Category Archives: Gene Medicine

For a long time, the thinking was the same. To make a career in medical research, it was critical to pick a promising area of study. That often meant steering clear of ALS.

Short for amyotrophic lateral sclerosis, ALS is a progressive and fatal illness that causes nerves to break down. The disease was first discovered more than a century ago, but became widely known only after famed baseball player Lou Gehrig was diagnosed with it in the late 1930s.

Today, estimates hold that about 30,000 people in the U.S. have ALS, with 5,000 new cases annually. These patients desperately need new treatments; yet, the complicated biology of their disease has thwarted most attempts at developing effective medicines. The Food and Drug Administration has approved only three so far, and each has limitations. ALS patients still live about four years on average once they're diagnosed.

Experts say there are reasons for hope, though. Scientific and technological breakthroughs have given drug hunters better tools to understand and potentially combat ALS. Patients may soon have another treatment, a pill shown to modestly slow people's decline and help them live longer, and could see more options arrive in the next several years if more advanced approaches pan out.

"The science is really exciting, and I think that's driving a lot of companies to have programs," said Merit Cudkowicz, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.

"I remember people telling me it was a dead-end career to go into ALS research," she added. Now, "it's a hot time to be an ALS scientist. They all want you."

But as with many diseases of the brain, much about ALS remains unclear. The vast majority of cases are "sporadic," for example, meaning their cause isn't fully understood.

For drugmakers hoping to crack the disease, these uncertainties create major roadblocks. In the last year alone, experimental treatments from Brainstorm Therapeutics, Alexion Pharmaceuticals and Biogen the world's largest biotech focused on neuroscience have all faltered in late-stage clinical trials, tempering enthusiasm among doctors, patients and investors.

And for patient advocates, these continued setbacks have only intensified calls for companies to accelerate research and for drug regulators to work more flexibly.

"The drug development process takes a long time. And when you're looking at one year, two years, three years of life left, you just don't have time," said Larry Falivena, who serves on the board of trustees of The ALS Association, a patient advocacy group, and who was diagnosed with a slower progressing form of the disease in 2017.

In the U.S., patients with ALS have few treatment options. There's one called riluzole, which was approved in 1995 and has been shown to extend survival by a few months. There's also Nuedexta, which was cleared in 2011 to treat a symptom of the disease. And then there's Radicava, which was greenlit in 2017 as a way to slow the physical decline associated with ALS.

About four in five U.S. patients take riluzole, according to Cudkowicz, as it appears to consistently extend people's lives without harsh side effects.

Far fewer are on Radicava, largely because of the way it's administered. The drug is given as an hourlong infusion each day for about a third of every month. That inconvenience, coupled with its often small effect, has led many patients to not consider it worthwhile.

"In any one patient, you don't really notice the difference whether they're on the drug or not. It's that type of benefit you only really see in trials," said Stephen Scelsa, a neurologist at Mount Sinai Hospital in New York City.

Another option could be on the horizon, though.

In 2019, Amylyx Pharmaceuticals, a small Cambridge, Massachusetts-based company, announced that a drug it has been developing appeared to slow ALS in a placebo-controlled clinical trial. Results later published in The New England Journal of Medicine showed those who took the drug, known as AMX0035, scored a couple points better on average on a scale used to evaluate how well ALS patients speak, walk, breathe and perform other essential functions.

Further analysis found early signs the drug kept people alive longer, too. Looking at 135 study participants, those treated with AMX0035 lived a median of just over two years about six and a half months longer than those who received a placebo.

Amylyx's co-founders Justin Klee and Josh Cohen at a manufacturing site for AMX0035

Courtesy of Amylyx Pharmaceuticals

Experts note that, while positive, the effect of Amylyx's drug is still modest. Patients who took it continued to decline, and the chances of them living up to two years after enrolling in the study were about 50%. The study also found AMX0035 didn't do significantly better than the placebo on secondary tests that looked at health measures like breathing, hospitalization rates and overall muscle strength.

Amylyx's founders acknowledge their drug's limitations. But they, along with others, argue it's a step in the right direction.

"I do think it's incremental, but it's an important increment," said Cudkowicz, who helped lead the investigation of AMX0035. "It is really the first drug to slow loss of function but also prolong survival. That is a big step."

Amylyx has asked regulators in Canada and the U.S. to approve its drug, and plans to do the same in Europe before the end of the year. The FDA has yet to decide whether it will review AMX0035, but if it does, an approval verdict would come sometime in 2022.

"We're really proud of the data we generated," said Justin Klee, one of Amylyx's co-founders. "But there's also so much else to do, and so many other opportunities."

Companies are already at work exploring some of these opportunities. Swiss pharmaceutical giant Novartis is investigating a drug designed to block a protein involved with inflammation in the nervous system. Another drug, from the neuroscience company Alector, targets a protein that performs critical duties for cells both in and outside the brain. That drug is being tested across multiple neurodegenerative disorders, including ALS.

Biogen and its longstanding partner Ionis Pharmaceuticals have attracted attention as well, with one of the few experimental medicines to have moved to the final stage of human testing.

Called tofersen, the medicine was created with a technology that, while not new, has been increasingly validated thanks to a string of recent FDA approvals in other diseases. Tofersen is also the byproduct of a flood of research aimed at the role genes play in ALS.

A recent setback, however, has raised doubts about its chances at ever becoming available outside of clinical trials.

The human genome has been an invaluable source of information in the fight against disease. DNA was first sequenced in the mid-1970s. Less than a decade later, Huntington's disease which is also characterized by the progressive breakdown of nerve cells became the first illness traced back to changes in a specific chromosome.

The first gene associated with ALS, named SOD1, was identified in 1993. Scientists have since uncovered at least several dozen more that look to have some effect on the disease.

These discoveries have encouraged ALS researchers and doctors, especially as technological advances in drugmaking have made it easier to target genes. Tofersen, for example, is a type of precision medicine known as an antisense therapy, meaning it blocks the body's cells from acting on the genetic instructions used to make certain proteins. Specifically, it's designed to inhibit the activity of the SOD1 gene.

"I do think the genetic forms, since we know the targets, will have some of the first big breakthroughs, where we find treatments that really modify the disease," Mount Sinai's Scelsa said.

But, nearly three decades after SOD1 was identified, researchers are still hunting for those breakthroughs. In many cases, drug developers aren't yet sure how best to target these genes, or how to regulate them in a way that positively impacts function or survival. Just two months ago, Biogen and Ionis disclosed results from a late-stage study of tofersen, and while the drug did substantially lower levels of SOD1 protein along with another chemical marker associated with ALS, it wasn't any better than a placebo at slowing down the disease.

Biogen said it will discuss the data with regulators and the broader ALS community to determine tofersen's future.

"Technology has advanced so much it's easy to identify a target," said Kuldip Dave, vice president of research at The ALS Association. "But then, can we really manipulate the target? I think that's the first challenge, the first transition: from target identification to target validation."

Moreover, the mutations tied to ALS have only been observed in a tiny fraction of patients. That fraction could grow with additional genetic research; but in the meantime, it's estimated that at least 90% of cases don't have a known cause.

For those patients, new treatments may be harder to come by.

"In the case of sporadic ALS, we really don't know," said Raymond Roos, director of the University of Chicago's ALS and Motor Neuron Disease Clinic. "We don't know whether there are multiple genes plus environment, or which genes and which environment. We're struggling."

An ALS researcher prepares a petri dish.

Courtesy of The ALS Association

Researchers aren't giving up, though. A search of a federal clinical trial database shows at least five dozen that are evaluating potential ALS drug treatments and currently recruiting participants. Many of these studies are enrolling people with sporadic disease.

Similar to how the treatment of cancer and certain genetic diseases like cystic fibrosis evolved over the past decade, the hope is that therapies like those or like Amylyx's, which was tested against both sporadic and genetic ALS, will improve patients' daily lives and help keep them alive until more specialized drugs are developed.

Technology that's been used in a more targeted fashion may also prove valuable to broader populations. Biogen, for one, is sponsoring a small study of a different antisense therapy aimed at preventing the buildup of a toxic protein observed in many ALS patients.

"The whole field finds that exciting," Cudkowicz said, "because it's basically learning from the tools and technologies for the familial form of the illness [to then have] something that could also be for sporadic disease."

As with other neurodegenerative diseases, researchers seem to agree that the best treatments for ALS will involve a mix of drugs. Yet, identifying and testing these combination therapies can be difficult, as Amylyx found with AMX0035, which itself is a pairing of two drugs.

"As we proceeded, we realized just how many things developing a combination drug makes more challenging," said Josh Cohen, Amylyx's other co-founder.

"With a single drug you have to worry about dose. For a combination drug you have to worry about dose squared," he said. "You have to worry about the levels of A and the levels of B, and the interaction between [them]. And that pervades everything" from toxicology studies to manufacturing.

Another obstacle is that, while many researchers believe treating patients earlier could lead to better outcomes, ALS is hard to diagnose even after symptoms start to show.

Falivena of The ALS Association knows this obstacle well. While training for a marathon, the now 53-year-old said he noticed weakness in his left arm that later spread to his leg. Despite numerous tests and doctor's visits, it took a few years before Falivena was officially diagnosed.

"It's not like you can just take a blood test," he said, "it's more a process of: 'we have to eliminate everything else.' I'm sure no doctor wants to tell a patient they have a terminal disease with no cure, so it makes sense they want to eliminate everything else. But it can be frustrating."

As scientists attempt to work through these problems, one source of hope among patients has been clinical trials.

At the Healey Center, for example, a first-of-its kind "platform" trial testing five experimental therapies at once has enrolled volunteers two- to three-times faster than is typical for an ALS study, according to Cudkowicz.

"It used to be that it was hard to find people to be in trials," she said. "We now have [situations] where the sites can't keep up with the waitlist. And it's not only because we're doing this platform trial; there's so much patient advocacy that's getting the word out."

Patients like Falivena, who participated in the tofersen study and has since enrolled in a subsequent "open-label" investigation of the drug, have found these trials valuable even when they don't succeed.

"There's so much about this disease that makes you feel like you have no control," he said. "This is a level of control; it's a level of hope, positivity, which in itself can help people live better."

And yet, there is also some resentment toward drug developers, which are often reluctant to broaden enrollment in their clinical trials beyond narrowly defined groups they see as most likely to benefit. Biogen, for one, was heavily pressured to expand access to tofersen and eventually did so after initially resisting.

Patient advocates have criticized the FDA as well for not moving fast enough to make promising yet unproven ALS treatments available to patients. The ALS Association even called out the agency earlier this year, after it looked as though Amylyx would have to conduct another clinical trial before asking for approval of AMX0035.

The FDA has since reversed course, allowing Amylyx to submit its drug before completing the additional trial. Falivena said he's optimistic the agency's change of heart means it was listening to patients.

Drugs used in ALS research

Courtesy of The ALS Association

Patients could have more trials to choose from, too, if recent moves by drug companies are any indication. In just the past year and a half, big-name companies like Merck & Co., Bristol Myers Squibb, GlaxoSmithKline and CRISPR Therapeutics have teamed up with smaller biotechs or research institutions in an effort to discover new treatments for ALS.

And on a broader scale, investors have demonstrated a renewed interest in battling brain diseases. Venture capitalists last year poured more than $2 billion into young biotechs focused on neuroscience, a 10-year high, according to data compiled by the trade group BIO. A bill passed last week by the U.S. House of Representatives, meanwhile, would provide $500 million in funding for ALS research via federal grants.

"The number of companies that are calling and having advisory boards is overwhelming," Cudkowicz noted.

While these investments are welcome, time will tell if they actually lead to treatments that improve the lives of ALS patients.

"Sometimes things take longer than one wants," said Roos from the University of Chicago.

"I've been surprised in my scientific career in the sense I thought, 'We're going to have a cure in Huntington's, it's around the block, we know what the mutation is,'" Roos added. "That was a while ago, and we're still working on it. Things are difficult."

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On the hunt for new ALS drugs, researchers see progress, and a long road ahead - BioPharma Dive

CHICAGO, Dec. 9, 2021 /PRNewswire/ -- In-depth analysis and data-driven insights on the impact of COVID-19 included in this Europe cell and gene therapy market report.

The Europe cell and gene therapy market is expected to grow at a CAGR of over 23% during the period 20202026.

Key Insights:

Key Offerings:

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Europe Cell and Gene Therapy Market Segmentation

Europe Cell and Gene Therapy Market by Product

Europe Cell and Gene Therapy Market by End-user

Europe Cell and Gene Therapy Market by Application

Europe Cell and Gene Therapy Market by Geography

The following factors are likely to contribute to the growth of the Europe cell and gene therapy market during the forecast period:

Europe Cell and Gene Therapy Market Vendor Landscape

Many regional vendors are also investing in the new therapy products in Europe. Many regional and local companies are posing a threat to global players due to their innovative and cost-effective products and technologies. This indicates that the market offers tremendous growth opportunities both for existing and future/emerging players. This is due to the presence of a large pool of target patient population with chronic diseases such as cancer, wound management, DFUs, CVDs, and other genetic diseases. The major players are focusing on strategic acquisitions, licensing, and collaboration agreements with emerging players to enter the cell and gene therapy market and to gain access to commercially launched products. They are also focusing on market expansion in existing and new markets to cater to the needs of a growing customer base, widen their product portfolios, and boost their production capabilities to gain traction from end-users.

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Europe Cell and Gene Therapy Market Size to Reach Revenues of USD 2.9 Billion by 2026 - Arizton - PRNewswire

In a new mouse study, scientists at the Icahn School of Medicine at Mount Sinai demonstrate how the activity of one gene, turned on in a newly discovered group of bone-bordering cells, may play an important role in shaping the skull.

The findings are published in the journalNature Communications in a paper titled, Single-cell analysis identifies a key role for Hhip in murine coronal suture development, and led by Greg Holmes, PhD, assistant professor of genetics and genomic sciences at Icahn Mount Sinai.

Craniofacial development depends on formation and maintenance of sutures between bones of the skull, the researchers wrote. In sutures, growth occurs at osteogenic fronts along the edge of each bone, and suture mesenchyme separates adjacent bones. Here, we perform single-cell RNA-seq analysis of the embryonic, wild type murine coronal suture to define its population structure.

Researchers focused on the cells of the coronal suture, a fibrous joint that connects the front and middle bone plates.

The Holmes lab worked with researchers in the labs of Bin Zhang, PhD, Harm van Bakel, PhD, and Ethylin Wang Jabs, MD, of Icahn Mount Sinai. Together they studied how the genetic activity in the cells of the coronal suture changes during early development.

Their findings suggested that a gene encoding a molecule called hedgehog interacting protein (HHIP) plays a unique role in coronal suture development. The researchers observed the gene was more active in a novel group of mesenchyme cells than it was in osteoblasts.

Using single-cell with bulk RNA-seq analysis we have better defined the distinctive composition of the coronal suture at the transcriptional and cell population levels, the researchers wrote.

Looking toward the future, the researchers hope that advanced single-cell genetic studies like this one will pave the way for a more thorough understanding of how a skull is shaped under healthy and disease conditions.

Our transcriptomic approach greatly expands opportunities for hypothesis-driven research in coronal and other suture development, concluded the researchers.

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Researchers Dig Up Genes and Cells Related to Skull Formation in Mice - Genetic Engineering & Biotechnology News

In the summer of 2015, a 7-year-old named Hassan was admitted to the burn unit of the Ruhr University Childrens Hospital in Bochum, Germany, with red, oozing wounds from head to toe.

It wasnt a fire that took his skin. It was a bacterial infection, resulting from an incurable genetic disorder. Called junctional epidermolysis bullosa, the condition deprives the skin of a protein needed to hold its layers together and leads to large, painful lesions. For kids, its often fatal. And indeed, Hassans doctors told his parents, Syrian refugees who had fled to Germany, the young boy was dying.

The doctors tried one last thing to save him. They cut out a tiny, unblistered patch of skin from the childs groin and sent it to the laboratory of Michele de Luca, an Italian stem cell expert who heads the Center for Regenerative Medicine at the University of Modena and Reggio Emilia. De Lucas team used a viral vector to ferry into Hassans skin cells a functional version of the gene LAMB3, which codes for laminin, the protein that anchors the surface of the skin to the layers below.

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Then the scientists grew the modified cells into sheets big enough for Ruhr University plastic surgeons Tobias Hirsch and Maximilian Kueckelhaus to graft onto Hassans raw, bedridden body, which they did over the course of that October, November, and the following January.

It worked better than the boys doctors could have imagined. In 2017, de Luca, Hirsch, Kueckelhaus, and their colleagues reported that Hassan was doing well, living like a normal boy in his lab-grown skin. At the time though, there was still a big question on all their minds: How long would it last? Would the transgenic stem cells keep replenishing the skin or would they sputter out? Or worse could they trigger a cascade of cancer-causing reactions?

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Today, the same team is out with an update. Five years and five months after the initial intervention, Hassan is still, for the most part, thriving in fully functional skin that has grown with the now-teenager. He is attending school, and playing sports with his friends and siblings, though he avoids swimming due to blistering in the areas that werent replaced by the lab-grown skin. One of his favorite activities is a pedal-powered go kart. There are no signs his modified stem cells have lost their steam, and no traces of tumors to be found.

The encouraging follow-up data has been instrumental in moving forward a larger clinical trial of the approach, offering hope to the 500,000 epidermolysis bullosa patients worldwide currently living without treatment options.

We were astonished by the speedy recovery, Kueckelhaus, now at University Hospital Muenster, told STAT via email. But experience from skin transplantation in other settings made him and his colleagues wary of the grafts failing as the months and years wore on. Thankfully, wrote Kueckelhaus, those fears never materialized. We are very happy to be able to prove that none of these complications appeared and the genetically modified skin remains 100% stable. The chances are good that he will be able to live a relatively normal life.

Over the last five years, Hassans team of doctors and researchers has put his new skin through a battery of tests checking it for sensitivity to hot and cold, water retention, pigmentation and hemoglobin levels, and if it had developed all the structures youd expect healthy skin to have, including sweat glands and hair follicles. Across the board, the engineered skin appeared normal, without the need for moisturizers or medical ointments. The only flaw they found was that Hassans skin wasnt as sensitive to fine touch, especially in his lower right leg. This mild neuropathy they attributed not to the graft itself, but to how that limb was prepared doctors used a more aggressive technique that might have damaged the nerves there.

The team also used molecular techniques to trace the cells theyd grown in the lab as they divided and expanded over Hassans body. They found that all the different kinds of cells composing the boys new skin were being generated by a small pool of self-renewing stem cells called holoclone-forming cells, carrying the Italian teams genetic correction.

This was quite an insight into the biology of the epidermis, said de Luca. Its an insight he expects will have huge consequences for any efforts to advance similar gene therapies for treating other diseases affecting the skin. You have to have the holoclone-forming cells in your culture if you want to have long-lasting epidermis, he said.

The approach pioneered by de Lucas team will soon be headed for its biggest clinical test yet, after nearly a decade of fits and starts. They expect to begin recruiting for a multi-center Phase 2/3 trial sometime next year.

De Luca first successfully treated a junctional EB patient in 2005. But then a change to European Union laws governing cell and gene therapies forced his team to stop work while they found ways to comply with the new rules. It took years of paperwork, building a manufacturing facility, and spinning out a small biotech company called Holostem to be ready to begin clinical research again. Hassan came along right as they were gearing up for a Phase 1 trial, but data from the boys case, which was granted approval under a compassionate use provision, convinced regulators that the cell grafts could move to larger, more pivotal trials, according to de Luca.

We didnt cure the disease, he told STAT. But the skin has been restored, basically permanently. We did not observe a single blister in five years. The wound healing is normal, the skin is robust. From this point of view, the quality of life is not even comparable to what it was before.

Continued here:
Syrian refugee is thriving five years after last-gasp gene therapy - STAT - STAT

Gideon Meyerowitz-Katz is an epidemiologist and writer based in Sydney, Australia. His work covers chronic disease, the pandemic response, and more recently, error detection in science. In this op-ed, he discusses issues with research that have become increasingly apparent during the pandemic.

There are no two ways about it: Science is flawed. Were not talking about the philosophical leanings of science or the origins of white coats and linoleum-floored laboratories, but about the nuts and bolts of the process by which we determine whether things are true or false.

In the decades before the pandemic, scientists spent endless hours wrestling with the painful fact that much of the knowledge base of science and medicine is reliant on research that is flawed, broken, or potentially never occurred at all.

Science has a gap between its mechanics and outputs. The mechanics of science are fine. The machines always get bigger and more efficient. New tools are always developed. Techniques become more sophisticated over time, and more knowledge is acquired.

The outputs of science are not. The culture of academia demands publication and warrants little retrospection about potential errors this means that mistakes are rarely corrected, and even outright fraud is often left undetected in academic literature.

And then along came a pandemic, and the gaps in science widened to an inescapable chasm. While biomedical research has had obvious and immediate success in COVID-19 mitigation, it has been accompanied by an enormous tidal wave of garbage, which instantly overwhelmed our garbage mitigation mechanisms.

From fraud to wasteful research to papers so error-filled that it is amazing that theyve been published, the pandemic has produced a tidal wave of woeful scientific output that has, nevertheless, had staggering consequences for peoples lives.

Take ivermectin. It is an amazingly successful antiparasitic medication that has treated literally billions of people in the time since it was invented, and it has almost eliminated some parasitic diseases from the world.

It has also been globally promoted as a cure for COVID-19 by a group of passionate fans. It is likely that more ivermectin has been taken to prevent or treat COVID-19 than any other single medication, except perhaps dexamethasone.

And yet, we do not know if ivermectin is actually useful in the treatment of COVID-19 at all.

A recent review from the Cochrane collaboration long considered the gold standard in medical research concluded that ivermectin should not be used for the treatment or prevention of COVID-19 outside of well-conducted clinical trials, which is a stark contrast to the hundreds of millions of doses still being taken for those exact reasons.

In early 2020, people were desperate for any kind of treatment for COVID-19. A melange of partial evidence emerged.

This included: a laboratory study showing that the drug acted as a strong antiviral in a petri dish, a study in a French nursing home where the residents took ivermectin to treat a scabies outbreak and seemed to subsequently enjoy higher survival rates, and preprint reporting that ivermectin reduced the mortality from COVID-19 by 90%.

All three were weak evidence in different ways. Single in vitro studies are very poorly predictive of eventual clinical outcomes, and the nursing home paper was an accidental and uncontrolled observational study what if the residents had never been exposed to SARS-CoV-2 in the first place?

The clinical study was entirely fabricated and later withdrawn from the preprint server, subsequent to great scandal.

The ivermectin story somehow got even worse from there. In late 2020, studies started popping up showing what can only be described as simply incredible results for the medication a 90% mortality benefit or a 100% reduction in cases when used as a prophylactic.

After nearly a year, myself and other data sleuths demonstrated that many of these studies probably never happened, but the damage was well and truly done long before the first fake paper was retracted.

A meta-analysis of ivermectin, which is usually considered the gold standard of research practices, found a huge benefit for the drug. However, the paper has not been corrected, even though the studies underlying its results were found to be likely fraudulent.

In any other discipline media, government, private enterprise such an analysis would be taken down with apologies immediately. Instead, the paper is allowed to stand as a testament to the general disinterest of the scientific world in correcting errors.

This story couldve been told very differently. Imagine a world where the initial laboratory paper came with a disclaimer, where the fraudulent preprint was looked on with skepticism immediately, and where the positive trials were assessed for fraud before they were even published.

Instead, at every stage, the process of highlighting concerns with data is ignored, with peer-review being the only flimsy barrier to publication for terrible research.

When we most needed effective fact-checking, our grand institutions of scientific research instead reviewed studies in a matter of days, if not hours, and posted fraudulent studies online to be shared across the world.

Its tempting to say that research into ivermectin is uniquely flawed, but thats clearly not true realistically, it would be remarkable if a broken system produced only one failure.

Trials of favapiravir, another repurposed COVID-19 medication, have recently been retracted due to data concerns.

There are now nearly a dozen studies looking at whether vitamin D has a benefit in COVID-19 that have been corrected or withdrawn entirely over the last 18 months.

The website Retraction Watch keeps a running tally of the pandemic-related studies that have been retracted. As of publication, the figure is 199 and growing every week.

Even worse, those are just the papers that people have looked into. Errors in science are rarely noticed because there is simply no reward for pointing out other peoples mistakes.

If we were to start looking at all of the useless, wasteful, terribly done research, we might expand that number to thousands, or even tens of thousands of papers.

There are published ecological studies of ivermectin where researchers compare entire countries drug use and COVID-19 mortality. These studies use mass drug administration protocols as their measure of the number of people who received ivermectin during the pandemic. This is despite those protocols mostly being disrupted or canceled early in 2020.

One study of vitamin D was retracted from the SSRN preprint server after it became clear that the authors had incorrectly labeled it as a randomized trial, though they had not randomized the participants at all. It has since been republished largely unchanged, with no mention of the previous retraction at all in the final paper.

None of this is to say that there is no good science. The vaccine trials alone are perhaps the most impressive scientific work that has ever been done, with efficacious immunizations developed, tested, and trialed in under 1 year.

The RECOVERY and SOLIDARITY clinical trials, which looked at repurposed drugs to treat COVID-19, have almost certainly saved millions of lives during the pandemic.

The problem is that large, well-conducted clinical trials are far from the norm. In a recent systematic review of hydroxychloroquine for COVID-19, the median number of people enrolled per arm in clinical trials was 59 one study looked at just two patients.

Without even carefully assessing these studies, we can say that most of them were probably a waste of time.

Indeed, if you look at the meta-analytic model from this review, virtually our entire knowledge of hydroxychloroquine for COVID-19 comes from just two studies, which recruited about 70% of all the people whom this drug had ever been tested on.

This is despite nearly 300 trials of the drug registered on clinicaltrials.gov, and the highest research spend of any single medication in the early pandemic.

If all of those tiny trials had been linked together, they may have achieved something useful, but instead, were left with two good studies and a smattering of largely pointless research.

All of this is, perhaps, the predictable outcome of a system that pushes publication above all else and punishes error-checking with disdain, scorn, and lawsuits. Publishing a terrible study can earn you praise and promotions; at worst, it might end up a line on your CV somewhere.

Checking studies for errors publicly earns you a steady payment of hate mail and death threats, and it nets you none of the citations, publications, and awards that academia regards as important.

Science has some enormous issues. Unless we can find a way to reward error-checking with actual money, we will continue to accept that a worrying proportion of our research output the studies that we use to make life-and-death decisions is either fake or incredibly problematic.

While it is tempting to think of this as a tedious problem among eggheads, that couldnt be further from the truth.

It is not unlikely that you or your family have personally been impacted by bad research during COVID-19 maybe you were given hydroxychloroquine during a hospital stay or took some metformin just in case. Perhaps you live in a place that reopened schools based on a study with mathematical errors or were told that masks constituted child abuse due to a paper that was later withdrawn.

Overall, there is a real impact of bad science in our everyday lives that the pandemic has thrown into stark relief.

Worse still, we know another pandemic is coming eventually. If we dont fix these issues now, the next time a new disease spreads through our world, we will be doomed to repeat the mistakes of COVID-19. And that is perhaps the most worrying thought of all.

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The perils of flawed research and the ivermectin debacle - Medical News Today

Basel, 13 December 2021 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced the launch of the AVENIO Edge System, a core component of Roches strategy to advance sequencing technologies. Built on best-in-class foundational capabilities to deliver a fully-automated, integrated sequencing solution.

The AVENIO Edge System is a pre-analytical platform for sequencing library preparation, target enrichment and quantification steps that deliver integrated, end-to-end control with reliable, consistent high-quality results.

Roche is committed to developing diagnostic solutions with the goal of providing the healthcare community with faster and more accurate medical information to predict risk and detect disease, said Thomas Schinecker, CEO Roche Diagnostics. We are pleased to offer next-generation sequencing laboratories and translational researchers the new automated AVENIO Edge System that aims to drastically reduce human error and help ensure fast, reliable and accurate results.

Next-generation sequencing samples are precious. Every step of sample preparation has the potential to impact results. The AVENIO Edge Systems high reproducibility and low error rate can support the goal of reducing the number of rejected samples which otherwise might have to be re-collected.

The new AVENIO Edge System offers ready-to-use components in addition to customisable workflow parameters, making it a scalable, cost-efficient solution for sequencing laboratories seeking high performance and agility. With a setup to initiation of 20 minutes, this walkaway system demonstrated more than a 96 percent lower error opportunity and an 84 percent reduction in hands-on time.

The AVENIO Edge System will be available at select locations worldwide with timelines that vary country by country.

About the AVENIO Edge SystemThe AVENIO Edge System is Class I, In Vitro Diagnostics (IVD), 510(k) exempt, in the US. It is Class A in the EU in accordance with EU Regulation 2017/746 (IVDR) of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices. At launch, the AVENIO Edge Instrument can be used for Research Use Only (RUO) workflows. Consumables are General Laboratory Use (GLU). Compatible reagents and workflows are Research Use Only (RUO). Not for use in diagnostic procedures.

The AVENIO Edge System simplifies next-generation sequencing (NGS) and elevates automated sample preparation with integrated workflows, reagents, barcoded consumables and connectivity to enable reliable, high-quality results and the freedom to do more.

The AVENIO Edge System delivered high sequencing performance and demonstrated high uniformity, specificity and reproducibility in our in-house technical validation and early customer studies. At an early evaluation study site, the AVENIO Edge System replaced 384 manual steps while preparing 24 DNA libraries in one run versus manually preparing 24 DNA libraries.

The AVENIO Edge System is a fully automated liquid handling technology consisting of all-in-one hardware and traceable solutions that guides the operators through the process, provides real-time tracking of samples and delivery of the results to the laboratory information system (LIS). It is intended for routine laboratory tasks and designed to support multiple library prep, target enrichment and quantification workflow steps with customizable parameters. The AVENIO Edge System offers a wide set of modular, barcoded and ready-to-run reagents in addition to customizable workflow parameters, making it a scalable, cost-efficient solution for sequencing laboratories seeking high performance and agility.

About Roche Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve peoples lives. The combined strengths of pharmaceuticals and diagnostics, as well as growing capabilities in the area of data-driven medical insights help Roche deliver truly personalised healthcare. Roche is working with partners across the healthcare sector to provide the best care for each person.

Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. In recent years, the company has invested in genomic profiling and real-world data partnerships and has become an industry-leading partner for medical insights.

Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. More than thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the thirteenth consecutive year, Roche has been recognised as one of the most sustainable companies in the pharmaceutical industry by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2020 employed more than 100,000 people worldwide. In 2020, Roche invested CHF 12.2 billion in R&D and posted sales of CHF 58.3 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit http://www.roche.com.

All trademarks used or mentioned in this release are protected by law.

Roche Group Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com

Roche Investor Relations

Investor Relations North America

Loren Kalm Phone: +1 650 225 3217 e-mail: kalm.loren@gene.com

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Roche launches the AVENIO Edge System to simplify and automate next-generation sequencing sample preparation, reduce human error and advance precision...

Dr. Koichi Kobayashi, adjunct professor at the College of Medicine and lead author of the paper.

Texas A&M College of Medicine

The immune system is a complex network of cells and proteins that is designed to fight off infection and disease, especially those likethe coronavirus, or SARS-CoV-2, that can cause numerous issues in the human body. But many individuals are still at risk of being infected with the coronavirus, letting it replicate in the body and further transmitting to other individuals.

The underlying mechanism of how SARS-CoV-2 escapes from the immune system has been poorly understood. However, researchers from theTexas A&M University College of Medicine and Hokkaido University have recently discovered a major mechanism that explains how SARS-CoV-2 can escape from the immune system and replicate in the human body.Their findings were recently publishedin the journalNature Communications.

We found that the SARS-CoV-2 virus carries a suppressive gene that acts to inhibit human gene in the immune system that is essential for destroying infected cells, said Dr. Koichi Kobayashi, adjunct professor at the College of Medicine and lead author of the paper.

Naturally, the cells in a humans immune system are able to control virus infection by destroying infected cells so that the virus cannot be replicated. The gene that is essential in executing this process, called NLRC5, regulates major histocompatibility complex (MHC) class I genes, which are genes that create a pathway that is vital in providing antiviral immunity.Kobayashi and his colleagues discovered this in 2012.

During infection, the amount and activity of NLRC5 gene become augmented in order to boost our ability of eradication of viruses, Kobayashi said. We discovered that the reason why SARS-CoV-2 can replicate so easily is because the virus carries a suppressive gene, called ORF6, that acts to inhibit the function of NLRC5, thus inhibiting the MHC class I pathway as well.

Kobayashi, who holds a joint appointment as a professor at Hokkaido University in Japan, collaborated withPaul de Figueiredo, associate professor in the Department of Microbial Pathogenesisand Immunology at the College of Medicine, on this paper.

Kobayashi and his teams discovery shed light on the mechanism to how SARS-CoV-2 can replicate in the human body and can potentially lead to the development of new therapeutics to prevent the coronavirus from escaping the immune system and replicating in the body.

Although the introduction of COVID-19 vaccines, such as the Pfizer and Moderna vaccines, can lower an individuals chance of contracting the virus, there is currently no permanent therapy that can entirely prevent a human from contracting SARS-CoV-2.

We hope that this new discovery will allow us to develop a new drug that can block this gene so our immune system will be able to fight off the coronavirus for good, de Figueiredo said.

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Why Does The COVID-19 Virus 'Escape' From Our Immune Systems? - Texas A&M University Today

In rivers and streams across the globe lives a tube-shaped carnivore. It paralyzes and captures prey with a crown of tentacles, then draws it in through its mouth (which also serves as its anus). This unsettling creature is a hydra, a freshwater-dwelling cnidarian no more than a half-inch long that eats mostly insect larvae and crustaceans. A hydras appearance and eating habits alone give it a sci-fi feel, but its ability to regenerate its body even its head from only a scrap of tissue or pile of cells raises it to another level.

Its one of these organisms thats thought to never die unless you try to kill it or, you know, starve it to death, Ali Mortazavi, a developmental biologist at the University of California, Irvine, said. A hydras regenerative abilities allow it to constantly replace bits of itself, so it doesnt succumb to things like old age or disease. Aside from the immortality perk, constant regeneration means a hydra doesnt have to sweat the small stuff, like losing body parts. Give it a few days and it will grow back anything.

Dr. Mortazavi and his colleagues have taken a big step in understanding how a hydra regenerates its head. Their research was published in Genome Biology and Evolution on Wednesday.

To investigate what makes this remarkable feat possible, the researchers looked at changes in gene expression whether a gene is copied from DNA into RNA throughout the course of hydra head regeneration. This control of gene expression is called epigenetic regulation. Hydras have a genome quite similar to that of species with little regenerative capacity, like humans, so its thought that epigenetic regulation plays a major role in making the hydras powers of regeneration possible.

The team discovered dynamic alterations in the regulation of stretches of DNA called enhancers. Enhancers increase the likelihood that a related gene will be copied from DNA into RNA. These enhancers were helping to ensure the expression of many genes, the team found, including those long known to be important for regeneration. Nobody knew hydras had these enhancer regions, said Dr. Mortazavi, who noted that the study put hydra in the same club as many other animals, including mammals.

The researchers then compared gene expression during head regeneration with gene expression during budding, a form of asexual reproduction where a hydra grows a polyp that is basically a copy of itself. That process requires growth of a second head, but the researchers found that a budding head forms in a very different way from a head regrowing after injury.

When I took a look at the trends in gene expression, the genes are kind of increasing slowly throughout the budding head development, but in regeneration, we noticed these sharp turns, said Aide Macias-Muoz, a developmental biologist at University of California, Santa Barbara, who was one of the study authors. A lot of genes are being turned on and then turned off and then turned back on. So even though the end result is the same, it looks like the trajectory is actually very different.

Dr. Mortazavi was also surprised to find that gene expression timing varied so much between head regeneration and budding. Clearly theres more than one way to make a head, he said.

The discovery of these enhancer regions and their role in hydra head regeneration also suggests that the evolution of enhancers predates the evolutionary divergence of cnidarians and bilaterians (animals with bilateral symmetry, like humans) around 750 million years ago. Erin Davies, a developmental biologist at the National Cancer Institute who studies regeneration but was not involved in the work, sees these findings as a reminder of the importance of studying ancient creatures like hydras.

They are really in a prime position for answering a lot of very fundamental questions in developmental biology, she said, including How did nervous systems evolve? How did you get bilateral symmetry?

This kind of work is also essential for the regenerative medicine field, Dr. Davies said, where a common goal is to restore diseased and injured tissues or even whole organs.

If you have a good handle on a paradigm in any animal system, she said, then you can start to think about how you might reverse engineer things in less regeneration-competent species, like mammals.

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Hydra DNA Reveals Theres More Than One Way to Regrow a Head - The New York Times

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Graphite Bio, Inc. (Nasdaq: GRPH), a clinical-stage, next-generation gene editing company focused on therapies that harness targeted gene integration to treat or cure serious diseases, today presented a trial-in-progress poster for the companys Phase 1/2 CEDAR trial for GPH101, an investigational therapy designed to directly correct the genetic mutation responsible for sickle cell disease (SCD). The poster is being presented at the 63rd American Association of Hematology (ASH) Annual Meeting and Exposition taking place virtually and at the Georgia World Congress Center in Atlanta from December 11-14. GPH101 was recently granted orphan drug designation from the U.S. Food and Drug Administration (FDA).

Sickle cell disease is a devastating illness for which a cure is desperately needed. By directly correcting the mutation that causes sickle cell disease, we believe that GPH101 has the potential to be a one-time cure that restores normal physiology and alleviates the life-threatening morbidities associated with the disease, said Josh Lehrer, M.Phil., M.D., chief executive officer at Graphite Bio. We are excited to share details about our CEDAR clinical trial for GPH101, in which we recently enrolled our first patient, and we look forward to continuing to advance GPH101s development in anticipation of sharing initial proof-of-concept data by the end of next year.

The trial-in-progress poster is being presented by Julie Kanter, M.D., associate professor of medicine and co-director of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham and an investigator in the CEDAR trial.

While allogeneic transplant is the only available cure for sickle cell disease, the procedure has several limitations, mainly lack of available donors and risk of graft-versus-host disease. Other available therapies are considered palliative as they do not specifically reverse end-organ damage. This type of gene therapy reducing sickle hemoglobin production at the same time as restoring adult hemoglobin expression through direct gene correction would be an ideal curative option in sickle cell disease, said Dr. Kanter. As an investigator in the CEDAR trial, I look forward to assessing GPH101s potential to be a curative option for patients.

The CEDAR trial is an open-label, single-dose, multi-site clinical trial evaluating GPH101 in approximately 15 participants with severe SCD. GPH101 is an autologous hematopoietic stem cell therapy developed using Graphite Bios next-generation targeted gene integration platform, which uses high-fidelity Cas9 and a non-integrating DNA template to precisely find the genetic mutation in the beta-globin gene and directly correct the mutation through the cells natural homology directed repair (HDR) cellular pathway. GPH101 has demonstrated in preclinical studies the potential to permanently reduce sickle hemoglobin (HbS) production and restore adult hemoglobin (HbA) expression. The trial-in-progress poster provides an overview of the GPH101 treatment process, which includes local stem cell selection and cryopreservation before shipment to a central manufacturing facility.

The primary objective of the CEDAR trial is to evaluate the safety of GPH101. Secondary objectives include pharmacodynamic and efficacy read-outs such as levels of HbA, HbS and total hemoglobin and effect on clinical manifestations such as vaso-occlusive crisis and acute chest syndrome. Additionally, characterization of gene correction rates, changes in the function of organs like the brain, heart, kidney and liver, and assessment of red blood cell health and function will be explored.

The poster is now available on the ASH website and on the Graphite Bio website here. Details are as follows:

Poster Session: 801. Gene Therapies: Poster IPoster #1864: CEDAR Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCDPresenting Author: Julie Kanter, M.D., University of Alabama at BirminghamDate/Time: Saturday, December 11, 2021, 5:30-7:30 p.m. ETLocation: Hall B5 (Georgia World Congress Center)

About Sickle Cell Disease (SCD)

SCD is a serious, life-threatening inherited blood disorder that affects approximately 100,000 people in the United States and millions of people around the world, making it the most prevalent monogenic disease worldwide. SCD is caused by a single mutation in the beta-globin gene that leads red blood cells to become misshapen, resulting in anemia, blood flow blockages, intense pain, increased risk of stroke and organ damage, and reduced life expectancy of approximately 20-30 years. Despite advancements in treatment and care, progressive organ damage continues to cause early mortality and severe morbidity, highlighting the need for curative therapies.

About GPH101

GPH101 is an investigational next-generation gene-edited autologous hematopoietic stem cell (HSC) therapy designed to directly correct the genetic mutation that causes sickle cell disease (SCD). GPH101 is the first investigational therapy to use a highly differentiated gene correction approach that seeks to efficiently and precisely correct the mutation in the beta-globin gene to decrease sickle hemoglobin (HbS) production and restore normal adult hemoglobin (HbA) expression, thereby potentially curing SCD.

Graphite Bio is evaluating GPH101 in the CEDAR trial, an open-label, multi-center Phase 1/2 clinical trial designed to assess the safety, engraftment success, gene correction rates, total hemoglobin, as well as other clinical and exploratory endpoints and pharmacodynamics in patients with severe SCD.

About Graphite Bio

Graphite Bio is a clinical-stage, next-generation gene editing company harnessing high efficiency targeted gene integration to develop a new class of therapies to potentially cure a wide range of serious and life-threatening diseases. Graphite Bio is pioneering a precision gene editing approach that could enable a variety of applications to transform human health through its potential to achieve one of medicines most elusive goals: to precisely find & replace any gene in the genome. Graphite Bios platform allows it to precisely correct mutations, replace entire disease-causing genes with normal genes or insert new genes into predetermined, safe locations. The company was co-founded by academic pioneers in the fields of gene editing and gene therapy, including Maria Grazia Roncarolo, M.D., and Matthew Porteus, M.D., Ph.D.

Learn more about Graphite Bio by visiting http://www.graphitebio.com and following the company on LinkedIn.

Forward-Looking Statements

Statements we make in this press release may include statements which are not historical facts and are considered forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act). These statements may be identified by words such as aims, anticipates, believes, could, estimates, expects, forecasts, goal, intends, may, plans, possible, potential, seeks, will, and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this press release that are not statements of historical fact, including statements regarding the clinical and therapeutic potential of our gene editing platform and our product candidates, and the timing for treating the first patient in the Phase 1/2 CEDAR trial of GPH101 and the availability of initial proof-of-concept data, may be deemed to be forward-looking statements. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions.

Any forward-looking statements in this press release are based on Graphite Bios current expectations, estimates and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements, including the risk that we may encounter delays in patient enrollment and in the initiation, conduct and completion of our planned clinical trials. These risks concerning Graphite Bios programs and operations are described in additional detail in its periodic filings with the U.S. Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report. Graphite Bio is providing the information in this press release as of this date and explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

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Graphite Bio Presents Overview of Phase 1/2 CEDAR Trial Evaluating Investigational Gene Editing Therapy GPH101 in Sickle Cell Disease at 63rd ASH...

Introduction

Despite race being a socio-political system of categorization without a biologic basis, race has historically and continues to play a role in medical teaching and clinical decision making within health care. Race permeates clinical decision making and treatment in multiple ways, including: (1) through providers attitudes and implicit biases, (2) disease stereotyping and clinical nomenclature, and (3) clinical algorithms, tools, and treatment guidelines. While some diseases have higher prevalence among individuals with certain genetic ancestry, genetic ancestry is poorly correlated with commonly used social racial categories. The use of race to inform clinical diagnoses and decision making may reinforce disproven notions of race as a biological construct and contribute to ongoing racial disparities in health and health care. This brief provides an overview of the role of race in clinical care and discusses the implications for health and health care disparities and efforts to advance health equity.

Despite there being no biologic basis to race, the medical and scientific community have used race to explain differences in disease prevalence and outcomes. The Western concept of race arose as a system of hierarchical human categorization to support European colonialization, oppression, and discrimination of non-European groups. Within U.S. medical curricula, the concept of race led to theories of biological inferiority of people of color and White supremacy, which fueled an array of atrocities in medicine including forced sterilization efforts targeting Black and Native American women, the use of Henrietta Lacks cells for scientific research without consent or acknowledgement, and the infamous Tuskegee Syphilis study, among others. Although research has since disproven the existence of universal biologic differences by race, some recent scientific studies continue to suggest that genetic differences between racial groups may explain differences in health outcomes. For example, an article published in 2020 originally suggested that unknown or unmeasured genetic or biological factors may be contributing to increased severity of COVID-19 illness among Black people, although the article was later revised to clarify that the difference is most likely explained by societal factors. Recent research further suggests that measures of demographic characteristics and socioeconomic position may be more effective than genetic characteristics in explaining disparities in cardiovascular disease between Black and White adults.

There have been growing calls against using race as a factor to explain health differences without acknowledging the role of racism. Contemporary science has demonstrated that race is a social category with no basis in biology. Race is a poor proxy for genetic ancestry and large genetic studies have demonstrated more variation within defined racial groups (intra-racially) than there are between different racial groups (inter-racially). Within the medical and scientific community, there have been longstanding critiques of using racial classifications in diagnosis and treatment of disease. Recently, there have been calls for research studies and guidance in the medical community to name and examine the role of racism versus race as a key driver of health inequities to avoid perpetuating disproven understandings of biologic differences by race.

Although race is not tied to biologic differences, understanding differences in health and health care by race and ethnicity remains important for identifying and addressing disparities in health and health care that stem from racism and social and economic inequities. Complete and accurate race and ethnicity data is key for identifying disparities and taking action to address them. However, there are longstanding gaps and limitations in racial and ethnic data within health care. In addition to deficiencies in survey and administrative data, many institutions report gaps in electronic health record (EHR) data on race, with substantial misclassification of self-reported race and preferred language. The largest discrepancies between EHR demographic data and self-reported data are among individuals who identify as Hispanic.

A significant and longstanding body of research suggests that provider and institutional bias and discrimination are drivers of racial disparities in health, contributing to racial differences in diagnosis, prognosis, and treatment decisions. Prior work suggests that providers historically were more likely to perceive individual patient factors rather than provider or health system influences as causes for health disparities. For example, studies have found that providers view Black patients as less cooperative with medical treatment and that providers associate Hispanic patients with noncompliance and risky behavior. A 2015 systematic review of published studies showed that most health care providers appear to have implicit bias in terms of positive attitudes towards White people and negative attitudes towards people of color. While some studies have found no link between bias and provider treatment behaviors, others have demonstrated that provider bias correlates with poorer patient-provider interactions and is associated with disparities in pain management and empathy. Providers who endorse false beliefs about biological differences by race report lower pain for Black patients compared to White patients, which has been linked to systematic undertreatment for pain of Black patients. Similarly, compared to White patients in emergency departments, Hispanic and Asian patients are less likely to receive pain assessments and appropriate pain medication.

Research also shows that patients report being treated unfairly because of their race/ethnicity while accessing health care. For example, a 2020 KFF/the Undefeated survey of adults found that Black and Hispanic adults are more likely than White adults to report they were personally treated unfairly because of their race and ethnicity while getting health care in the past year. Black adults also are more likely than White adults to report negative experiences with health care providers, including feeling a provider did not believe they were telling the truth, being refused a test or treatment they thought they needed, and being refused pain medication. In addition, Black and Hispanic adults are more likely than their White counterparts to say it is difficult to find a doctor who shares their background and experiences and one who treats them with dignity and respect.

Some medical training approaches and materials use imprecise labels conflating race and ancestry, portray diseases through racial stereotypes, and rely on racial heuristics (i.e., mental shortcuts or associations) for teaching clinical diagnosis. Preclinical lectures and clinical vignettes for teaching use nonspecific labels (e.g., Black instead of Nigerian/Haitian and Asian instead of Chinese/Vietnamese/Pakistani) and may misuse race as a surrogate for genetic ancestry. In some cases, they inappropriately use race as a proxy for differences in socioeconomic status, health behaviors (such as diet), or other factors that may influence access to health care or risk of disease. In addition, lecture materials commonly present racial differences in disease burden without historical or social context, which may contribute to students connecting diseases with certain racial groups and ascribing differences to genetic predisposition. For example, preclinical lecturers often teach that recurrent lung infections in White individuals are indicative of cystic fibrosis, which may result in missed diagnoses of cystic fibrosis among Black patients. The hereditary condition glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can cause severe anemia, affects individuals of all racial and ethnic backgrounds, with highest prevalence in Africa, the Middle East, and certain parts of the Mediterranean and Asia. However, lecturers and board materials teach students to have higher clinical suspicion for diagnosis of this deficiency in Black patients. In nearly all medical learning resources, Lyme disease is depicted predominantly on White skin and is often diagnosed much later when the disease has progressed to arthritic stages among Black patients. Other examples of connecting race to disease exist in medical textbooks. For example, Black skin is more commonly used to depict sexually transmitted diseases. A recently recalled textbook for nursing students published in 2017 suggested that there were racial differences in how patients experience and respond to pain. The text described Black patients as reporting higher pain intensity than other cultures, Hispanic patients as having wide expression of pain (some are stoic and some are expressive), Asian patients as valuing stoicism as a response to pain, and Native American patients as being less expressive both verbally and nonverbally. Beyond teaching materials, medical board examinations often test students based on race-based guidelines and heuristics.

Some disease names use racial or geographic terms that link diseases to certain groups or communities. For example, congenital dermal melanocytosis was formerly referred to as Mongolian spot. Similarly, Down syndrome was first described as Mongolism by a 19th century British physician who believed that patients with the genetic disorder resembled individuals of Mongolian descent. As another example, vancomycin infusion reaction was formerly called Red Man syndrome, evoking racist connotations against Indigenous American people. Clinical nomenclature has shifted towards more descriptive language, although in some cases, disease naming is tied to place of discovery. Disease names incorporating geography may still perpetuate racist-xenophobic sentiment. In 2015, the World Health Organization noted associating disease names with geography may result in backlash towards members of particular ethnic communities. This experience was seen in the recent use of the label China virus for the COVID-19 virus, which has been associated with an increase in public anti-Asian sentiment and Asian hate crimes, as well as an increase in depressive symptoms among individuals identifying with multiple Asian subgroups. Moreover, a recent KFF survey of Asian community health center patients found that one in three felt more discrimination based on their racial/ethnic background since the COVID-19 pandemic began in the U.S. and 15% said they had been accused of spreading or causing COVID-19.

While some diseases have higher prevalence among individuals with certain genetic ancestry, the practice of using race within clinical calculators and screening metrics may contribute to health disparities. Today, clinical calculators across multiple specialties assign differential risk for certain diseases or conditions based on race. Prior work has identified a range of examples of clinical calculators that use race (Appendix Table 1). One of the most well-known examples of this practice is within nephrology, where separate measures of kidney function (i.e., estimated glomerular filtration rates, eGFRs) are applied to Black patients compared to non-Black patients. However, similar examples are seen across medicine. For example, a common calculator used to predict success of vaginal birth after Cesarian (VBAC) section had a correction factor for both Black and Hispanic race that decreases the success of VBAC for Black and Hispanic patients by 67% and 68% respectively. This tool may bias providers into disproportionately counseling these patients towards undergoing a Cesarian section. Similarly, pulmonary function tests have a race correction factor, East Asian race is considered a major risk factor for neonatal jaundice, and a different Body Mass Index threshold is used to recommend diabetes testing among asymptomatic Asian and Pacific Islander patients. Given that race is an extremely inconsistent proxy for genetic ancestry, this use of race within clinical calculators may lead to both undertreatment and overtreatment of racialized individuals, and delays in diagnosis and clinical care.

Research shows that some clinical tools may be less effective or misused for certain populations. For example, pulse oximeters have low accuracy in measuring oxygen saturation in darker skin and are three times as likely to miss low oxygen levels in Black patients compared to White patients. Such discrepancies may contribute to delayed intervention and increased mortality for Black patients with COVID-19. In pediatrics, findings suggest that jaundice measurement tools (i.e., bilirubinometer for measurement of transcutaneous bilirubin) have varied reliability based on skin color, with underestimates of risk in lighter skin and overestimates in darker skin tone. Overestimates of bilirubin using transcutaneous measurements may result in unnecessary follow-up blood work (an invasive process for infants), increases in follow-up visits and commute to clinics, and increased infant caregiver distress. In lower resource settings where serum bilirubin measurement is unavailable and transcutaneous bilirubinometry continues to be the primary method for infant monitoring, underestimates of risk may result in delayed intervention for the life-threatening condition neonatal kernicterus, while overestimates of risk for hyperbilirubinemia may result in unnecessary prolonged hospital stays and treatment. In dermatology, the dearth of images depicting lesions on dark skin in medical and dermatologic textbooks and lack of representation of providers with darker skin in the specialty may result in reduced clinician ability to identify life-threatening dermatological presentation on people of color (e.g., sepsis, cellulitis, or severe drug reactions to medications). Skin cancer, while less common in Black and Hispanic patients, is often diagnosed later with subsequently lower survival rates. Fitzpatrick skin type (FS) is the most commonly used skin type classification system in dermatology. It was originally designed to describe the likelihood of skin to burn from UV light exposure but is misused by many providers to describe skin color as a proxy for race.

Preventing against racial bias will be important as use of artificial intelligence and algorithms to guide clinical decision-making continue to expand. The health care system is increasingly using artificial intelligence and algorithms to guide health decisions. Research has shown that these algorithms may have racial bias because the underlying data on which they are trained may be biased and/or may not reflect a diverse population. For example, one study found that an algorithm designed to identify patients with complex health needs resulted in Black patients being assigned the same level of risk as White patients despite being sicker. This unintended bias occurred because of underlying racial bias in how the algorithm was designed, implemented, and interpretedthe algorithm used health care costs to predict health care needs, but Black patients have lower health care costs in part because they face greater barriers to accessing health care. Other examples have found that skewed dermatological datasets result in less accurate models and decreased ability to diagnose skin conditions among darker skin tones. However, research also suggests that carefully designed algorithms can mitigate bias and help to reduce disparities in care.

Race also factors into some medication prescribing decisions, but the use of race is often based on limited evidence from small studies and may result in inappropriate dosing and treatment. In 2005, the U.S. Food and Drug Administrative approved the drug BiDil as a race-specific drug to treat heart failure among African Americans. It was subsequently critiqued for misguided marketing due to using race as a proxy for genotype, which was not evaluated in the study from which conclusions were drawn, although it remains approved as a race-based drug today. There are additional examples of race-based prescribing guidelines. For example, hydrochlorothiazide is recommended as first line hypertension therapy for Black patients based on Joint National Committee (JNC) Hypertension guidelines, as opposed to ACE inhibitor therapy for all other groups due to presumed inefficacy of these agents among Black patients. Eltrombopag, a drug used to treat thrombocytopenia, has a lower recommended starting dose for East Asian patients compared to all other patients. Similarly, the Food and Drug Administration recommends a lower starting dose for Crestor (a statin, used to lower lipid levels) for Asian patients based on a gene that confers metabolic variability, despite the understanding that this gene may be prevalent among any population. There has been ongoing discussion around race-based dosing and the utility of race-based genetic screening for drugs such as warfarin (commonly used for anticoagulation therapy) and abacavir for HIV treatment. Medical community viewpoints on race-based prescribing vary. For example, a study of American cardiologists found that many providers believe race-based drug labels in treatment of heart failure may help prescribe effective medications sooner, while others expressed concerns that considering race could potentially harm patients by resulting in some patients not receiving the drug.

The use of race in the emerging field of pharmacogenomics has come under increasing scrutiny. Pharmacogenomics explores the relationships between genes and drug effects and is viewed as a way to potentially personalize medical therapy. Pharmacogenomics research often uses race to guide decisions about genetic screening prior to using certain drugs to prevent against adverse drug events based on the assumption that certain racial categories may have high or low prevalence of certain genes. Proponents argue that race-based targeting in the field of pharmacogenetics is useful to propel personalized medicine for patient care at the individual level. However, critiques of race-specific therapies express concerns around attempting to address health disparities through commercial drug development versus examining upstream structural factors that may explain differences in treatment response. Moreover, as noted, genetic variation within certain racial/ethnic groups can exceed variation across racial/ethnic categories, suggesting limited utility of this approach and that it may run counter to personalized medicine by treating people based on groupings that have limited genetic association. Current work has limited representation from communities of color, resulting in less extrapolatable, premature recommendations for clinical screening for diverse communities. In addition, inequities across the continuum of drug development and clinical trial participation and evaluation may exacerbate existing disparities in medication access for communities of color, including decreased access to novel, high-cost medications and lower-cost generic therapies.

The use of race within clinical decision making and treatment may reinforce disproven concepts of racial biology and exacerbate health inequities. Race continues to permeate medical teaching and clinical decision making and treatment in multiple ways, including: (1) through providers attitudes and implicit biases, (2) disease stereotyping and nomenclature, and (3) clinical algorithms and treatment guidelines. Racial bias among providers may contribute to poorer quality of care and worse health outcomes. Racial stereotyping of disease and use of race in clinical algorithms and treatment guidelines may lead to errors in clinical diagnosis and management (overtreatment or undertreatment and other delays in clinical care), which may perpetuate and potentially worsen health disparities. Moreover, continued use of race as a biological concept limits examination and understanding of social drivers of health inequities, including racism, and contributes to ongoing racial bias and discrimination among providers.

There have been growing efforts within the medical community to re-evaluate and revise practices around the use of race within clinical care and efforts to move towards race-conscious (as opposed to race-based) medicine. In 2020, the American Medical Association (AMA) adopted new policies to recognize race as a social construct and, as part of these policies, encourages medical education programs to recognize the harmful effects of using race as a proxy for biology in medical education through curriculum changes that explain how racism results in health disparities. In September 2020, the House Ways and Means Committee announced a Request for Information around the misuse of race in clinical care. The Agency for Healthcare Research and Quality (AHRQ) similarly announced in March 2021 a Request for Information on the use of clinical algorithms that have the potential to introduce racial/ethnic bias into healthcare delivery. A subsequent Ways and Means final report released in October 2021 found that professional societies suggest more research (with evaluation of unintended consequences of removing race correctors) is needed before decisions can be made, as a growing number of institutions have removed race from clinical calculators. For example, in the past year-and-a-half, Mass General Brigham hospital, the University of Washington, Vanderbilt University, and NYC Health and Hospitals have all removed race corrections from kidney function estimates. The UC Davis School of Medicine also eliminated race-based reference ranges from renal function estimates, followed shortly by UCSFs release of a new approach to estimate kidney function without race. Moreover, both the American Society of Nephrology and National Kidney Foundation have outlined approaches to diagnose kidney disease without race. In November 2021, the New York City Department of Health launched a Coalition to End Racism in Clinical Algorithms, pledging to end race adjustment in at least one clinical algorithm and to create plans for evaluation of racial inequities and patient engagement. Additionally, some commonly used medical calculators have made use of race correction factors optional, while others have removed them entirely (see Appendix Table 1). In contrast, other institutions have held off on making changes to clinical calculators or guidelines, noting potential downstream implications for other aspects of clinical care and management.

Looking ahead, continued education of health care providers and students to eliminate beliefs of biologic differences by race, improving pedagogy around distinctions between race and genetic ancestry, and reducing racial bias and discrimination will be important, as will efforts to increase the diversity of our health care workforce. Moreover, continued careful evaluation of how race factors into clinical decision-making through clinical guidelines, tools, and algorithms will be important for mitigating biased decision making, particularly as the use of artificial intelligence and machine-driven algorithms to guide clinical decisions expand.

Michelle Tong is a fourth year medical student at the University of California, San Francisco, completing a health policy fellowship with the Kaiser Family Foundation. Samantha Artiga serves as Vice President and Director of the Racial Equity and Health Policy Program at KFF. The authors thank Dr. Louis H. Hart III and Dr. Monica Hahn for their expertise and subject matter review. Dr. Louis Hart is the Medical Director of Health Equity for Yale New Haven Health System and Assistant Professor of Pediatric Hospital Medicine at the Yale School of Medicine. Dr. Monica Hahn is the Co-Founder of the Institute for Healing and Justice in Medicine and Associate Clinical Professor at UCSF in the Department of Family and Community Medicine.

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Use of Race in Clinical Diagnosis and Decision Making: Overview and Implications - Kaiser Family Foundation