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The brain is a remarkably complex and adaptable organ. However, adaptability decreases with age: as new connections between nerve cells in the brain form less easily, the brain’s plasticity decreases. If there is an injury to the central nervous system such as after a stroke, the brain needs to compensate for this by reorganising itself. To do this, a dense network of molecules between the nerve cells — known as the extracellular matrix — must loosen. This is the job of a wide variety of enzymes that ultimately regulate how plastic or how stable the brain is. Researchers at the University of Göttingen studied what happens when certain enzymes are blocked in mice. Depending on whether the brain is healthy or diseased, the inhibition had opposite effects. The results were published in the Journal of Neuroscience.
Learning and recovery from injuries depend on the plasticity of neuronal connections. Important for this are the macromolecules of the extracellular matrix, which are located between the nerve cells. When we grow up, the “stability” of this extracellular matrix increases, providing a scaffold for stabilising existing connections between the nerve cells, and consolidating what we have learned. If we experience something new, the extracellular matrix must be loosened to allow new connections to form. This relationship between stability and plasticity in the brain is regulated in the matrix with the help of enzymes such as matrix metalloproteinases (MMPs), which can “digest” the extracellular matrix and thus “loosen” it. A team from the University of Göttingen has now been able to show in a new study that blocking the matrix metalloproteinases MMP2 and MMP9 can have opposing effects depending on whether the brain is sick or healthy.
To measure neuronal plasticity, the scientists let adult mice see only through one eye for several days and recorded the resulting activity changes in the animals’ visual cortex. In a first experiment, they examined the adaptability of the visual cortex of healthy mice in which the enzymes MMP2 and MMP9 were blocked (with SB3CT). As a result, neuronal plasticity was also blocked. In a second experiment, the team researched mice immediately after a stroke. It was already known that a stroke leads to a strong short-term increase in MMPs. In this case, the targeted, short-term inhibition of the enzymes MMP2 and MMP9 produced the opposite effect: the plasticity that had been greatly reduced by the stroke was restored, so blocking the enzymes MMP2 and MMP9 had a clear therapeutic effect.
“What made the design of our study different from many previous studies, is that the ‘matrix-degrading’ enzymes were blocked only after the experimental stroke, which simulates treatment,” says Professor Siegrid Löwel from the Department of Systems Neuroscience at Göttingen University. “We also show that the MMPs in the brain have to be very well monitored and precisely adjusted. Too low a level in the healthy brain prevents neuronal plasticity and too high a level — as after a stroke — also blocks neuronal plasticity.”
The study is part of the DFG Collaborative Research Centre 889 “Cellular Mechanisms of Sensory Processing.”
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Materials provided by University of Göttingen. Note: Content may be edited for style and length.

A new study has shown that stress alone can drive women to excessive drinking.
Men who experienced the same stress only drank to excess when they had already started consuming alcohol.
Though rates of alcohol misuse are higher in men than women, women are catching up. Women also have a greater risk than men of developing alcohol-related problems.
Participants consumed alcoholic beverages in a simulated bar while experiencing stressful and non-stressful situations. Stress led women, but not men, to drink more than intended, a finding that demonstrates the importance of studying sex differences in alcohol consumption. The study was published in Psychology of Addictive Behaviors.
“Some people can intend to have one or two alcoholic beverages and stop drinking, but other people just keep going. This impaired control over drinking is one of the earliest indicators of alcohol use disorders, and we know stress contributes to both impaired control over drinking and dysregulated drinking. The role of stress in impaired control over drinking is understudied, especially in women,” said Julie Patock-Peckham, assistant research professor at ASU and lead author on the study.
The study took place in a research laboratory designed to simulate a bar, complete with a bartender, bar stools and lively conversations. The participants included 105 women and 105 men. They were randomized into different groups, with some either experiencing a stressful situation and others a non-stressful situation. Next, half the participants received an alcoholic drink that was equivalent to three cocktails, and the other half received three non-alcoholic drinks. After that, all participants had unrestricted access to alcoholic drinks from the bar for 90 minutes.
“We know that both genes and the environment play a role in problematic drinking. We can’t do anything about the genes, but we can intervene with the environment. Stress and impaired control over drinking are tightly connected, and because stress is something we can manipulate, we tested whether stressors cause dysregulated drinking,” said Patock-Peckham, who leads the Social Addictions Impulse Lab at ASU.
The experimental set-up let the research team determine whether stress, the initial drink or the combination of the two caused how much alcohol the participants consumed. The team measured alcohol consumption in total number of drinks consumed and by using breath blood alcohol content (BAC).
Exposure to stress led to heavier drinking in all participants. Men who received a first drink with alcohol in it and experienced stress drank more than men who received the placebo.
Whether the first drink was alcoholic or not did not matter for women: Experiencing stress led to heavy drinking.
“That women just needed the stress but men needed the push of already having alcohol on board shows how important this type of research is,” Patock-Peckham said. “The outcomes from alcohol use are not the same for men and women, and we cannot keep using models that were developed in men to help women.”
The study was funded by the National Institute on Alcohol Abuse and Alcoholism and Burton Family Foundation. In addition to Patock-Peckham, the research team consisted of William Corbin, professor of psychology at ASU; Heather Smyth and Arian Rouf, graduate students at ASU; Jessica Canning of the University of Washington; and J. Williams of RTI International.
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Materials provided by Arizona State University. Original written by Kimberlee D’Ardenne. Note: Content may be edited for style and length.

GPs have stepped up plans to roll out Covid-19 booster jabs. Dr Silvana McCaffrey told Adam Fleming she’s cancelled her Christmas holiday to organise the vaccination programme for patients in Herefordshire.You can hear the full interview on Newscast on BBC Sounds.

New research published in the Proceedings of the National Academy of Sciences shows that examining genetic mutations in individuals with severe schizophrenia can improve the ability to detect disease-associated rare genetic variants. The research was conducted at Columbia University Irving Medical Center and led by Dr. Anthony Zoghbi, now assistant professor of molecular and human genetics and psychiatry and behavioral sciences at Baylor College of Medicine.
Schizophrenia patients have a diverse spectrum of observable symptoms. For this study, the researchers focused on the extreme end of that spectrum — a group of 112 patients with severe, extremely treatment-resistant schizophrenia who have required long-term hospitalization in New York State inpatient facilities.
“The hypothesis is that these patients might have a greater prevalence of disease-causing mutations because they have such a severe form of the illness, and that’s what we ended up seeing,” said Zoghbi, corresponding author of the study and Beth K. And Stuart C. Yudofsky Scholar at Baylor.
Zoghbi and his team examined mutations across a set of “intolerant” genes, which are infrequently mutated in the healthy, general population. They conducted genetic sequencing and examined the burden of rare, damaging variants impacting gene function in three groups: people with severe schizophrenia, people with typical schizophrenia and a control group of healthy individuals.
More than 48% of individuals with extremely treatment-resistant schizophrenia carried at least one of the rare, damaging variants, versus approximately 30% of those with typical schizophrenia and 25% of the control group. The severe schizophrenia group also had a higher variant burden in genes previously associated with schizophrenia than the group with typical schizophrenia.
“We think that this method of study could be a new paradigm for trying to understand how to enrich a genetic signal in a psychiatric disorder by focusing on individuals who are very severely affected by the disease,” said Zoghbi, who also is chief of psychiatric genetics in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor.
Identifying rare variant risk factors in individuals with severe schizophrenia could lead to better understanding of prognosis and treatment resistance and to more opportunities for genetic counseling for families impacted by this disease. Zoghbi says this study also may lay the groundwork for future research on therapeutics to target genetic mutations associated with schizophrenia.
“We hope that this research brings light and attention to these patients who are often left out of cutting-edge research because of the severity of their condition,” Zoghbi said.
Other authors of this work include: Dr. Ryan S. Dhindsa, Dr. Terry E. Goldberg, Aydan Mehralizade, Dr. Joshua E. Motelow, Dr. Xinchen Wang, Dr. Anna Alkelai, Dr. Matthew B. Harms, Dr. Jeffrey A. Lieberman, Dr. Sander Markx and Dr. David B. Goldstein. They are affiliated with the following institutions: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Columbia University Irving Medical Center, New York State Psychiatric Institute and Waypoint Bio.
The study is funded in part by the Chapman Perelman Foundation and the National Institute of Mental Health.
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Materials provided by Baylor College of Medicine. Original written by Molly Chiu. Note: Content may be edited for style and length.

Decreasing vehicle emissions since 2008 have reduced by thousands the number of deaths attributable to air pollution, yielding billions of dollars in benefits to society, according to a new study led by researchers at Harvard T.H. Chan School of Public Health.
The study also found that although the public health burden of large trucks has been greatly reduced, passenger light-duty vehicles, such as SUVs and pickup trucks, continue to contribute a significant amount of air pollution in major metropolitan areas.
The study will be published online on December 13, 2021 in the journal PNAS.
“Recent reductions in vehicle emissions have yielded major health benefits, even though only small progress has been made on reducing their climate impact,” said first author Ernani Choma, a research fellow in Harvard Chan School’s Department of Environmental Health. “Our results indicate that to achieve further public health and climate gains, even more stringent policies will be required.”
Although the health and climate burden of vehicle emissions in the U.S. has been widely studied, the benefits of recent reductions in vehicle emissions — spurred by federal air pollution regulations and technological innovations by car manufacturers — were not well known. The new study provides estimates that compare the actual health and climate impact of reduced vehicle emissions with what that impact would have been had emissions not been reduced. Researchers calculated the so-called “social benefits” attributable to decreasing emissions — in this case, the monetary value to society of the reduction in deaths attributable to air pollution and climate impacts avoided.
Using recent national emissions data, the researchers modeled four scenarios for emissions in 2017: actual emissions as well as three alternative scenarios in which county-level emissions were the same as they were in 2014, 2011, and 2008. Each of the scenarios factored in the types of vehicles being driven and how many miles they traveled, detailed data about air pollution levels across the U.S., mortality rates, and trends in demographics — including an aging population that is becoming more susceptible to air pollution over time.
The researchers estimated that reductions in emissions yielded $270 billion in social benefits in the U.S. in 2017 — mostly due to the estimated value of reduced mortality risk from fine particulate matter (PM2.5) air pollution — and, to a lesser degree, to reduced “social costs” from greenhouse gas emissions, which are calculated from a range of factors such as human health impacts, changes in agricultural productivity, natural disasters, risk of conflict, and more.
The researchers also estimated that deaths attributable to air pollution due to vehicle emissions dropped from 27,700 in 2008 to 19,800 in 2017. The decrease in deaths was not as large as researchers expected, because many factors offset the progress in reducing emissions, such as a larger and aging population, larger vehicles replacing smaller ones, and more miles traveled per vehicle. On the other hand, the authors noted, if vehicles were still emitting at 2008 levels, those emissions would have caused 48,200 deaths attributable to air pollution in 2017 — which would have represented a 74% increase between 2008 and 2017.
The study found significant recent progress in reducing emissions from heavy-duty trucks, but less progress with passenger light-duty vehicles, including cars, SUVs, and pickup trucks. Passenger light-duty vehicles accounted for two-thirds of the public health burden from transportation-related air pollution in 2017, the authors said. They noted that emissions from these vehicles in large metropolitan areas are so harmful that they are responsible for 30% more attributable deaths than all heavy-duty trucks across the nation.
“If the trends of increased population density with an aging population, and a shift to larger passenger vehicles continue, emissions, especially in urban areas, will continue to become more harmful and it will be harder to achieve further public health gains by small incremental improvements in new vehicles,” said John Spengler, Akira Yamaguchi Professor of Environmental Health and Human Habitation and senior author of the study. “Our study findings strengthen the case for policies at the municipal level that encourage electric vehicles while discouraging conventional gasoline vehicles and for making our cities more accessible for non-motorized transportation such as biking or walking.”
Other Harvard Chan School co-authors of the study included John Evans, Joel Schwartz, and James Hammitt.
Funding for the study was provided by Harvard University, from which Choma received financial support during his doctoral program.

Humans and fruit flies respond to many of the same tastes — sweet, salty, bitter and so on. The receptors that identify these substances, however, are very different between us and insects. Except when it comes to sour.
In a new study, postdoctoral fellow Anindya Ganguly and Distinguished Professor Craig Montell of UC Santa Barbara identify and describe a taste receptor sensitive to acidity in fruit flies. The protein is in the same group as human sour receptors, a family of ion channels known as otopetrins. The results appear in the Proceedings of the National Academy of Sciences.
“What’s exciting about this paper is that it solves the very longstanding question of what the sour receptor is in an insect,” said Montell, the Duggan Professor in UC Santa Barbara’s Department of Molecular, Cellular, and Developmental Biology. “And it turns out that, unlike other taste receptors, this one has been conserved over the 800 million years since flies and humans last shared a common ancestor.”
The finding indicates that sensing acids — a taste we interpret as sour — must be very important for survival. It’s perhaps more surprising that so many other important taste pathways aren’t conserved between flies and humans, since the unrelated receptors detect many of the same chemicals.
The identity of sour taste receptors has been enigmatic up until now. No one knew the sour taste receptor in any animal until a few years ago, according to Montell. And otopetrins wouldn’t have been obvious candidates. They weren’t known to play any role in taste at all until the recent discovery that they function in mammalian acid taste made by Professor Emily Liman at USC — a co-author on this latest study.
Fruit flies have three otopetrins: OtopLA, OtopLB and OtopLC. The team found that knocking out expression of the gene for OtopLA greatly impaired the flies’ behavior toward acids. These flies couldn’t recognize the acidity of different acid-sugar solutions they were presented with. Indeed, the mutants showed much less activity in their taste neurons when presented with acidic sugar solutions.

A study of an investigational gene therapy for sickle cell disease has found that a single dose restored blood cells to their normal shape and eliminated the most serious complication of the disease for at least three years in some patients.
Four patients at NewYork-Presbyterian/Columbia University Irving Medical Center participated in the multicenter study, the first to report on such long-term outcomes of a sickle cell gene therapy. The study was published online December 12 in the New England Journal of Medicine with John F. Tisdale, MD, senior investigator at the NIH’s National Heart, Lung and Blood Institute, as corresponding author.
The single-dose therapy, tested on 35 adults and adolescents with sickle cell disease, essentially corrected the shape of the patient’s red blood cells, but also completely eliminated episodes of severe pain, caused when rigid, crescent-shaped red blood cells clump together and block blood vessels. The painful episodes often result in widespread organ damage. Such episodes are a frequent cause of emergency department visits and hospitalizations and lead to early death.
“You cannot overstate the potential impact of this new therapy,” said Markus Y. Mapara, MD, PhD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and a co-author of the study. “People with sickle cell disease live in constant fear of the next pain crisis. This treatment could give people with this disease their life back. We hope this therapy will also be successful in younger patients so they can grow up without experiencing pain crises and live longer.”
Sickle cell disease is caused by mutations in the beta-globin gene, leading to the production of abnormal hemoglobin, the oxygen-carrying molecule in red blood cells. Normal red blood cells are shaped like donuts, but in sickle cell disease, the abnormal hemoglobin causes red blood cells to stiffen and adopt a spiky, sickle-like shape. The disease is estimated to affect 100,000 people in the United States and is more common among Black Americans. Sickle cell disease can be cured with a donor bone marrow transplant but use of this therapy has the best chance of success in patients with a closely matched sibling donor, which is only a minority of patients. Median lifespan for patients with sickle cell disease still remains in their 40s.
With the new gene therapy, called LentiGlobin, blood-forming stem cells are collected from the patient’s blood. Harmless lentiviruses are then used to deliver a modified copy of the beta-globin gene into the stem cells. When the cells are later reinfused into the patient, they take up residence in the bone marrow and start making healthy new red blood cells.
In the clinical trial the therapy completely eliminated severe pain crises in the months following infusion (follow-up ranged from 4 to 38 months) — the longest period in which a gene therapy for sickle cell disease has been studied.
“The effects have been sustained throughout the trial period, which suggests that the results may be durable,” says Mapara, who is also the director of the Bone Marrow Transplantation and Cell Therapy Program at NewYork-Presbyterian/Columbia University Irving Medical Center.
Because LentiGlobin uses a patient’s own stem cells, there’s no risk of rejection, a common complication of conventional bone marrow transplants, Mapara adds.
One limitation of the gene therapy is that patients must first be treated with high-dose chemotherapy to eliminate old stem cells and make room for the modified stem cells, a process known as conditioning. Chemotherapy can be toxic and is associated with a small risk of cancer. Two patients in the trial developed leukemia, which the researchers suspect was related to the chemotherapy, not to LentiGlobin treatment.
Researchers are currently working on less toxic approaches to conditioning the bone marrow before gene therapy. “The eventual goal will be to give this treatment as early as possible, well before patients develop organ damage and other complications of sickle cell disease,” says Mapara. “But before we can do this, we need to find a safer alternative to chemotherapy for conditioning strategies, such as antibodies.”
NewYork-Presbyterian/Columbia University Irving Medical Center is one of the few centers in the world participating in gene therapy clinical trials for sickle cell disease. In addition, investigators at Columbia are hoping to identify strategies to make gene therapies for sickle cell disease financially attainable.

Health authorities in Europe are warning of a sharp increase in Omicron cases, adding to an existing surge from the Delta variant.Public health authorities in Denmark and Norway on Monday released grim projections for the coming wave of the Omicron coronavirus variant, predicting that it will dominate both countries in a matter of days. Although scientists don’t yet know how often the variant causes severe disease, they say its rapid rate of spread will lead to an explosion of cases and could potentially increase pressure on hospitals, even if it proves to be mild.The reports follow similarly worrisome findings from England released over the weekend, although researchers caution that the trend could change as the variant comes into clearer view. It’s not yet certain how often Omicron infections will send people to the hospital, or how many hospitalized patients are likely to die. And while Omicron can partly evade immune defenses, researchers have yet to determine how well vaccinations and previous infections will protect people against severe disease.The authors of both new reports also observed that swift actions now, such as booster campaigns and reducing opportunities for Omicron to spread, could lessen the variant’s impact.American researchers have yet to release models of Omicron’s rise in the United States. But experts point out that the country is similar to Norway and Denmark in terms of vaccination levels and certain Covid risk factors, like the average age of the population.“It would be naïve to think the United States would be any different than Denmark,” Mads Albertsen, a microbiologist at Aalborg University, said. “Denmark is likely a best-case scenario.”In recent weeks, many epidemiologists have been paying close attention to Denmark, a country of 5.8 million residents, about the population of Wisconsin.Early in the pandemic, the country set up a sophisticated surveillance system combining large-scale coronavirus testing with genetic sequencing of many samples. That strategy has allowed Denmark to spot newly emerging variants, even when they’re at low levels, and adjust public health policies to prepare for new surges.The first Omicron sample from Denmark was sequenced on Dec. 3. The specimen was collected on Nov. 23, around the same time researchers in South Africa first told the world about a rise in cases there.The Statens Serum Institute in Copenhagen, where researchers on Monday released an estimate that Omicron cases in Denmark were doubling every two days.Mads Claus Rasmussen/Ritzau Scanpix, via Agence France-Presse — Getty ImagesBecause sequencing genetic material from coronavirus samples can take days, Danish researchers developed a quick genetic test that picks up a few key mutations found only in Omicron. Every positive test result in Denmark is now screened for the new variant, resulting in an exceptionally comprehensive picture of Omicron’s spread.In the report released on Monday by the Statens Serum Institute in Copenhagen, researchers estimated that Omicron cases in Denmark were doubling every two days. Omicron is spreading much faster than Delta, which means that the new variant will become dominant by midweek, the report found.Three-quarters of the Omicron cases are in people who have received two vaccine doses, which is about the same fraction of the entire country that’s fully vaccinated. That high percentage indicates that vaccines are providing little protection from infection, though most scientists believe that the shots will still fend off severe disease and death.The Danish data are consistent with a smaller report of Omicron infections in the United States. Out of 43 documented cases, 34 — or about 79 percent — were people who were fully vaccinated.“This thing can spread, and it can spread whether or not you were vaccinated,” Christina Ramirez, a biostatistician at the University of California, Los Angeles, said.In England, researchers also found that full vaccination provided low protection against a breakthrough infection. But they found that booster shots restored defenses to much higher levels.In these European countries, Omicron will not simply replace Delta: It will drive up cases. Currently, Denmark is seeing around 6,000 cases a day — already a record for the country and driven almost entirely by Delta. The Danish researchers project that Omicron will drive the daily cases to 10,000 by the end of the week, and the numbers will continue to climb from there.The model predicts that the explosive growth could send large numbers of people to the hospital, even if the Omicron variant turns out to be milder than earlier variants. The Danish researchers also warned that Omicron outbreaks at hospitals, even if mild, could lead to dangerous drops in staffing as doctors and nurses are sent home to quarantine.Standing in line for Covid booster shots in London on Monday.Andy Rain/EPA, via ShutterstockThe authors of the new report cautioned that their model was preliminary. It did not take into account the potent protection that boosters can afford, for example. Right now, 21 percent of people in Denmark have gotten a booster shot, and the country is pursuing an aggressive booster campaign.Even so, Troels Lillebaek, the director of the Statens Serum Institute, said that the next few weeks would be a major challenge for the country’s hospitals.“Regardless of the uncertainty about the precise severity and contagiousness of Omicron, there is a very high risk of an increasing number of admissions,” he said.In Norway, researchers have also observed a rapid rise of Omicron in recent days. “The Omicron variant is becoming established in Norway and will soon dominate,” the Norwegian Institute of Public Health said in a statement on Monday.The Coronavirus Pandemic: Key Things to KnowCard 1 of 5U.S. nears 800,000 Covid deaths.

Cancer chemotherapy has undergone a paradigm shift in recent years with traditional treatments like broad-spectrum cytotoxic agents being complemented or replaced by drugs that target specific genes believed to drive the onset and progression of the disease.
This more personalized approach to chemotherapy became possible when genomic profiling of individual patient tumors led researchers to identify specific “cancer driver genes” that, when mutated or abnormally expressed, led to the onset and development of cancer.
Different types of cancer — like lung cancer versus breast cancer — and, to some extent, different patients diagnosed with the same cancer type — show variations in the cancer driver genes believed to be responsible for disease onset and progression. “For example, the therapeutic drug Herceptin is commonly used to treat breast cancer patients when its target gene, HER-2, is found to be over-expressed,” says John F. McDonald, professor in the School of Biological Sciences.
McDonald explains that, currently, the identification of potential targets for gene therapy relies almost exclusively on genomic analyses of tumors that identify cancer driver genes that are significantly over-expressed.
But in their latest study, McDonald and Bioinformatics Ph.D. student Zainab Arshad have found that another important class of genetic changes may be happening in places where scientists don’t normally look: the network of gene-gene interactions associated with cancer onset and progression.
“Genes and the proteins they encode do not operate in isolation from one another,” McDonald says. “Rather, they communicate with one another in a highly integrated network of interactions.”
“What I think is most remarkable about our findings is that the vast majority of changes — more than 90% — in the network of interactions accompanying cancer are not associated with genes displaying changes in their expression,” adds Arshad, co-author of the paper. “What this means is that genes playing a central role in bringing about changes in network structure associated with cancer — the ‘hub genes’ — may be important new targets for gene therapy that can go undetected by gene expression analyses.”

It’s worth noting, in light of recently published research, that a majority of people won’t be diagnosed with cancer in their lifetimes. According to the National Cancer Institute, about 40% of people will, which means 60% won’t.
These percentages are worth remembering because research conducted by University of Colorado Cancer Center Deputy Director James DeGregori, PhD, a professor of biochemistry and molecular genetics, and Edward J. Evans, PhD, a postdoctoral fellow in the Department of Biochemistry and Molecular Genetics, found that most cancer-free individuals over age 60 carry at least 100 billion cells harboring at least one oncogenic, or tumor-causing, mutation.
The research, published in Aging and Cancer, involved a meta-analysis of previously published sequencing data on normal tissues, which DeGregori and Evans used to categorize somatic mutations, or mutations that occur after egg fertilization, based on their presence in cancer and showcase the quantity of cells with cancer-associated mutations in cancer-free individuals.
“When you have trillions of cells and they’re being maintained for up to a century, they’re going to accumulate mutations,” DeGregori explains. “The fact that we get mutations is not surprising, just based on known mutation rates. One thing this research points to is that we need to start looking at these mutations, and how or whether they cause cancer, from a different light.”
Gathering data to associate mutations with cancer
“To understand the genesis of cancer, we need to look at normal tissue,” Evans says. “By the time it’s developed into cancer, all the mutations are there and we don’t always know which ones are contributing to the actual genesis of cancer.