have a vaccine ready next year perhaps even the first in the world.

The laboratories at Imperial are part of the global fightback against Covid-19. At Oxford Universitys Jenner Institute, researchers are producing a vaccine seed stock, 1,000 doses of which will be manufactured in Italy for use in clinical trials. At present around 35 pharmaceutical companies are similarly working to develop a Covid-19 vaccine.

It is competitive in that people always like to be first but its a friendly competition, Prof Shattock explains. More a race against the virus than each other.

The problem is the virus is winning, coursing across the globe with a speed and severity that has shocked seasoned virologists. At a press conference on Friday afternoon, Dr Michael Ryan, head of the World Health Organisation emergencies programme, warned of a "major funding gap" for potential vaccines. Even if one does appear early next year, that would be scant defence against the months of unprecedented global devastation we are warned could lie ahead.the WHO's Dr Mike Ryan said that there is a major funding gap for potential vaccines against the virus.Even if a vaccine appears early next year, that would be scant defence against the months of unprecedented global devastation we are warned could lie ahead.

Another concern is Covid-19 has already evolved into two major lineages - dubbed L and S types. The older S-type appears to be milder and less infectious, while the L-type which emerged later, spreads quickly and currently accounts for around 70 per cent of cases. Health experts fear the virus could hit Britain in multiple waves meaning new vaccines might not work against mutated strains.

Accordingly this is a war now being waged on multiple fronts. Alongside vaccine development, researchers are focusing on antivirals to treat patients (of which currently there are none) either by hoping to create new antivirals in record time or dust off old drugs developed for previous outbreaks. At the same time scientists are working to develop better rapid diagnostics in order to more efficiently test large-scale populations for the virus something that has been hailed in South Korea for preventing its further spread.

In China alone, about 300 clinical trials are attempting to treat patients with standard antiviral therapies, while in the west attempts are being made to repurpose old treatments for Ebola, malaria and HIV to see if they can impact against Covid-19.

Many see a drug called remdesivir, originally developed to treat Ebola and production of which is currently being ramped up by the US pharmaceutical firm Gilead, as a frontrunner and one of the very few antivirals that has a reasonable prospect of helping patients in the near-term.

Should these old drugs fail then the scientific community will be required to think more creatively and it is here where a 39-year-old US tech genius called Jacob Glanville steps in. Born in Guatemala to US hippy ex-pat parents, Glanville is already something of an outlier in a field that is dominated by the pharmaceutical giants. But he is currently being backed by the US government to embark on super-accelerated engineering of antibodies produced during the SARS outbreak of 2002 to see if they might apply to the latest member of the same family of coronavirus.

It is a process that Glanville, chief executive of Distributed Bio, describes as taking five billion pieces of spaghetti and throwing them all against a wall to see what sticks.

Glanville appears in a recent Netflix series, Pandemic, which focused on a separate branch of his pioneering work to develop universal influenza vaccines. He is described as the David to the influenzas Goliath andwith Covid-19 he faces a similarly outsized challenge. Should his attempt to discover an antibody which reacts against Covid-19 prove a success then he says it is conceivable that a drug could be ready by September.

Even that would be too late for many. By next month, he is predicting 40,000 cases of Covid-19 in his home state of California overwhelming intensive care wards.

There is an enemy here and that is the virus, he says. We all want to protect our families.

Scientists across the world are indebted to their Chinese counterparts who on January 10 openly published the genetic sequencing of Covid-19. Organisations such as Cepi, set up in response to the lack of scientific progress during the Ebola crisis, are funding the rapid research of vaccines while governments are also pouring money into development.

At the University of Toronto, Sachdev Sidhu, a professor of molecular genetics, is leading a team part-funded by the Canadian federal government to develop successful antivirals. His work involves a pioneering technique he has developed to test millions of molecules stored in a library to assess whether one contains the crucial protease inhibitor for Covid-19 (which would help neutralise the virus).

He describes the rapid global progress that has been made so far as a triumph of science with the work that took a decade to understand the HIV virus being done in a month.

While he works on exploiting its Achilles heel, he says it is best to block out the human impact of Covid-19. You cant get emotional. That doesnt help. Our job is to figure out what it is, how it works, and shut it down.

Dunfermline-born researcher Kate Broderick is senior vice president of research and development at the US firm Inovio and admits she has averaged about two hours sleep each night since the virus first emerged.

As a scientist and also a mum Im extremely worried, says the 42-year-old. In my wildest nightmares I couldnt have predicted two months ago, one month ago, or even a week ago, that we would be in the situation were in today.

The day the Chinese authorities released the full genetic sequence of Covid-19, her company (which had previously worked on vaccines for the likes of Ebola, Sika, MERS and Lassa fever) designed a vaccine in just three hours and immediately started manufacturing small batches to test in the laboratory.

Inovio plans to begin testing the vaccine on humans in the US next month with parallel trials running in China and South Korea and will then move into phase two (of three) clinical trials experimenting on a wider group of people. She declines to put a timeline on when a vaccine might be ready but admits it will require at the very least tens of millions dollars in funding. Her team has been given a $9 million grant from the Coalition for Epidemic Preparedness Innovations, an initiative backed by Bill Gates, but far more investment is needed to make any vaccine widely available.

The crippling costs involved are where previous vaccines have faltered but with Covid-19 already proving to be like no virus the world has ever seen, precedent currently is being left by the wayside.

This virus is absolutely remarkable to me, she says, commenting on the speed and scale of the contagion. And I do think people should be taking this extremely seriously.

Back on the streets of London, thousands of volunteers are currently being assessed for their suitability for clinical trials of vaccine or antivirals for Covid-19. Hvivo (a subsidiary of the company Open Orphan) which has developed a rapid testing model has in recent days received 10,000 applications of those wishing to be injected with a close relative of Covid-19 to help discover an effective treatment.

Andrew Catchpole, a virologist and chief scientist at the firm, admits the offer of 3500 per person to spend two weeks in quarantine will be the prime motivation for some. But he detects in the surge in interest a wider appetite to pull together and be a force for societal good.

This is areal human emergency, he says. And a lot of people genuinely want to do their bit.

Follow this link:
The vaccine hunters racing to save the world from the coronavirus pandemic - Telegraph.co.uk

The first case of COVID-19 appeared in Italy on January 30th. A couple of Chinese tourists coming from Wuhan via Beijing were admitted to Spallanzani Hospital in Rome, highly specialised in infectious diseases.

The same day, the Minister of Health Roberto Speranza announced an air traffic embargo for flights coming to Italy from any Chinese city, including the autonomous regions of Hong Kong and Macau, in an attempt to block the spread of the infection.

In the days following the hospitalisation of the Chinese couple in Rome, a few new cases were detected in a group of Italians who were repatriated from the Wuhan region. Experts started to sigh in relief as all cases came from abroad and no local contagion seemed to show up.

Then, quite abruptly, on February 20th at midnight, the Councillor for Welfare in Lombardy, Giulio Gallera, announced that Mattia, a 38-year-old Italian from the small city of Codogno, in Lombardy, was hospitalised for a severe case of atypical pneumonia and tested positive for coronavirus. He had not travelled to China nor had any contact with people coming from Asia. He was tested only because a young anaesthesiologist, faced with the worsening condition of the patient, broke protocol and asked for permission to test a patient with no apparent risk factors. Codogno was the focus of a local outbreak of the disease: new cases were identified in the following days and the whole area was put under strict quarantine for 2 weeks. But it was too late.

As of March 12th, Italy has 15,113 official cases, 1016 deaths and 1258 recovered patients. The whole country is on lockdown. Cities like Milan and Bergamo, in Lombardy, are facing an exponential growth of hospitalised people with COVID-19. Schools, universities, and most shops are closed (all except the ones selling basic goods like food, drugs, electronics, and warehouses) and the National Health System is trying to cope with the flood of patients needing ventilation support. Roberto Cosentini, head of the Emergency Department at Pope John XXIII Hospital in Bergamo, one of the most affected cities, has been living in the hospital for the last 3 weeks: "It's like a wave," he says. "We have now around 60-80 new COVID-19 patients per day coming to the emergency. Most of them are in severe conditions and they arrive all together between 4 and 6 pm. We learnt that the respiratory distress worsens at the end of the afternoon and we now know that we will have to deal with most of the severe cases showing up one after another in a short time, every day." But Italy learnt from the Chinese experience: Italian experts looked at Wuhan's management of the crisis and Foreign Minister Luigi Di Maio asked his Chinese counterpart Wang Yi for assistance with supplies. Other countries in Europe are looking at Italy in order to prepare for SARS-CoV-2,the virus which causes COVID-19.

"There is a huge debate about the way we test for the SARS-CoV-2 virus," explains Giovanni Maga, director of the Institute of Molecular Genetics of the Italian National Research Council in Pavia, in Lombardy. "Many countries test only people with symptoms. At the beginning of the crisis, we decided to test everyone who was in contact with a person infected with the virus and this is what WHO also recommends. But in the long run it became impossible and now we test only symptomatic people with severe impairment."

However, this makes the analysis of the epidemic trends quite challenging. "If you test everybody, you will find more positive cases, with mild symptoms," says Maga. The strategy for testing might heavily influence the visible part of the epidemic: "According to many epidemiologists, other countries could be in the same situation as Italy was a few weeks ago," continues Maga. "But since they do not check asymptomatic people, they just don't know it." The choice of testing strategies is a crucial one for preparedness. "There are pros and cons for any choice, but what is important is to try to be as consistent as possible on the criteria since the beginning of the outbreak," he says.

The COVID-19 outbreak is a stress test for health services. Italy's Health Service, which provides universal coverage for the whole population, is national, but the organisation is distributed to regional health authorities.

When the crisis became evident, the Government regained control of crucial decisions, such as the coordination of intensive care unit availability. Antonio Pesenti, the coordinator of the ICU network in Lombardy and head of the Crisis Unit explains how Italy is trying to cope with the situation. "Since the first days of the outbreak we established a protocol to transfer patients needing ICU for non-COVID-19 diseases to the regions in Central and Southern Italy using the Civil Protection CROSS system. We prefer not to transfer COVID-19 patients because they require special isolation." Italy has around 6000 beds for intensive care, which the government plans to increase to 9000 in the coming weeks, partly by repurposing and refitting operating rooms used for elective surgeries. According to Pesenti, the projected demand of ICU beds is up to 10 times the current availability: "The number of hospitalised patients expected by March 26th, in 2 weeks, is 18,000 just in Lombardy. Between 2700 and 3200 will require intensive care."

To face such a tsunami, Italy is learning from China. Intermediate care units will be opened both in the hospitals and in other areas, such as exhibition pavilions in the Bergamo and Milan Fair. They will be equipped with ventilators coming from China and with special helmets to facilitate non-invasive ventilation support that seems to be very useful for patients who can manage without invasive ventilation. "We need such tools because 33%of the people in intensive care are between 50 and 64 years old: they are fit people who do not have pre-existing conditions. If we put them in invasive ventilation, they occupy an intensive care unit for 2-3 weeks," says Pesenti. "Any alternative is useful to relieve ICUs."

Doctors also had to deal with ethical issues. The Italian College of Anaesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) published guidelines for triage when there's a shortage of ventilatorsto help with decision making in a critical situation. The authors chose "the most widely shared criteria regarding distributive justice and the appropriate allocation of limited health resources" to draw their recommendations. "Informed by the principle of maximising benefits for the largest number, the allocation criteria need to guarantee that those patients with the highest chance of therapeutic success will retain access to intensive care," the document says.

Epidemiological curves are the new weather forecast for citizens in quarantine. And policy makers rely on them to decide new policies for containment. "The available predictive models are based on data we got from China," explains Paolo Vineis, an Italian epidemiologist based at Imperial College in London, who is consulting for the scientific committee supporting the Italian Government in the decision-making process. "They mainly use the SIR model, that consists of three compartments: S for the number of susceptible, I for the number of infectious, and R for the number recovered (or immune) individuals. Any of those components can change during the epidemic, because of the local development. That's why data collection is extremely important for modelling." Italy had to face a challenge due to the regional nature of its health system: different regions used to collect data in different ways, using different templates. Regions like Lombardy, that were overwhelmed by the epidemic, had trouble feeding the databases with all the details, like comorbidities. "Epidemiological analysis needs to be centralised and properly supported to help the decision makers" says Vineis.

At first glance, the death rate from COVID-19 in Italy appears to be much higher than it was in China, but according to experts, this is likely to be due to a combination of several factors, ranging from the testing strategy to the advanced age and comorbidities of most patients. "The average age of deceased patients is over 80 years, but when one looks at the age-stratified data the lethality is very similar to China," explains Giovanni Rezza, epidemiologist and director of the Department of Infectious Diseases at the Higher Institute of Health in Rome, who sits on the scientific committee advising the Italian Government. Based on the analysis of medical records, the first 100 deceased patients had an average of 2.5 concurrent diseases. Still, in the Italian system they are accounted for when calculating the lethality of COVID-19. Another confounding factor is the testing strategy, which was concentrated on people with serious symptoms, worth being hospitalised. Those who had mild symptoms were recommended to stay at home, but were not systematically tested for SARS-CoV-2. "This has likely kept the denominator very low," explains Rezza.

Italian doctors followed the suggestions from China on the use of antiviral drugs that were already tested during the SARS epidemic, but are also working actively for new clinical trials. A phase III clinical trial with remdesivir, an investigational antiviral drug being developed by Gilead Sciences to treat Ebola, is being conducted on patients recruited in the main hospitals like Spallanzani Hospital in Rome, Pavia Polyclinic, Padua and Parma University hospitals and Sacco Hospital in Milan.

The drug is not yet approved for any indication globally but is provided for compassionate use. The US Food and Drug Administration (FDA) granted investigational new drug authorisation to study it in February 2020. The same hospitals will be involved in the trial using the antiviral combination lopinavir/ritonavir as COVID-19 treatment. Paolo Ascierto, from Fondazione Pascale Cancer Institute in Naples, announced on March 10th to have observed good results on two very critical patients receiving tocilizumab, a monoclonal antibody used in rheumatoid arthritis acting on IL6 cytokine and on the spike proteins of the virus. The drug is also used to reduce severe side effects in chemotherapies. After this anecdotal report, a proper clinical trial is being planned.

General practitioners have been hit hard, acting as a first line to identify patients with symptoms suggesting COVID-19. And they are paying a high price for the lack of training, appropriate tools and a proper plan. Filippo Anelli, president of the National Federation of the Orders of Doctors and Dentists (FNOMCeO) sent a letter to Prime Minister Giuseppe Conte asking permission to stop all outpatient health activities. "By March 11th, 50 doctors were infected by the virus and three of them died," he wrote. General practitioners face a shortage of protective tools like gloves, masks and disposable scrubs. And even when they have them, they are not trained to properly manage potentially infected clothes and tools, said Claudio Cricelli, president of the Italian Society of General Practice (SIMG).

Since the end of February, the hospitals in Northern Italy have been reorganised. Most of them have special areas for COVID-19 patients. In Milan, some hospitals are working as 'hubs' to collect patients with the same disease. Most of the outpatient clinics have been closed and non-urgent visits are postponed, to make resources available for the most severe cases. This was a good strategy to increase the availability in hospitalwards but a very challenging and stressful burden on general practice. Protocols for patients with flu-like symptoms have been established by the Health Authorities. The first evaluation is done by telephone or e-mail. In case of symptoms suggesting a possible COVID-19 infection, the patient is invited to stay home, isolated from the rest of the family. The GP monitors the evolution of the symptoms while avoiding as much direct contact as possible with these patients. In case of respiratory distress, a special hotline number has been set up to dispatch a team that can transfer the patient to the hospital. "This is the only way to guarantee a proper care of the patients with other diseases," says Cricelli.

A lockdown like the one Italy is experiencing, together with continuous news coverage on the epidemic risks, are not without mental health risks. On February 26th, the Lancet published a paper by Samantha Brooks and colleagues from King's College in London, reviewing studies on the psychological effects of quarantine and how to reduce it. "Most reviewed studies reported negative psychological effects including post-traumatic stress symptoms, confusion, and anger.

Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma," the review said. "Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable." Enrico Zanalda, president of the Italian Society of Psychiatry (SIP) confirms: "Patients with depression and OCD tend to relapse," he says. "And the general level of anxiety is very high." Children and adolescents are particularly at risk of post-traumatic stress disorder, according to the review. "A proper planning for psychiatric support and for the diagnosis of PTSD is necessary."

When the lockdown was extended to the whole country, the association of medical oncologists (AIOM, Associazione Italiana di Oncologia Medica) published a statement inviting specialists to reschedule all 'non-urgent' activities, such as cancer screenings and follow-up visits for successfully-treated patients, and in some cases adjuvant therapy.

"The rationale is to make sure that the oncology wards, especially in general hospitals that are also treating COVID-19-positive patients, can respect all the safety procedures, including social distancing, for cancer patients who are being treated or may need to start a new treatment," explains vice-president of AIOM Saverio Cinieri, who is co-director of Milan's European Institute of Oncology (IEO). "This also reduces the social interactions of immunocompromised persons who are at higher risk both of infection and of developing more serious symptoms." AIOM recommended contacting patients via phone or e-mail, to verify which patients may need to be visited, and is developing an app for video consultations.

Daniela Ovadia is a writer for Agenzia Zoe.

Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N, Rubin GJ. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020 Feb 26. pii: S0140-6736(20)30460-8. doi: 10.1016/S0140-6736(20)30460-8. [Epub ahead of print]

Adapted from Univadis from Medscape.

Continue reading here:
COVID-19: What Can the World Learn From Italy? - Medscape

Researchers from the University of Torontos Donnelly Centre for Cellular and Biomolecular Research are working on developingantivirals that can combat thenovel coronavirus outbreak.

Led bySachdev Sidhu, a professor of molecular genetics, the team will apply their protein engineering technology to identify promising therapeutics.

We have diverse expertise on our team from across U of T and the University of Manitoba, which is renowned for its virology research, and we have already demonstrated that we can engineer proteins that inhibit MERS, a related coronavirus, says Sidhu, who, in addition to the Donnelly Centre holds cross appointments in the Faculty of Medicine and at the Institute of Biomaterials and Biomedical Engineering. We will now expand on this work to design therapeutics for COVID-19.

The team recently received almost $900,000 over two years from the federal government through a rapid funding competition announced on Feb. 10 to address the COVID-19 outbreak.

Sidhu is collaborating withRoman Melnyk, a senior scientist at the Hospital for Sick Children and assistant professor of biochemistry at U of T, andBrian Mark, a structural virologist and professor at the University of Manitoba. In a 2016 proof-of-principle study withMarjolein Kikkert, a virologist at Leiden University in the Netherlands, they applied a protein engineering pipeline developed by Sidhus team to create proteins that inhibit a related coronavirus that caused the Middle East Respiratory Syndrome (MERS) outbreak in 2012.

Wei Zhang, then a post-doctoral researcher in Sidhus lab and now an assistant professor at the University of Guelph,received a national innovation award for this research.

The researchers now plan to use the same strategy to battle the coronavirus behind the COVID-19global health crisis, which the World Health Organization today declared a pandemic.

Since the outbreak began in China in late 2019, the virus has spread to every continentexcept Antarctica, with more than 120,000 confirmed cases and more than 4,000 deaths, according to the latest figures. And while researchers around the world are racing to develop a vaccine, that is only a part of the solution, Sidhu says.

Even if a vaccine becomes available, not everyone is going to get vaccinated, says Sidhu. We see that with the flu the vaccination rates are far from 100 per cent. Should the virus become endemic and end up circulating in the population like the flu, medicines that stop the virus from replicating in an already infected person will be as important as vaccines, which prevent infection, according to Sidhu.

Jacky Chung, a research associate in the Sidhu lab, will spearhead the project by first engineering proteins that can inhibit the virus. The team will then search for small molecules that behave in the same way since they are easier to develop into therapeutics than proteins.

It's important to get the therapeutic inside the cells, which is where the virus replicates, says Chung. And small molecules can get into cells much more readily than proteins, which are much larger.

At the heart of the approach lies a protein called ubiquitin, named for being present in all plant and animal cells. Ubiquitin is an essential part of the cellular machinery that the virus hijacks for its own benefit. Upon infection, the virus releases proteins that interfere with human ubiquitin and allow it to bypass the hosts defence system and spread in the body.

To block the virus, the researchers will create synthetic ubiquitin variants (UbV) that thwart rather than aid its ability to replicate. By analyzing the molecular structures of different UbVs bound to the viral protein, they will gain clues into the kinds of small molecules that are most likely to be effective against the virus.

Sidhu says that, within two years, they should have candidate molecules that could be developed into therapeutics. We know there are literally armies of medicinal chemists and various companies that could then optimize the molecule into a drug that can be given to humans, says Sidhu who was previously at pharmaceutical giant Genentech and has founded six startups since joining the university.

Read more here:
U of T researchers hunt for antivirals to treat COVID-19 patients - News@UofT

The genie is out of the coronavirus bottle and has officially arrived in Minnesota.

Although this particular genie is not easily seen based on clinical symptoms, fortunately, science has provided us with genie glasses. If you believe in that kind of thing you know science.

From a testing standpoint, viruses have always been hard to detect. Theyre difficult to grow in a culture, like we often do with bacteria, and checking for antibodies against a specific virus is often imprecise, particularly early in an infection, when the body hasnt had enough time to produce antibodies.

Then came reverse transcription-polymerase chain reaction (RT-PCR) testing, a lab technique that allows us to identify fragments of genetic material (RNA in the case of coronavirus) in a body fluid sample. Like giving a search-and-rescue dog a sniff of the victims clothing, a specific RT-PCR test has to be developed for each specific viral or bacteria: It has to be told what its supposed to be looking for. (Visit tinyurl.com/molecular-assays for more information.)

RT-PCR testing isnt exactly new, but like so many other things in modern life, technological advances have made it much more accessible and affordable. In scientific terms, its a damn good test. It rarely misses a virus thats there, and it rarely mistakes another virus (or something else) for the virus it was seeking. It wont mistake influenza or strep throat for coronavirus. RT-PCR testing isnt perfect, but its the best weve ever had.

Ideally, we would have made a lot of RT-PCR genie glasses before the genie actually arrived on our shores. The delay wasnt because we couldnt figure out the gene sequence of this new coronavirus. In a tribute to the stunning sophistication of modern genetics, scientists in China released the viruss mug shot its entire genome sequence on Jan. 10, a month after they became aware of the infection (or so we are told, China being China).

An aside here for freaky cool genome science: Because RNA viruses mutate at a somewhat predictable rate, scientists can use mutations to estimate the age of a virus, like counting growth rings on a tree stump. A young virus will have few if any extra mutations. Scientists believe the COVID-19 virus was born no earlier than Oct. 30, 2019, and no later than Nov. 29th (tinyurl.com/coronvirus-genome).

This genome map provides the template for developing both vaccines and RT-PCR testing. When Germany flew 126 of its citizens home from Hubei province on Feb. 1, they PCR-tested each of them. Two of the 126 tested positive, and they were not among the 11 people with symptoms.

In medicine, we are trained to avoid testing in situations where the likelihood of finding anything is low. Routine testing for rare or low-likelihood diseases, or in healthy people, just wastes a lot of money and generates more testing for those inevitable cases where the test returns falsely positive. It rarely saves lives. Men do get breast cancer, but not at a rate that justifies routine mammograms.

All that is different with the COVID-19 virus.

At the beginning of the outbreak, when the virus was thought to be isolated to a single province in China, travel history screening was an incredibly cheap and powerful test. But as the virus continues on its worldwide tour, travel history will become an increasingly nondiscriminating test (example: Have you or a close contact traveled to any one of the following 30-and-counting states?). And thanks to widespread RT-PCR testing in other countries, we now know that our other test signs and symptoms of an upper respiratory infection has been a crude one from the beginning. It appears that a majority of those infected have either no symptoms or minor symptoms and yet remain capable of passing the virus to others. Never mind that we are still in the midst of our winter cold and flu season, where COVID-19 impostors abound.

So now that we know travel history and signs/symptoms are no more than beer-goggle-quality tests, its time to break out the genie glasses: RT-PCR. If the airline industry alone stands to lose $100 billion, it could offer the Centers for Disease Control and state and private labs $20 billion to rev up RT-PCR production, and still save itself $80 billion.

I asked Joanne Bartkus, director of the Minnesota Department of Healths Public Health Laboratory, exactly how does a RT-PCR lab rev up capacity? Is it more machines, more reagents (substances used in chemical reactions), more staff?

Yes to all of those things, she replied as she went on to explain the COVID-19 virus testing process.

Somewhat surprisingly, the RT-PCR test itself is the simplest part of the process: The samples are placed in a machine called a thermal cycler, and in 2.5 fully automated hours, the data is ready to be interpreted. The rate-limiting, most-tedious part of the process is getting the specimens ready for the cycler.

As test kits arrive from around the state, each sample must be accessioned: Information such as patient identifiers, location and ordering physician must be logged into the computer, and the sample must be tagged with a bar code. It might sound mundane, but imagine the implications of attributing a particular test result to the wrong patient. This is serious stuff.

Then comes the process of extracting the viral RNA out of the immunological fog of war found in any snot sample. In the beginning, the RNA extraction process certified by the CDC was labor-intensive.

It really limited the number of samples we could turn around in a day, and thats one of the reasons that initial testing was limited to individuals with known risk factors, Barkus told me. But as we move toward community surveillance, well need higher throughput extraction methods, and who could ever argue with higher-throughput extraction methods? Good news: On the day I spoke with Barkus, the CDC had just greenlighted a technical change that will allow 96 tests to be done in a platform that previously handled 24.

So things are heating up at MDH labs, and elsewhere, too, as the Mayo Clinic and private labs like Quest Diagnostics and LabCorp have all recently rolled out their own RT-PCR testing. Under normal circumstances, every new RT-PCR would need to be tested and approved by the FDA, but under emergency conditions like COVID-19, the FDA can loosen the reins and allow labs to internally validate their new test and get the FDA seal of approval later.

All of that, and the prospect of broader testing, is welcome news. Then well have some real data to guide our containment strategy, rather than hunches and case reports, or the difficult, labor-intensive, gumshoe detective work by public health workers.

And then well have a much better chance of putting this genie back in the bottle.

Craig Bowron is a physician and writer in the Twin Cities. On Twitter: @billcarlosbills.

Read more from the original source:
OPINION EXCHANGE | The testing that can help us put the coronavirus genie back in the bottle - Minneapolis Star Tribune

Theres a lot that scientists know about the benefits of zinc. The essential nutrient boosts the immune system, heals wounds and supports brain development in children. We even need zinc to smell and taste. Dive a little deeper, however, and the real mysteries of zinc emerge.

One of them how zinc is distributed to tissues and cells is the root of Prof. Shannon Kellehers research, which aims to reveal the role that zinc plays in the development of inflammatory bowel disease and food allergies.

Zinc is critical for intestinal health, but we have little information on what it actually does in the intestine, says Kelleher, who is based in UMass Lowells Biomedical and Nutritional Sciences Departmentin the Zuckerberg College of Health Sciences. Our goal is to understand how zinc affects intestinal function, the gut microbiome and the risk for intestinal disease.

We asked her to explain.

Q. What do we know about zinc and its effect on intestinal health?

A. We know that the right amount of zinc is critical to intestinal health. If we consume too much or too little zinc, the intestinal barrier falls apart. An over- or underabundance of zinc can cause shifts in the gut microbiome, and cause diarrhea and inflammation.

The only way that people can consume too much zinc is through supplements. If you get zinc only through foods in your diet, then you really cant consume toxic amounts. However, if you only rely on your diet, then you may not be consuming enough. So finding the right balance is important.

Q. Is zinc deficiency a big problem?

A. One study from the National Institutes of Health shows that 35 to 45 percent of adults over 60 years old had lower-than-average zinc intakes. Scientists believe that about 7 to 10 percent of the U.S. population is severely lacking in the nutrient. Women of reproductive age are most likely moderately zinc-deficient due to menstruation and not eating the right foods. Symptoms of too little zinc include dry and itchy skin, loss of hair, reduced ability to taste food and a compromised immune system that leads to more colds.

Q. How much zinc should we be consuming?

A. The recommended daily allowances for zinc are 11 mg for men and 9 mg for women. Foods high in zinc include red meat, oysters, poultry, fish and some fortified breakfast cereals. But since excess zinc is also not healthy, dont overdo it with supplements.

Q. Why is it important to find out how zinc travels through our bodies and cells?

A. If we knew how zinc gets into our cells, where it goes in our cells and what it does, then we could use this information to develop new therapies to fight a variety of diseases. These could include new drugs, delivery systems or personalized dietary recommendations.

Q. What else could your research results be used for?

A. Our research could also inform personalized nutrition. I teach an undergraduate course about an emerging field called nutrigenetics. We are now able to sequence your DNA and, based on your genetic blueprint, assess your risk for nutritional disorders and develop personalized diets that match your genetics. It helps to understand why individuals who eat similar diets can have different health outcomes. Your genetics play a crucial role in how you respond to what you eat.

Q. How does your work differ from nutritional science?

A. Nutritional science is often thought of as studies that look at how diet and foods affect human health and the risk for disease. The type of research we do is referred to as molecular nutrition. My research dives a little deeper to understand how specific nutrients in this case, zinc affect cellular and molecular processes that then cause the positive or negative effects we see in the body.

Read more from the original source:
The Role of Zinc: It's More Important than You Think - UMass Lowell

Researchers from the University of Torontos Donnelly Centre for Cellular and Biomolecular Research are working on developing antivirals that can combat the novel coronavirus outbreak.

Led by Sachdev Sidhu, a professor of molecular genetics, the team will apply their protein engineering technology to identify promising therapeutics.

We have diverse expertise on our team from across U of T and the University of Manitoba, which is renowned for its virology research, and we have already demonstrated that we can engineer proteins that inhibit MERS, a related coronavirus, says Sidhu, who, in addition to the Donnelly Centre holds cross appointments in the Faculty of Medicine and at the Institute of Biomaterials and Biomedical Engineering. We will now expand on this work to design therapeutics for COVID-19.

The team recently received almost $900,000 over two years from the federal government through a rapid funding competition announced on Feb. 10 to address the COVID-19 outbreak.

Sidhu is collaborating with Roman Melnyk, a senior scientist at the Hospital for Sick Children and assistant professor of biochemistry at U of T, and Brian Mark, a structural virologist and professor at the University of Manitoba. In a 2016 proof-of-principle study with Marjolein Kikkert, a virologist at Leiden University in the Netherlands, they applied a protein engineering pipeline developed by Sidhus team to create proteins that inhibit a related coronavirus that caused the Middle East Respiratory Syndrome (MERS) outbreak in 2012.

Wei Zhang, then a post-doctoral researcher in Sidhus lab and now an assistant professor at the University of Guelph, received a national innovation award for this research.

The researchers now plan to use the same strategy to battle the coronavirus behind the COVID-19 global health crisis, which the World Health Organization today declared a pandemic.

Since the outbreak began in China in late 2019, the virus has spread to every continent except Antarctica, with more than 120,000 confirmed cases and more than 4,000 deaths, according to the latest figures. And while researchers around the world are racing to develop a vaccine, that is only a part of the solution, Sidhu says.

Even if a vaccine becomes available, not everyone is going to get vaccinated, says Sidhu. We see that with the flu the vaccination rates are far from 100 per cent. Should the virus become endemic and end up circulating in the population like the flu, medicines that stop the virus from replicating in an already infected person will be as important as vaccines, which prevent infection, according to Sidhu.

Jacky Chung, a research associate in the Sidhu lab, will spearhead the project by first engineering proteins that can inhibit the virus. The team will then search for small molecules that behave in the same way since they are easier to develop into therapeutics than proteins.

Its important to get the therapeutic inside the cells, which is where the virus replicates, says Chung. And small molecules can get into cells much more readily than proteins, which are much larger.

At the heart of the approach lies a protein called ubiquitin, named for being present in all plant and animal cells. Ubiquitin is an essential part of the cellular machinery that the virus hijacks for its own benefit. Upon infection, the virus releases proteins that interfere with human ubiquitin and allow it to bypass the hosts defence system and spread in the body.

To block the virus, the researchers will create synthetic ubiquitin variants (UbV) that thwart rather than aid its ability to replicate. By analyzing the molecular structures of different UbVs bound to the viral protein, they will gain clues into the kinds of small molecules that are most likely to be effective against the virus.

Sidhu says that, within two years, they should have candidate molecules that could be developed into therapeutics. We know there are literally armies of medicinal chemists and various companies that could then optimize the molecule into a drug that can be given to humans, says Sidhu who was previously at pharmaceutical giant Genentech and has founded six startups since joining the university.

View original post here:
University researchers hunt for antivirals to treat COVID-19 patients - Mirage News

The mammals of New Zealand have long posed a threat to native species. The Predator Free 2050program is an effort to rid the island of these invaders including using the tools of CRISPR-based genome editing to create a gene drive to jumpstart extinctions.

Its a very bad idea.

In the 1993 film Jurassic Park, mathematician Ian Malcolmlistens to arrogant dinosaur daddy John Hammond describe the islands supposedly all-female populations of the giant reptiles:

John, the kind of control youre attempting simply is its not possible. If there is one thing the history of evolution has taught us its that life will not be contained. Life breaks free, it expands to new territories and crashes through barriers, painfully, maybe even dangerously, but, there it is Im simply saying that life, uh finds a way.

The wise Dr. Malcolm may prove prescient when it comes to using gene drive technology to get rid of pesky species.

Today reptiles, albeit smaller ones than dinosaurs, are among the threatened natives of New Zealand. Prior to the arrival of people, only bats and marine species represented class Mammalia, except for a few archaic types a few million years ago. Then the Mori people introduced Polynesian rats and dogs in about 1250 CE, and Europeans five centuries later contributed mice, pigs, more rats (ship stowaways), possums, weasels, stoats, and ferrets. Native birds, reptiles, invertebrates, snails, insects, and even the forest canopies began to lose out in the competition for natural resources and to predation.

The New Zealand government painted the newcomers as pests, interlopers, invaders. Introduced predators: the bad guys, states one pamphlet.

In a simpler and perhaps more violent time, pests might have been shot, drowned, or poisoned. But a 2003 paper fromAustin Burt, a selfish gene proponent from Imperial College, London, proposed the concept of a gene drive.

A gene drive harnesses one of the ways that cells repair DNA, called homing, that snips out one copy of a gene and replaces it with a copy of whatever corresponding gene variant (allele) is on the paired chromosome. It would be like cutting out a word in this sentence and replacing it with a copy of the word below it. If done to a gene that affects fertility in a fertilized ovum aka the germline the intervention can lead, within a few generations, to mass sterility and a plummeting population a gene drive towards extinction.

A gene drive skews Mendelian inheritance. Instead of one of a pair of genes coming from the father and one from the mother, both copies are from one parent. In the language of genetics, the intervention can turn a heterozygote (2 different copies of a gene) into a homozygote (2 identical copies). Nature does this in several ways, but the tools of CRISPR-Cas9, first described in 2012,offer a faster route to a gene drive, and can target several genes at once.

Visions of vanquishing the mosquitoes that carry the malaria parasite or zika virus dampened initial scrutiny of gene drives. In 2016, the National Academies of Sciences, Engineering, and Medicine (NASEM) released a 200+ page reportthat discussed reasons to proceed with caution, but endorsed continued laboratory experimentation as well as limited field trials of gene drives.

In 2017, a short paper in Science responded to the NASEM report with Guiding principles for the sponsors and supporters of gene drive research. Ill return to the new recommendations after a trip down biotech memory lane what distinguishes this blog from the clonal regurgitations of aggregated science news.

I was in graduate school in 1976 when recombinant DNA technology was under heated debate. My mentor dubbed the rising public fear of genetics and biotech the triple-headed purple monster mindset.

In February 1975, a whos who of molecular biologists had convened at Asilomar, on Californias Monterey peninsula, to explore the implications of combining genes of two species, starting with insertion of a bacterial gene into a cancer-causing virus.

The 150 scientists discussed fail-safe measures to control recombinant organisms. The Asilomar conference begat guidelines for physical containment via specialized hoods and airflow systems and biological containment to weaken organisms so that they couldnt survive outside the lab.

Despite initial concerns, recombinant DNA technology turned out to be safer than expected, and it spread to industry fast and in diverse ways. A handful of important drugs, starting with human insulin, became safer and more abundant thanks to recombinant DNA techniques. In the agricultural arena, weve been eating GMO foods for decades, although the containment hasnt exactly worked, as the example of canolagrowing along the roadways of North Dakota illustrates.

In 1985geneticists met again to assess the safety, feasibility, and value of another huge project: sequencing the human genome. I doubt any of them could have foreseen a time when we would carry our genome sequences on our smartphones.

Back then, researchers packed a room at the Cold Spring Harbor Laboratory on New Yorks Long Island. At first those against outnumbered those for 5:1, ticking off their fears: shifting research from inquiry-based experimentation to data dumps, comparing the sequencing effort to climbing Mt. Everest just because its there, and diverting funds to fight HIV/AIDs. Finally, the National Academy of Sciences jumped in to debate both sides, and in 1988, Congress authorized the National Institutes of Health (NIH) and the Department of Energy to start sequencing. Foreshadowing of gene drives?

On the reproductive front, the first test-tube baby, Louise Joy Brown, was discussed as if she were a space alien until her ordinariness became apparent, and today more than 5 million folkshave been born beginning with in vitro fertilization. Similarly, one of the first families to speak to the media about their use of preimplantation genetic diagnosis (PGD) to select an embryo who would one day provide stem cells to save his sister was vilified PGD is now a common adjunctto IVF to select the healthiest embryos.

But a gene drive doesnt provide information, drugs, improved cabbages, or babies. It has the potential to tilt the biosphere.

When the inventors of a new biotechnology pull a 180 on applications of their brainchild, its time to take notice. Thats what Kevin Esvelt from MIT and Neil Gemmell from the University of Otago, Dunedin, New Zealand, did in their Perspective in the November 16, 2017 issue of PLOS Biology,Conservation demands safe gene drive. They shout out a warning.

Back in 2014, Esvelt and his colleagues suggested using self-propagating CRISPR-based drive systems for conservation.They also discussed variations on the theme, including a daisy drive systemthat sets up a series of interventions, like a series of locks on a bank vault, and the trojan femaletechnique that sneaks male infertility mutations into mitochondrial DNA.

Second thoughts about deploying gene drives were perhaps already lurking in the minds of people familiar with the nature of DNA, as Jurassic Parks mathematician intuited. DNA changes! Thats why its the genetic materialand why the idea that we arent still evolving is absurd.

A gene swapped into a rat or a possums genome to squelch fertility can change. Such spontaneous mutation happens because of the nature of the DNA molecule. Each of the 4 types of DNA bases exists, when unlinked, fleetingly, in a slightly alternate form. If a DNA replication fork should happen down the old double helix and catch a clinging base in its rare form, a base pair can be replaced with a different one creating a new allele. Its simply the chemistry of life.

A gene drive also assumes that one allele is predominant in a population, and that isnt necessarily the case. What if the harnessed repair mechanism lassos another variant of that gene, a rarer one? Different outcome.

The inherent changeability of DNA alerted the scientists at Asilomar and Cold Spring Harbor. We can never predict all risks, about anything, and surprises have consequences. Who would have thought wed all have to haul off our boots when checking in at the airport thanks to a lone shoe bomber?

DNA also flits from cell to cell, aboard elements called transposons or, more colorfully, jumping genes. Thats how bacteria share sets of antibiotic resistance genes. What if a CRISPR gene drive harpoons something other than its intended target? Goodbye beloved kiwi birds rather than the weasels that eat their eggs? What if a targeted species hitches a ride to other islands and continents before it eliminates the local population and extinguishes itself? Drs. Esvelt and Gemmell write.

The bottom line: gene drives may create the equivalent of the very thing they are being deployed to fight: invasive species. Write Drs. Esvelt and Gemmell of their former approval of gene drives for conservation, We now believe that inclusion was a mistake: such drive systems lack control mechanisms and are consequently highly invasive.

And so also in November of 2017, Dr. Esvelt, with Charleston Noble, Ben Adlam, George Church, and Martin Nowak from Harvard, published Current CRISPR gene drive systems are likely to be highly invasive in wild populations in bioRxiv. Their paper warns against even limited field tests because of mitigating factors, including scenarios as yet unimagined. They did a mathematical analysis to counter recent reports that downplayed the potential ecological danger of a gene drive by claiming that natural resistances will emerge to block the spread to untargeted wild populations. Sound familiar? Contrary to the National Academy report on gene drive, our results suggest that standard drive systems should not be developed nor field-tested in regions harboring the host organism, they conclude.

The guiding principles for the sponsors and supporters of gene drive research published in todays Science, from Claudia Emerson, Stephanie James, Katherine Littler, and Filippo Randazzo, are dj vu all over again for those of us who recall Asilomar circa 1975. Perhaps the principles are attempting to prevent the public outcry at town hall meetings and destruction of some GM crops (most notablyice minus bacteria on plants)that accompanied the entry and acceptance of recombinant organisms.

According to the principles, gene drive experiments should

have goals of social value and the public good take biosafety measures, comply with regulations, and conduct ecological risk assessment have transparency and accountability, with sharing of data engage the public

Dr. Emerson and her colleagues make a good case for the need to find new ways to limit the spread of vector-borne infectious diseases like malaria and zika. Lets hope that gene drive technology goes the successful way of recombinant DNA technology and not the way of GMO escapees in agriculture or in the hands of bioterrorists.

Lets listen to Dr. Malcolm.

[Editors note: Kevin Esvelt of MIT commented on this article on PLOS Blogs. He wrote:

Respectfully, this somewhat mischaracterizes our point.

We think it unwise to build gene drive systems capable of spreading indefinitely beyond the target population.

Because standard self-propagating gene drive systems can spread indefinitely, we think they should only be developed and used for a handful of applications such as malaria eradication, for which the target population includes every Anopheles gambiae s.l. mosquito in Africa.

In contrast, we feel that self-propagating gene drive should not be used for invasive species control because there is always a native population that could be affected.

Instead, we should focus on developing locally-confined drive systems that cannot spread indefinitely. Local drive systems could enable each community to make decisions about its own environment without necessarily affecting people far away. There are several forms that have been modeled or are under development, including Trojan female, killer-rescue, daisy drive, and threshold drive, and hopefully still better ones will be invented.

A final note: there is essentially no risk that transposons, a natural and nearly ubiquitous form of gene drive, will cause a CRISPR-based drive system to spread in another species. The reason is that CRISPR is highly specific and the target DNA sequences would not be present in the genome, so the system would not function exactly the same way that laboratory genome editing fails when there is a strain-specific mutation in the CRISPR-targeted sequence.

Life usually does find a way eventually; the question is how long it will take. We have a remarkable opportunity to address many serious ecological problems using natures own language. With care, humility, and collective scrutiny as obtained through open research and broadly inclusive societal discussions we have a chance to do so wisely. Sometimes, that means walking away from an exciting idea.]

Ricki Lewis is the GLPs senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis

A version of this article previously appeared on the GLP on December 7, 2017and was originally published on PLOS Blogs website as An Argument Against Gene Drives to Extinguish New Zealand Mammals: Life Finds a Way.

Link:
The risks of using gene drives to get rid of 'pesky species' - Genetic Literacy Project

Promising results were observed in a small, single-arm, phase 2 studyevaluating the efficacy and safety of the programmed cell death-1 (PD-1)inhibitor, pembrolizumab, plus radiation therapy (RT) in patients with locallyadvanced head and neck cancers who were ineligible to receive cisplatin-basedchemoradiation therapy. These findings were presented during the 2020Multidisciplinary Head and Neck Cancers Symposium in Scottsdale, Arizona.

Cisplatin-based chemoradiation therapyis considered a standard of care for the treatment of locally advanced squamouscell carcinoma of the head and neck (LA-HNSCC), with cisplatin acting as both achemotherapeutic agent and a sensitizer to ionizing radiation. However, it isnot uncommon for patients to have contraindications to the receipt of cisplatintherapy, thereby necessitating selection of another radiosensitizer forconcomitant use with RT.

The choice of pembrolizumab as asubstitute for cisplatin in the setting of LA-HNSCC was based, in part, onprevious studies showing that radiation elicitsand promotes tumor-directed immune-stimulation, which may potentiate antiPD-1therapy, the study authors commented.

None of the 29 adult patients enrolled in this study (ClinicalTrials.gov Identifier: NCT02609503) had undergone prior curative treatment for LA-HNSCC, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 was a study inclusion criterion. Pembrolizumab was administered concurrently with RT every 3 weeks for 3 cycles followed by 3 cycles of pembrolizumab. The primary study endpoint was progression-free survival (PFS), with overall survival (OS) and safety included as secondary study endpoints.

Twenty patients hadcancers of the tongue or tonsil, with a variety of other sites of disease,including supraglottic larynx and hypopharynx, present in the remaining patients.Nonmetastatic stage III or IV disease was present in approximately three-quartersof study patients. Reasons for ineligibility to receive cisplatin includedotopathology (69.0%), nephropathy (20.7%), and neuropathy (6.9%).

One-yearrates of PFS and OS for the overall study population were 76% and 86%,respectively. Furthermore, at a median follow-up of 21 months, the median PFShad not been reached and exceeded the hypothesized median PFS of 16 months,leading study authors to conclude that this approach deserves evaluation in arandomized trial.

Whilerespective 1-year PFS and OS rates were 88% and 94% for patients with p16/humanpapilloma virus (HPV)-positive cancers of the oropharynx, the correspondingrates were 58% and 75% for those with other type of LA-HNSCC.

Although the presence of programmed celldeath-ligand 1 (PD-L1)positive disease was not found to be associated withlikelihood of disease progression, the relative percentages of specific B-cellpopulations, such as a higher percentage of baseline naive B-cells and a lowerpercentage of marginal zone B cells, were associated with an increased risk ofprogressive disease.

Toxicitiesfrequently associated with administration of RT were observed, although grade 3or grade 4 lymphopenia was observed in over half of the study patients.

In their concluding remarks, the study authors stated that concurrent pembrolizumab and radiotherapy has demonstrated promising PFS and OS in LA-HNSCC, regardless of p16 status or anatomic location, with a favorable toxicity profile.

Disclosure: Some of the authors of theabstract disclosed financial relationships with pharmaceutical companies,medical device companies, and/or health-related companies. For a full list ofdisclosures, please refer to the abstract.

Reference

Weiss J, Vincent B, Deal A, et al. Progression-free survival, overall survival and immunophenotyping outcomes for patients with stage III-IV head and neck cancer and cisplatin contraindication treated immunophenotyping outcomes for patients with stage III-IV head and neck cancer and cisplatin contraindication treated with definitive radiotherapy plus pembrolizumab. Presented at: Multidisciplinary Head and Neck Cancers Symposium; February 27-29, 2020; Scottsdale, AZ. Abstract LBA1.

See original here:
Promising Clinical Activity for RT Plus ICIs in Locally Advanced Head and Neck Cancers - Cancer Therapy Advisor

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"

Excerpt from:
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"

Read more here:
Understanding SARS-CoV-2 and the drugs that might lessen its power - The Economist

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.

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

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

See the original post here:
Stem cells to help the heart - Science Magazine

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.

Read the original post:
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

Read this article:
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.

Continued here:
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.

Here is the original post:
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.

WPA PoolGetty Images

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.

China News ServiceGetty Images

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.

THOMAS KIENZLEGetty Images

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."

View original post here:
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?"

See more here:
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

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