Investigation into Covid Origins Sought

• Virginie Courtier, Evolutionary geneticist, Institut Jacques Monod, CNRS, France (ORCID 0000-0002-9297-9230). • Francisco A. de Ribera, Industrial Engineer, MBA, MSc(Res), Data scientist, Madrid, Spain (ORCID 0000-0003-4419-636X) • Etienne Decroly, DR CNRS, molecular virologist, Aix Marseille University, France, (ORCID 0000-0002-6046-024X) • Rodolphe de Maistre, MSc engineering, MBA, ex auditor IHEDN, France (ORCID 0000- 0002-3433-2420) • Gilles Demaneuf, Engineering (ECP), Data Scientist at BNZ, Auckland, NZ, (ORCID: 0000-0001-7277-9533) (Co-Organizer) • Richard H. Ebright, Professor of Chemistry and Chemical Biology, Rutgers University, USA • André Goffinet, MD, PhD, Emeritus Professor, University of Louvain Med Sch, Belgium • François Graner, biophysicist, Research Director, CNRS and Université de Paris, France, (ORCID 0000-0002-4766-3579) • José Halloy, Professor of Physics, Biophysics and Sustainability, Université de Paris, France, (ORCID 0000-0003-1555-2484) • Milton Leitenberg, Senior Research Associate, School of Public Affairs, University of Maryland, USA • Filippa Lentzos, Senior Lecturer in Science & International Security, King’s College London, United Kingdom (ORCID 0000-0001-6427-4025) • Rosemary McFarlane, PhD BVSc, Assistant Professor of Public Health, University of Canberra, Australia (ORCID 0000-0001-8859-3776) • Jamie Metzl, Senior Fellow, Atlantic Council, USA (Co-Organizer) • Dominique Morello, Biologist, DR CNRS and Museum of Natural History, Toulouse, France • Nikolai Petrovsky, Professor of Medicine, College of Medicine and Public Health, Flinders University, Australia • Steven Quay, MD, PhD, Formerly Asst. Professor, Department of Pathology, Stanford University School of Medicine, USA (ORCID 0000-0002-0363-7651) • Monali C. Rahalkar, Scientist ‘D’, Agharkar Research Institute, Pune, India • Rossana Segreto, PhD, Department of Microbiology, University of Innsbruck, Austria (ORCID 0000-0002-2566-7042) • Günter Theißen, Dr. rer. nat., Professor of Genetics, Matthias Schleiden Institute, Friedrich Schiller University Jena, Germany, (ORCID 0000-0003-4854-8692) • Jacques van Helden, Professor of bioinformatics, Aix-Marseille University, France, (ORCID 0000-0002-8799-8584)

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Team of bioethicists and scientists suggests revisiting 14-day limit on human embryo

An international team of bioethicists and scientists, led by a researcher at Case Western Reserve University, contends it may be justified to go beyond the standing 14-day limit that restricts how long researchers can study human embryos in a dish. Going beyond this policy limit could lead to potential health and fertility benefits, and the authors provide a process for doing so.
In an article published March 5 in Science, Insoo Hyun, a bioethics professor at the Case Western Reserve University School of Medicine and the paper’s lead author, and colleagues urge policymakers and the International Society for Stem Cell Research (ISSCR) to consider “a cautious, stepwise approach” to scientific exploration beyond the 14-day limit.
“But first,” they write, “one must appreciate the scientific reasons for doing so. Any such proposed research must serve important goals that cannot be adequately met by other means.”
ISSCR is expected to soon release updated guidelines for stem cell and embryo research.
Among the potential benefits of studying human embryos beyond the 14-day limit include understanding how early development disorders originate and developing therapies that address causes of infertility, developmental disorders and failed pregnancy.
Since the first successful birth from in vitro fertilization in the late 1970s, human embryo research has been subject to limits of time and developmental benchmarks. The general rationale for imposing those limits was that, although considered acceptable to benefit human health and improve reproduction, in vitro research should conclude 14 days after fertilization — about when implantation in the womb is normally completed.

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National guidelines, laws and international norms have prohibited scientists from culturing human embryos for research after 14 days, or beyond the appearance of a structure called the “primitive streak,” which defines the period when principal tissues of the body begin to form and an embryo can no longer divide into identical twins. Thus, the 14-day limit allowed research to proceed until the human embryo in a dish starts to become biologically unique.
When this limit was put in place, there were no methods to culture embryos in a dish for anywhere close to two weeks.
But research since 2016 shows that it is likely possible to culture human research embryos past the two-week limit, and suggests that doing so will yield scientific insights that could prove important for human health and fertility.
The authors acknowledge that researchers should adhere to the 14-day limit, “unless a strong scientific justification can be offered to culture human embryos longer in locales where it would be legally permissible to do so. Any such proposed research must serve important goals that cannot be adequately met by other means.”
Hyun and colleagues propose six principles that can be used to weigh whether research on human embryos can move beyond the 14-day limit, in incremental, measured steps. They note their principles apply for extending the 14-day limit, but also for other complex research.
Among their principles, they emphasize that extended embryo culture should begin in small steps, with frequent interim evaluations. For instance, it would first be necessary to assess feasibility of culture past 14 days, and, if so, to assess whether those newly permitted experiments were informative enough to justify the further use of human embryos.
Their other principles include advocating for research proposals to be peer-reviewed by qualified and independent science and ethics committees; for public dialogue at the local institutional level and, more broadly.
“Realistically,” they conclude, “an incremental approach seems to be our only path forward, both from a scientific and a policy standpoint.”

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Less inflammation with a traditional Tanzanian diet than with a Western diet

Urban Tanzanians have a more activated immune system compared to their rural counterparts. The difference in diet appears to explain this difference: in the cities, people eat a more western style diet, while in rural areas a traditional diet is more common. A team of researchers from Radboud university medical center in the Netherlands, the LIMES Institute at the University of Bonn in Germany and the Kilimanjaro Clinic Research Center in Tanzania believe that this increased activity of the immune system contributes to the rapid increase in non-communicable diseases in urban areas in Africa.
The survey was conducted among more than 300 Tanzanians, some of whom live in the city of Moshi and some in the countryside. The team found that immune cells from participants from Moshi produced more inflammatory proteins. The people surveyed had no health problems and were not ill, but an activated immune system may increase the risk for lifestyle diseases, such as cardiovascular disease.
The researchers used new techniques to investigate the function of the immune system and the factors that influence its activity. Quirijn de Mast, internist-infectious diseases specialist at Radboud university medical center explains: “We looked at active RNA molecules in the blood — known as the transcriptome — and the composition of metabolic products in the blood.”
Major differences in diet
These analyses showed that metabolites derived from food had an effect on the immune system. Participants from rural areas had higher levels of flavonoids and other anti-inflammatory substances in their blood. The traditional rural Tanzanian diet, which is rich in whole grains, fibre, fruits and vegetables, contains high amounts of these substances. In people with an urban diet, which contains more saturated fats and processed foods, increased levels of metabolites that are involved in cholesterol metabolism were found. The team also found a seasonal change in the activity of the immune system. In the dry season, which is the time of harvest in the study area, the urban people had a less activated immune system.
Migration to the cities of Africa
It has been known for some time that a Western lifestyle and eating habits lead to chronic diseases. According to de Mast, two important findings have emerged from this study. “First of all, we showed that a traditional Tanzanian diet has a beneficial effect on inflammation and the functioning of the immune system. This is important because rapid urbanization is ongoing, not only in Tanzania, but also in other parts of Africa. The migration from the countryside to the city is leading to dietary changes and is accompanied by a rapid increase in the number of lifestyle diseases, which puts a heavy burden on the local healthcare systems. That is why prevention is essential, and diet can be very important for this.”
Western countries can learn from the results Second, these findings from Africa are also relevant for Western countries. Urbanization took place a long time ago in most western countries. By studying populations at different stages of urbanization, researchers therefore have unique opportunities to improve their understanding of how diet and lifestyle affect the human immune system.

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Materials provided by Radboud University Medical Center. Note: Content may be edited for style and length.

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Proteomics analysis identifies potential drug targets for aggressive human cancers

Researchers at Baylor College of Medicine show that analysis of the proteomics, or all the protein data, from aggressive human cancers is a useful approach to identify potential novel therapeutic targets. They report in the journal Oncogene, the identification of “proteomic signatures” that are associated with clinical measures of aggressive disease for each of the seven cancer types studied. Some signatures were shared between different types of cancer and included cellular pathways of altered metabolism. Importantly, experimental results provided proof-of-concept that their proteomics analysis approach is a valuable strategy to identify potential therapeutic targets.
“There are two notable aspects of this study. One is that we explored the proteomic landscape of cancer looking for proteins that were expressed in association with aggressive forms of cancer,” said co-corresponding author Dr. Chad Creighton, professor of medicine and co-director of Cancer Bioinformatics at the Dan L Duncan Comprehensive Cancer Center at Baylor. “We analyzed protein data that included tens of thousands of proteins from about 800 tumors including seven different cancer types — breast, colon, lung, renal, ovarian, uterine and pediatric glioma — made available by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets.”
Computational analysis for the CPTAC datasets identified proteomic signatures associated with aggressive forms of cancer. These signatures pointed at altered cellular pathways that might be driving aggressive cancer behavior and could represent novel therapeutic targets. Each cancer type showed a distinctive proteomic signature for its aggressive form. Interestingly, some signatures were common to different types of cancer.
The other aspect of this study was to provide proof-of-concept that the proteomic analysis was a useful strategy to identify drivers of aggressive disease that could potentially be manipulated to control cancer growth.
“That’s exactly what we were able to do with this new, very powerful dataset,” said co-corresponding author Dr. Diana Monsivais, assistant professor of pathology and immunology at Baylor. “We focused on the uterine cancer data for which the computational analysis identified alterations in a number of proteins that were associated with aggressive cancer. We selected protein kinases, enzymes that would represent stronger candidates for therapeutics.”
Of hundreds of initial candidates, the researchers selected four kinases for functional studies in uterine cancer cell lines. They found that the kinases not only were expressed in the uterine cancer cells lines, but also that manipulating the expression of some of the kinases reduced the survival or the ability to migrate for some uterine cancer cells. Cell migration is a property of cancer cells that allows them to spread cancer to other tissues.
This work is the result of a productive collaboration between two Baylor centers, the Dan L Duncan Comprehensive Cancer Center and the Center for Drug Discovery.
“Chad conducted this wonderful analysis on new CPTAC datasets and was interested in validating it in a human cancer. He approached us about performing functional studies to determine whether some proteins could translate to new targets for endometrial cancer,” Monsivais said. “Our experiments provided proof-of-concept that proteomics analysis is a useful strategy not only to better understand what drives cancer, but to identify new ways to control it or eliminate it.”
“Historically, researchers have only been generating transcriptomic data (the messenger RNA (mRNA) that is translated into protein). Looking at the protein data itself, which is made available by the CPTAC, enables researchers to extract a new layer of information from these cancers,” Creighton said. “In this study, we compared mRNA and protein signatures and, although in many cases they overlapped, about half the proteins in the proteomic signatures were not included in the corresponding mRNA signature, suggesting the need to include both mRNA and protein data in cancer studies.”

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Materials provided by Baylor College of Medicine. Original written by Ana María Rodríguez, Ph.D.. Note: Content may be edited for style and length.

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Retracing the history of the mutation that gave rise to cancer decades later

There is no stronger risk factor for cancer than age. At the time of diagnosis, the median age of patients across all cancers is 66. That moment, however, is the culmination of years of clandestine tumor growth, and the answer to an important question has thus far remained elusive: When does a cancer first arise?
At least in some cases, the original cancer-causing mutation could have appeared as long as 40 years ago, according to a new study by researchers at Harvard Medical School and the Dana-Farber Cancer Institute.
Reconstructing the lineage history of cancer cells in two individuals with a rare blood cancer, the team calculated when the genetic mutation that gave rise to the disease first appeared. In a 63-year-old patient, it occurred at around age 19; in a 34-year-old patient, at around age 9.
The findings, published in the March 4 issue of Cell Stem Cell, add to a growing body of evidence that cancers slowly develop over long periods of time before manifesting as a distinct disease. The results also present insights that could inform new approaches for early detection, prevention, or intervention.
“For both of these patients, it was almost like they had a childhood disease that just took decades and decades to manifest, which was extremely surprising,” said co-corresponding study author Sahand Hormoz, HMS assistant professor of systems biology at Dana-Farber.
“I think our study compels us to ask, when does cancer begin, and when does being healthy stop?” Hormoz said. “It increasingly appears that it’s a continuum with no clear boundary, which then raises another question: When should we be looking for cancer?”
In their study, Hormoz and colleagues focused on myeloproliferative neoplasms (MPNs), a rare type of blood cancer involving the aberrant overproduction of blood cells. The majority of MPNs are linked to a specific mutation in the gene JAK2. When the mutation occurs in bone marrow stem cells, the body’s blood cell production factories, it can erroneously activate JAK2 and trigger overproduction.

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To pinpoint the origins of an individual’s cancer, the team collected bone marrow stem cells from two patients with MPN driven by the JAK2 mutation. The researchers isolated a number of stem cells that contained the mutation, as well normal stem cells, from each patient, and then sequenced the entire genome of each individual cell.
Over time and by chance, the genomes of cells randomly acquire so-called somatic mutations — nonheritable, spontaneous changes that are largely harmless. Two cells that recently divided from the same mother cell will have very similar somatic mutation fingerprints. But two distantly related cells that shared a common ancestor many generations ago will have fewer mutations in common because they had the time to accumulate mutations separately.
Cell of origin
Analyzing these fingerprints, Hormoz and colleagues created a phylogenetic tree, which maps the relationships and common ancestors between cells, for the patients’ stem cells — a process similar to studies of the relationships between chimpanzees and humans, for example.
“We can reconstruct the evolutionary history of these cancer cells, going back to that cell of origin, the common ancestor in which the first mutation occurred,” Hormoz said.

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Combined with calculations of the rate at which mutations accumulate, the team could estimate when the JAK2 mutation first occurred. In the patient who was first diagnosed with MPN at age 63, the team found that the mutation arose around 44 years prior, at the age of 19. In the patient diagnosed at age 34, it arose at age 9.
By looking at the relationships between cells, the researchers could also estimate the number of cells that carried the mutation over time, allowing them to reconstruct the history of disease progression.
“Initially, there’s one cell that has the mutation. And for the next 10 years there’s only something like 100 cancer cells,” Hormoz said. “But over time, the number grows exponentially and becomes thousands and thousands. We’ve had the notion that cancer takes a very long time to become an overt disease, but no one has shown this so explicitly until now.”
The team found that the JAK2 mutation conferred a certain fitness advantage that helped cancerous cells outcompete normal bone marrow stem cells over long periods of time. The magnitude of this selective advantage is one possible explanation for some individuals’ faster disease progression, such as the patient who was diagnosed with MPN at age 34.
In additional experiments, the team carried out single-cell gene expression analyses in thousands of bone marrow stem cells from seven different MPN patients. These analyses revealed that the JAK2 mutation can push stem cells to preferentially produce certain blood cell types, insights that may help scientists better understand the differences between various MPN types.
Together, the results of the study offer insights that could motivate new diagnostics, such as technologies to identify the presence of rare cancer-causing mutations currently difficult to detect, according to the authors.
“To me, the most exciting thing is thinking about at what point can we detect these cancers,” Hormoz said. “If patients are walking into the clinic 40 years after their mutation first developed, could we have caught it earlier? And could we prevent the development of cancer before a patient ever knows they have it, which would be the ultimate dream?”
The researchers are now further refining their approach to studying the history of cancers, with the aim of helping clinical decision-making in the future.
While their approach is generalizable to other types of cancer, Hormoz notes that MPN is driven by a single mutation in a very slow growing type of stem cell. Other cancers may be driven by multiple mutations, or in faster-growing cell types, and further studies are needed to better understand the differences in evolutionary history between cancers.
The team’s current efforts include developing early detection technologies, reconstructing the histories of greater numbers of cancer cells, and investigating why some patients’ mutations never progress into full-blown cancer, but others do.
“Even if we can detect cancer-causing mutations early, the challenge is to predict which patients are at risk of developing the disease, and which are not,” Hormoz said. “Looking into the past can tell us something about the future, and I think historical analyses such as the ones we conducted can give us new insights into how we could be diagnosing and intervening.”
Study collaborators include scientists and physicians from Brigham and Women’s Hospital, Boston Children’s Hospital, Massachusetts General Hospital, and the European Bioinformatics Institute. The other co-corresponding authors of the study are Ann Mullally and Isidro Cortés-Ciriano.
The study was supported in part by the National Institutes of Health (grants R00GM118910, R01HL158269), the Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the William F. Milton Fund at Harvard University, an AACR-MPM Oncology Charitable Foundation Transformative Cancer Research grant, Gabrielle’s Angel Foundation for Cancer Research, and the Claudia Adams Barr Program in Cancer Research.

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Cancer 'guardian' breaks bad with one switch

A mutation that replaces a single amino acid in a potent tumor-suppressing protein turns it from saint to sinister. A new study by a coalition of Texas institutions shows why that is more damaging than previously known.
The ubiquitous p53 protein in its natural state, sometimes called “the guardian of the genome,” is a front-line protector against cancer. But the mutant form appears in 50% or more of human cancers and actively blocks cancer suppressors.
Researchers led by Peter Vekilov at the University of Houston (UH) and Anatoly Kolomeisky at Rice University have discovered the same mutant protein can aggregate into clusters. These in turn nucleate the formation of amyloid fibrils, a prime suspect in cancers as well as neurological diseases like Alzheimer’s.
The condensation of p53 into clusters is driven by the destabilization of the protein’s DNA-binding pocket when a single arginine amino acid is replaced with glutamine, they reported.
“It’s known that a mutation in this protein is a main source of cancer, but the mechanism is still unknown,” said Kolomeisky, a professor and chair of Rice’s Department of Chemistry and a professor of chemical and biomolecular engineering.
“This knowledge gap has significantly constrained attempts to control aggregation and suggest novel cancer treatments,” said Vekilov, the John and Rebecca Moores Professor of Chemical and Biomolecular Engineering and Chemistry at UH.

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The mutant p53 clusters, which resemble those discovered by Vekilov in solutions of other proteins 15 years ago, and the amyloid fibrils they nucleate prompt the aggregation of proteins the body uses to suppress cancer. “This is similar to what happens in the brain in neurological disorders, though those are very different diseases,” Kolomeisky said.
The p53 mechanism described in the Proceedings of the National Academy of Sciences may be similar to those that form functional and pathological solids like tubules, filaments, sickle cell polymers, amyloids and crystals, Vekilov said.
Researchers at UH combined 3D confocal images of breast cancer cells taken in the lab of chemical and biomolecular engineer Navin Varadarajan with light scattering and optical microscopy of solutions of the purified protein carried out in the Vekilov lab.
Transmission electron microscopy micrographs of cluster and fibril formation contributed by Michael Sherman at the University of Texas Medical Branch at Galveston (UTMB) supported the main result of the study, as did molecular simulations by Kolomeisky’s group
All confirmed the p53 mutant known as R248Q goes through a two-step process to form mesoscopic condensates. Understanding the mechanism could provide insight into treating various cancers that manipulate either p53 or its associated signaling pathways, Vekilov said.
In normal cell conditions, the concentration of p53 is relatively low, so the probability of aggregation is low, he said. But when a mutated p53 is present, the probability increases.
“Experiments show the size of these clusters is independent of the concentration of p53,” Kolomeisky said. “Mutated p53 will even take normal p53 into the aggregates. That’s one of the reasons for the phenomenon known as loss of function.”
If even a small relative fraction of the mutant is present, it’s enough to kill or lower the ability of normal, wild-type p53 to fight cancer, according to the researchers.
The Rice simulations showed normal p53 proteins are compact and easily bind to DNA. “But the mutants have a more open conformation that allows them to interact with other proteins and gives them a higher tendency to produce a condensate,” Kolomeisky said. “It’s possible that future anti-cancer drugs will target the mutants in a way that suppresses the formation of these aggregates and allows wild-type p53 to do its job.”

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Materials provided by Rice University. Note: Content may be edited for style and length.

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Covid: Italy 'blocks' AstraZeneca vaccine shipment to Australia

SharecloseShare pageCopy linkAbout sharingimage copyrightReutersThe Italian government has blocked the export of an Oxford-AstraZeneca vaccine shipment to Australia.The decision affects 250,000 doses of the vaccine produced at an AstraZeneca facility in Italy.Italy is the first EU country to use the bloc’s new regulations allowing exports to be stopped if the company providing the vaccines has failed to meet its obligations to the EU.The move has been backed by the European Commission, reports say.AstraZeneca is on track to provide only 40% of the agreed supply to member states in the first three months of the year. It has cited production problems for the shortfall.In January, then Italian Prime Minister Giuseppe Conte described delays in vaccine supplies by both AstraZeneca and Pfizer as “unacceptable” and accused the companies of violating their contracts.The EU has been widely criticised for the slow pace of its vaccination programme. Why is the EU having vaccine problems?Italian PM brands vaccine delay ‘unacceptable’ EU-AstraZeneca disputed jab contract made publicUnder the EU vaccine scheme, which was established in June last year, the bloc has negotiated the purchase of vaccines on behalf of member states.There has been no official comment on the Italian move by Australia, the EU or AstraZeneca.image copyrightEPAAustralia began its vaccination programme last week using the Pfizer/BioNTech vaccine. It was due to start inoculations with the AstraZeneca jab on Friday.What does Italy say?The Italian government approached the European Commission last week to say that it was its intention to block the shipment.In a statement on Thursday, the foreign ministry explained the move, saying it had received the request for authorisation on 24 February.It said that previous requests had been given the green light as they included limited numbers of samples for scientific research, but the latest one – being much larger, for more than 250,000 doses – was rejected.It explained the move by saying that Australia was not on a list of “vulnerable” countries, that there was a permanent shortage of vaccines in the EU and Italy, and that the number of doses was high compared with the amount given to Italy and to the EU as a whole. Italy flexes its musclesIn the acrimonious vaccine war, this is a muscular move by one of the European Union’s heavyweights. It is the first such ban under a new EU scheme in which manufacturers must request authorisation for export from the country in which the vaccine is produced. Italy’s new Prime Minister Mario Draghi, an influential figure in Europe as the former president of the European Central Bank, argued in a videoconference with EU leaders that the rules should be applied rigorously, furious at reductions by AstraZeneca of up to 70% in the doses it was contracted to provide. Mr Draghi has prioritised ramping up the vaccination programme. He is clearly determined to show that his country – and the EU – will use all means necessary to do so.How did the row with AstraZeneca come about?The EU signed a deal with AstraZeneca in August for 300 million doses, with an option for 100 million more, but earlier this year the UK-Swedish company reported production delays at plants in the Netherlands and Belgium.Instead of receiving 100 million doses by the end of March, the EU is now expected to get just 40 million.The EU accused the company of reneging on its deal, with EU Health Commissioner Stella Kyriakides saying that UK factories making the vaccine should make up the shortfall.Ms Kyriakides also rejected AstraZeneca CEO Pascal Soriot’s characterisation of the contract as one of “best effort” rather than an obligation to meet a deadline for delivery of vaccines.As a result of the row, the EU announced export controls which began on 30 January, known as the “transparency and authorisation mechanism”.

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Artificial intelligence reveals current drugs that may help combat Alzheimer's disease

New treatments for Alzheimer’s disease are desperately needed, but numerous clinical trials of investigational drugs have failed to generate promising options. Now a team at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has developed an artificial intelligence-based method to screen currently available medications as possible treatments for Alzheimer’s disease. The method could represent a rapid and inexpensive way to repurpose existing therapies into new treatments for this progressive, debilitating neurodegenerative condition. Importantly, it could also help reveal new, unexplored targets for therapy by pointing to mechanisms of drug action.
“Repurposing FDA-approved drugs for Alzheimer’s disease is an attractive idea that can help accelerate the arrival of effective treatment — but unfortunately, even for previously approved drugs, clinical trials require substantial resources, making it impossible to evaluate every drug in patients with Alzheimer’s disease,” explains Artem Sokolov, PhD, director of Informatics and Modeling at the Laboratory of Systems Pharmacology at HMS. “We therefore built a framework for prioritizing drugs, helping clinical studies to focus on the most promising ones.”
In an article published in Nature Communications, Sokolov and his colleagues describe their framework, called DRIAD (Drug Repurposing In Alzheimer’s Disease), which relies on machine learning — a branch of artificial intelligence in which systems are “trained” on vast amounts of data, “learn” to identify telltale patterns and augment researchers’ and clinicians’ decision-making.
DRIAD works by measuring what happens to human brain neural cells when treated with a drug. The method then determines whether the changes induced by a drug correlate with molecular markers of disease severity.
The approach also allowed the researchers to identify drugs that had protective as well as damaging effects on brain cells.
“We also approximate the directionality of such correlations, helping to identify and filter out neurotoxic drugs that accelerate neuronal death instead of preventing it,” says co-first author Steve Rodriguez, PhD, an investigator in the Department of Neurology at MGH and an instructor at HMS.
DRIAD also allows researchers to examine which proteins are targeted by the most promising drugs and if there are common trends among the targets, an approach designed by Clemens Hug, PhD, a research associate in the Laboratory of Systems Pharmacology and a co-first author.
The team applied the screening method to 80 FDA-approved and clinically tested drugs for a wide range of conditions. The analysis yielded a ranked list of candidates, with several anti-inflammatory drugs used to treat rheumatoid arthritis and blood cancers emerging as top contenders. These drugs belong to a class of medications known as Janus kinase inhibitors. The drugs work by blocking the action of inflammation-fueling Janus kinase proteins, suspected to play a role in Alzheimer’s disease and known for their role in autoimmune conditions. The team’s analyses also pointed to other potential treatment targets for further investigation.
“We are excited to share these results with the academic and pharmaceutical research communities. Our hope is that further validation by other researchers will refine the prioritization of these drugs for clinical investigation,” says Mark Albers, MD, PhD, the Frank Wilkins Jr. and Family Endowed Scholar and associate director of the Massachusetts Center for Alzheimer Therapeutic Science at MGH and a faculty member of the Laboratory of Systems Pharmacology at HMS. One of these drugs, baricitinib, will be investigated by Albers in a clinical trial for patients with subjective cognitive complaints, mild cognitive impairment, and Alzheimer’s disease that will be launching soon at MGH in Boston and at Holy Cross Health in Fort Lauderdale, Florida. “In addition, independent validation of the nominated drug targets could provide new insights into the mechanisms behind Alzheimer’s disease and lead to novel therapies,” says Albers.
This work was supported by the National Institute on Aging, the CART fund and the Harvard Catalyst Program for Faculty Development and Diversity Inclusion.

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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

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New evidence COVID-19 antibodies, vaccines less effective against variants

New research at Washington University School of Medicine in St. Louis indicates that three new, fast-spreading variants of the virus that cause COVID-19 can evade antibodies that work against the original form of the virus that sparked the pandemic. With few exceptions, whether such antibodies were produced in response to vaccination or natural infection, or were purified antibodies intended for use as drugs, the researchers found more antibody is needed to neutralize the new variants.
The findings, from laboratory-based experiments and published March 4 in Nature Medicine, suggest that COVID-19 drugs and vaccines developed thus far may become less effective as the new variants become dominant, as experts say they inevitably will. The researchers looked at variants from South Africa, the United Kingdom and Brazil.
“We’re concerned that people whom we’d expect to have a protective level of antibodies because they have had COVID-19 or been vaccinated against it, might not be protected against the new variants,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “There’s wide variation in how much antibody a person produces in response to vaccination or natural infection. Some people produce very high levels, and they would still likely be protected against the new, worrisome variants. But some people, especially older and immunocompromised people, may not make such high levels of antibodies. If the level of antibody needed for protection goes up tenfold, as our data indicate it does, they may not have enough. The concern is that the people who need protection the most are the ones least likely to have it.”
The virus that causes COVID-19, known as SARS-CoV-2, uses a protein called spike to latch onto and get inside cells. People infected with SARS-CoV-2 generate the most protective antibodies against the spike protein.
Consequently, spike became the prime target for COVID-19 drug and vaccine developers. The three vaccines authorized by the Food and Drug Administration (FDA) for emergency use in the U.S. — made by Pfizer/BioNTech, Moderna and Johnson & Johnson — both target spike. And potent anti-spike antibodies were selected for development into antibody-based drugs for COVID-19.
Viruses are always mutating, but for nearly a year the mutations that arose in SARS-CoV-2 did not threaten this spike-based strategy. Then, this winter, fast-spreading variants were detected in the United Kingdom, South Africa, Brazil and elsewhere. Sparking concern, the new variants all carry multiple mutations in their spike genes, which could lessen the effectiveness of spike-targeted drugs and vaccines now being used to prevent or treat COVID-19. The most worrisome new variants were given the names of B.1.1.7 (from the U.K.), B.1.135 (South Africa) and B.1.1.248, also known as P.1 (Brazil).
To assess whether the new variants could evade antibodies made for the original form of the virus, Diamond and colleagues, including first author Rita E. Chen, a graduate student in Diamond’s lab, tested the ability of antibodies to neutralize three virus variants in the laboratory.
The researchers tested the variants against antibodies in the blood of people who had recovered from SARS-CoV-2 infection or were vaccinated with the Pfizer vaccine. They also tested antibodies in the blood of mice, hamsters and monkeys that had been vaccinated with an experimental COVID-19 vaccine, developed at Washington University School of Medicine, that can be given through the nose. The B.1.1.7 (U.K.) variant could be neutralized with similar levels of antibodies as were needed to neutralize the original virus. But the other two variants required from 3.5 to 10 times as much antibody for neutralization.
Then, they tested monoclonal antibodies: mass-produced replicas of individual antibodies that are exceptionally good at neutralizing the original virus. When the researchers tested the new viral variants against a panel of monoclonal antibodies, the results ranged from broadly effective to completely ineffective.
Since each virus variant carried multiple mutations in the spike gene, the researchers created a panel of viruses with single mutations so they could parse out the effect of each mutation. Most of the variation in antibody effectiveness could be attributed to a single amino acid change in the spike protein. This change, called E484K, was found in the B.1.135 (South Africa) and B.1.1.248 (Brazil) variants, but not B.1.1.7 (U.K.). The B.1.135 variant is widespread in South Africa, which may explain why one of the vaccines tested in people was less effective in South Africa than in the U.S., where the variant is still rare, Diamond said.
“We don’t exactly know what the consequences of these new variants are going to be yet,” said Diamond, also a professor of molecular microbiology and of pathology & immunology. “Antibodies are not the only measure of protection; other elements of the immune system may be able to compensate for increased resistance to antibodies. That’s going to be determined over time, epidemiologically, as we see what happens as these variants spread. Will we see reinfections? Will we see vaccines lose efficacy and drug resistance emerge? I hope not. But it’s clear that we will need to continually screen antibodies to make sure they’re still working as new variants arise and spread and potentially adjust our vaccine and antibody-treatment strategies.”
The research team also included co-corresponding author Ali Ellebedy, PhD, an assistant professor of pathology & immunology, of medicine, and of molecular microbiology at Washington University; and co-corresponding author Pei-Yong Shi, PhD, and co-first author Xianwen Zhang, PhD, of the University of Texas Medical Branch.

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WOX9: A jack of all trades

Over evolutionary time scales, a single gene may acquire different roles in diverging species. However, revealing the multiple hidden roles of a gene was not possible before genome editing came along. Cold Spring Harbor Laboratory (CSHL) Professor and HHMI Investigator Zach Lippman and CSHL postdoctoral fellow Anat Hendelman collaborated with Idan Efroni, HHMI International Investigator at Hebrew University Faculty of Agriculture in Israel, to uncover this mystery. They dissected the activity of a developmental gene, WOX9, in different plants and at different moments in development. Using genome editing, they found that without changing the protein produced by the gene, they could change a plant’s traits by changing the gene’s regulation.
“Genes” are the DNA that code for proteins, but other nearby stretches of DNA regulate the activity of genes, instructing them where, when, and to what degree they should be active. With the genome-editing tool CRISPR, scientists can introduce precise mutations into DNA, including these regulatory regions. Though scientists would like to use CRISPR to fine-tune plant traits, the technique sometimes yields surprising results; some genes turn out to have functions that were previously unknown.
WOX9 is one of several “homeobox” genes that help plants and animals set borders in developing structures. While the gene plays a role in early development in arabidopsis, a weedy relative of broccoli, it influences later development — reproduction and flowering — in tomatoes. Lippman and Hendelman used CRISPR to create a series of mutations in the regulatory DNA surrounding WOX9 to reveal additional functions in tomato, groundcherry, and arabidopsis plants. Given the right regulatory sequence, the gene could induce more flowers to form in all three species. WOX9 is thus a candidate to increase yields in these and other crop plants just by changing its regulation. This discovery suggests that other genes may also have hidden multiple roles. Lippman says:
“We know about a whole bunch of genes that you might want to target with genome editing to improve crops, but there’s a whole other set of genes for which they might have really useful functions that could also help improve crops. And so by using this approach, you can expose those roles and then you can predictably fine-tune the activity of that gene for that specific role to get the desired trait modification.”
Lippman’s team published their findings in the journal Cell. Their work will make it easier to improve crop traits more predictably.

Story Source:
Materials provided by Cold Spring Harbor Laboratory. Original written by Jasmine Lee. Note: Content may be edited for style and length.

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