Publisher Health

Generative artificial intelligence platforms, from ChatGPT to Midjourney, grabbed headlines in 2023. But GenAI can do more than create collaged images and help write emails — it can also design new drugs to treat disease.
Today, scientists use advanced technology to design new synthetic drug compounds with the right properties and characteristics, also known as “de novo drug design.” However, current methods can be labor-, time-, and cost-intensive.
Inspired by ChatGPT’s popularity and wondering if this approach could speed up the drug design process, scientists in the Schmid College of Science and Technology at Chapman University in Orange, California, decided to create their own genAI model, detailed in the new paper, “De Novo Drug Design using Transformer-based Machine Translation and Reinforcement Learning of Adaptive Monte-Carlo Tree Search,” to be published in the journal Pharmaceuticals. Dony Ang, Cyril Rakovski, and Hagop Atamian coded a model to learn a massive dataset of known chemicals, how they bind to target proteins, and the rules and syntax of chemical structure and properties writ large.
The end result can generate countless unique molecular structures that follow essential chemical and biological constraints and effectively bind to their targets — promising to vastly accelerate the process of identifying viable drug candidates for a wide range of diseases, at a fraction of the cost.
To create the breakthrough model, researchers integrated two cutting-edge AI techniques for the first time in the fields of bioinformatics and cheminformatics: the well-known “Encoder-Decoder Transformer architecture” and “Reinforcement Learning via Monte Carlo Tree Search” (RL-MCTS). The platform, fittingly named “drugAI,” allows users to input a target protein sequence (for instance, a protein typically involved in cancer progression). DrugAI, trained on data from the comprehensive public database BindingDB, can generate unique molecular structures from scratch, and then iteratively refine candidates, ensuring finalists exhibit strong binding affinities to respective drug targets — crucial for the efficacy of potential drugs. The model identifies 50-100 new molecules likely to inhibit these particular proteins.
“This approach allows us to generate a potential drug that has never been conceived of,” Dr. Atamian said. “It’s been tested and validated. Now, we’re seeing magnificent results.”
Researchers assessed the molecules drugAI generated along several criteria, and found drugAI’s results were of similar quality to those from two other common methods, and in some cases, better. They found that drugAI’s candidate drugs had a validity rate of 100% — meaning none of the drugs generated were present in the training set. DrugAI’s candidate drugs were also measured for drug-likeness, or the similarity of a compound’s properties to those of oral drugs, and candidate drugs were at least 42% and 75% higher than other models. Plus, all drugAI-generated molecules exhibited strong binding affinities to respective targets, comparable to those identified via traditional virtual screening approaches.
Ang, Rakovski and Atamian also wanted to see how drugAI’s results for a specific disease compared to existing known drugs for that disease. In a different experiment, screening methods generated a list of natural products that inhibited COVID-19 proteins; drugAI generated a list of novel drugs targeting the same protein to compare their characteristics. They compared drug-likeness and binding affinity between the natural molecules and drugAI’s, and found similar measurements in both — but drugAI was able to identify these in a much quicker and less expensive way.
Plus, the scientists designed the algorithm to have a flexible structure that allows future researchers to add new functions. “That means you’re going to end up with more refined drug candidates with an even higher probability of ending up as a real drug,” said Dr. Atamian. “We’re excited for the possibilities moving forward.”

Smart accessories are increasingly common. Rings and watches track vitals, while Ray-Bans now come with cameras and microphones. Wearable tech has even broached brooches. Yet certain accessories have yet to get the smart touch.
University of Washington researchers introduced the Thermal Earring, a wireless wearable that continuously monitors a user’s earlobe temperature. In a study of six users, the earring outperformed a smartwatch at sensing skin temperature during periods of rest. It also showed promise for monitoring signs of stress, eating, exercise and ovulation.
The smart earring prototype is about the size and weight of a small paperclip and has a 28-day battery life. A magnetic clip attaches one temperature sensor to a wearer’s ear, while another sensor dangles about an inch below it for estimating room temperature. The earring can be personalized with fashion designs made of resin (in the shape of a flower, for example) or with a gemstone, without negatively affecting its accuracy.
Researchers published their results Jan. 12 in Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies. The device is not currently commercially available.
“I wear a smartwatch to track my personal health, but I’ve found that a lot of people think smartwatches are unfashionable or bulky and uncomfortable,” said co-lead author Qiuyue (Shirley) Xue, a UW doctoral student in the Paul G. Allen School of Computer Science & Engineering. “I also like to wear earrings, so we started thinking about what unique things we can get from the earlobe. We found that sensing the skin temperature on the lobe, instead of a hand or wrist, was much more accurate. It also gave us the option to have part of the sensor dangle to separate ambient room temperature from skin temperature.”
Creating a wearable small enough to pass as an earring, yet robust enough that users would have to charge it only every few days, presented an engineering challenge.
“It’s a tricky balance,” said co-lead author Yujia (Nancy) Liu, who was a UW masters student in the electrical and computer engineering department when doing the research and is now at the University of California San Diego. “Typically, if you want power to last longer, you should have a bigger battery. But then you sacrifice size. Making it wireless also demands more energy.”
The team made the earring’s power consumption as efficient as possible, while also making space for a Bluetooth chip, a battery, two temperature sensors and an antenna. Instead of pairing it with a device, which uses more power, the earring uses Bluetooth advertising mode — the transmissions a device broadcasts to show it can be paired. After reading and sending the temperature, it goes into deep sleep to save power.

Because continuous earlobe temperature has not been studied widely, the team also explored potential applications to guide future research. In five patients with fevers, the average earlobe temperature rose 10.62 degrees Fahrenheit (5.92 degrees Celsius) compared with the temperatures of 20 healthy patients, suggesting the earring’s potential for continuous fever monitoring.
“In medicine we often monitor fevers to assess response to therapy — to see, for instance, if an antibiotic is working on an infection,” said co-author Dr. Mastafa Springston, a clinical instructor at the Department of Emergency Medicine in the UW School of Medicine. “Longer term monitoring is a way to increase sensitivity of capturing fevers, since they can rise and fall throughout the day.”
While core body temperature generally stays relatively constant outside of fever, earlobe temperature varies more, presenting several novel uses for the Thermal Earring. In small proof-of-concept tests, the earring detected temperature variations correlated with eating, exercising and experiencing stress. When tested on six users at rest, the earring’s reading varied by 0.58 F (0.32 C) on average, placing it within the range of 0.28 C to 0.56 C necessary for ovulation and period tracking; a smartwatch varied by 0.72 C.
“Current wearables like Apple Watch and Fitbit have temperature sensors, but they provide only an average temperature for the day, and their temperature readings from wrists and hands are too noisy to track ovulation,” Xue said. “So we wanted to explore unique applications for the earring, especially applications that might be attractive to women and anyone who cares about fashion.”
While researchers found several promising potential applications for the Thermal Earring, their findings were preliminary, since the focus was on the range of potential uses. They need more data to train their models for each use case and more thorough testing before the device might be used by the public. For future iterations of the device, Xue is working to integrate heart rate and activity monitoring. She’s also interested in potentially powering the device from solar or kinetic energy from the earring swaying.
“Eventually, I want to develop a jewelry set for health monitoring,” Xue said. “The earrings would sense activity and health metrics such as temperature and heart rate, while a necklace might serve as an electrocardiogram monitor for more effective heart health data.”
Joseph Breda, a doctoral student in the Allen School, was a co-author on the paper. Vikram Iyer, a professor in the Allen School, and Shwetak Patel, a professor in the Allen School and the electrical and computer engineering department, were co-senior authors. This research was funded by the Washington Research Foundation.

Lung adenocarcinoma is the most common lung cancer and the cause of most cancer-related deaths in the United States. There are several ways lung adenocarcinoma can arise, one of which is a mutation in a protein called EGFR (epidermal growth factor receptor). Non-mutated EGFR helps cells grow in response to injury, but mutated EGFR promotes out-of-control growth that can turn into cancer. Modern immunotherapies don’t work against EGFR-driven lung adenocarcinoma, and while some drugs exist to treat the cancer, patients typically develop a resistance to them within just a few years. This gap in the treatment toolchest inspired Salk Institute researchers to probe for weak spots in the cancer’s growth pathway.
The team discovered that EGFR-driven lung adenocarcinoma hijacks a specialized population of lung-resident immune cells called macrophages, which are designed to dispose of diseased and damaged cells, as well as maintain a delicate balance of protective lipids (fats) around lung alveoli, which are essential for breathing. The lung cancer cells pull macrophages into the tumor microenvironment and alter their lipid metabolism to turn them into cancer fuel-suppliers. The newly energized tumor cells then spur further macrophage proliferation to supply more fuel — a novel self-perpetuating cancer mechanism.
The findings, published in Cancer Discoveryon January 25, 2024, provide new inspiration for lung adenocarcinoma interventions that disrupt this tumor cell-macrophage relationship. The researchers suggest that treatments using EGFR inhibitors may be more successful when paired with statins, a class of drugs commonly used to lower cholesterol levels.
“We have discovered a novel way that lung cancer cells manipulate their local environment and other cell types surrounding them to promote their own growth. In this case, the tumor cells exploit lung-resident macrophages — remodeling them to provide nutrients, like cholesterol, to the cancer cells and stimulate tumor growth,” says senior and co-corresponding author Susan Kaech, professor, director of the NOMIS Center for Immunobiology and Microbial Pathogenesis, and holder of the NOMIS Chair at Salk. “One exciting implication of this work is that lung cancer treatments may be improved by simply adding statins, an already widely used class of drugs, to the patient’s treatment plan.”
Lungs rely on tiny bulbs called alveoli, which expand and deflate with our breath, to facilitate the exchange of oxygen and carbon dioxide between the air and our blood. Alveoli are crucialto human survival, and their health is dependent on a lipid-rich environment created by alveolar cells and sustained by macrophages. Lipids, such as cholesterol, are fatty compounds that support bodily function by helping cells move, store energy, and absorb vitamins.
This unique ability of lung-resident macrophages to maintain lipid balance becomes more complicated when tumor cells begin to exploit those lipids to help themselves grow. A better understanding of the mechanisms macrophages use to regulate their metabolism and lipid production can provide insight into how tumor cells selfishly manipulate those mechanisms to help themselves.
“The tumor cells excrete even more of a growth factor called GM-CSF (granulocyte macrophage colony-stimulating factor), which then causes the macrophages to grow alongside them and change their metabolism, resulting in excess lipids that the tumor cells use to strengthen themselves,” says first author Alexandra Kuhlmann-Hogan, former postdoctoral researcher in Kaech’s lab and current postdoctoral researcher at UC Los Angeles. “The cancer was effectively hijacking this normal macrophage process of maintaining the lungs with healthy lipids in order to fuel itself.”
“Not only were the tumor cells metabolically reprogramming the macrophages — they were also instigating a feedback loop that encouraged an optimal metabolic state in the tumor cells themselves,” says co-corresponding author Katerina Politi,scientific director of the Center for Thoracic Cancers at Yale Cancer Center and professor of pathology at Yale School of Medicine.

When the EGFR-driven lung adenocarcinoma cells secreted GM-CSF, it stimulated a gene in the macrophages called PPARγ (peroxisome proliferator-activated receptor gamma), which jump-started their metabolic reprogramming and subsequent secretion of lipids. In addition to using these macrophage-curated lipids to grow, the tumor cells also use the lipids to power the continued activation of the EGFR-drive that helps the cancer grow.
Kaech predicts that disrupting this loop could be a novel intervention for slowing down EGFR-driven cancer growth. Exactly how the delivery of lipids like cholesterol to tumor cells powers the EGFR oncogenic pathway, the researchers aren’t yet sure.
“Our results reveal new therapeutic possibilities for immunotherapy-resistant EGFR-driven lung adenocarcinomas,” says co-corresponding author Christian Metallo, professor and holder of the Daniel and Martina Lewis Chair at Salk. “We have identified a key metabolic relationship between macrophages and alveoli that is exploited by tumor cells to support the cancer’s metabolic demands — now we just have to disrupt that exploitation.”
In future clinical trials, the researchers recommend pairing PPARy inhibitors, which would disrupt macrophage hijacking, with statins, which would limit available cholesterol along with the currently used EGFR inhibitors. They are also curious whether similar immunological hijacking occurs in other tumor microenvironments around the body, suggesting these results may prompt further discoveries across other cancer types and immune cells.
Other authors include Ziyan Xu, Ramya Kuna, Kacie Traina, Anna-Maria Globig, and Reuben Shaw of Salk; Thekla Cordes of Technishe Universität Braunschweig in Germany; Elizabeth Kwong and Sandra Leibel of UC San Diego School of Medicine and Sanford Consortium for Regenerative Medicine; Matthew Nobari and George Cheng of UC San Diego Department of Medicine; and Camila Robles-Otei?za, Deborah Ayeni, Stellar Levy, and Robert Homer of Yale School of Medicine.
The work was supported by the National Institutes of Health (R01CA230275, R01CA195720, R35CA220538, R01CA234245, R01CA216101S1), the Yale Cancer Biology Training Program (T32CA193200-01A1), Mark Foundation for Cancer Research, Yale University Interdisciplinary Immunology Training Grant (T32AI-007019), NOMIS Foundation, Waitt Foundation, Chapman Foundation, Helmsley Charitable Trust, and Helmsley Center for Genomic Medicine.

Researchers with McMaster University and Denmark-based pharmaceutical company ALK-Abello A/S have made a groundbreaking discovery: a new cell that remembers allergies.
The discovery gives scientists and researchers a new target in treating allergies and could lead to new therapeutics. The research, published in Science Translational Medicine on Feb. 7, 2024, coins the brand-new cell as a type-2 memory B cell (MBC2).
“We’ve discovered a type of memory B cell that had unique characteristics and a unique gene signature that has not been described before,” says Josh Koenig, assistant professor with McMaster’s Department of Medicine and co-lead of the study. “We found allergic people had this memory B cell against their allergen, but non-allergic people had very few, if any.”
B cells are a type of immune cell that makes antibodies. These cells help fight off infections but can also cause allergies.
“Let’s say you’re allergic to peanuts. Your immune system, because of MBC2, remembers that you’re allergic to peanuts, and when you encounter them again, it creates more of the antibodies that make you allergic,” Koenig says.
To come to this discovery, researchers created tetramers — a type of fluorescent molecule — out of allergens like Birch pollen and peanuts to locate difficult-to-find memory B cells. Koenig and his team previously wrote the instruction manual on how to use tetramers to locate these elusive cells.
Researchers further leveraged samples from ALK clinical trials with tablet sublingual immunotherapy which allows for sequencing large amounts of IgE producing B cells. Using cutting-edge technology such as single cell transcriptomics and deep sequencing of antibody gene repertoires on clinical trial samples, they were able to make direct connections between MBC2 and IgE, the type of antibody that triggers the allergic reaction. This provided necessary context ultimately revealing the MBC2 as the home of allergy.

“Even though allergies are the most prevalent disease worldwide, it is still not fully understood how allergy occurs and evolves into a life-long condition. Finding the cells that hold IgE memory is a key step forward and a game-changer in our understanding of what causes allergy and how treatment, such as allergy immunotherapy, can modify the disease,” says Peter Sejer Andersen, senior vice-president and head of research at ALK. Sejer Andersen co-led the study with Koenig.
The discovery of MBC2 gives scientists and researchers a new target in treating allergies and could lead to new therapeutics.
“The discovery really pinpoints two potential therapeutic approaches we might be able to take,” says Kelly Bruton, who co-led the research alongside Koenig when she was a PhD student at McMaster. Bruton is now a postdoctoral fellow at Stanford University.
“The first is targeting those MBC2s and eliminating them from an allergic person. The other option could involve changing their function and have them do something that’s not going to be ultimately harmful when the individual is exposed to the allergen.”
Further work will be needed to better understand and ultimately create therapeutics, but the discovery of MBC2s offers new hope for those affected by food allergies.
“These are the types of discoveries that you really need to make in order to develop the right therapeutics to block the right cells to stop the disease,” Koenig says.
The research was also co-led by Niels Peter Knudsen and Allyssa Phelps. Manel Jordana, a professor of medicine at McMaster, is also cited by Koenig as being integral to the discovery.
Funding for the research was provided by the Schroeder Allergy and Immunology Research Institute, Food Allergy Canada, ALK Abelló A/S, the Zych Family, the Satov Family, the Canadian Allergy Asthma and Immunology Foundation, and the Cancer Research Institute Irvington Postdoctoral Fellowship.

The speed at which England’s oldest adults became frailer accelerated during the UK Government’s era of austerity politics, according to a new study.
Researchers say that the rate of frailty in people aged 85 and over in England increased 50 per cent faster per year between 2012 and 2018 compared with the preceding eight years.
The impact of frailty — a decline in a person’s mental and physical resilience to illness and injury — on the oldest in society must be considered should any new austerity measures be introduced, experts warn.
The study, led by researchers from the University of Edinburgh’s Advanced Care Research Centre, analysed data from 16,410 people in the English Longitudinal Study of Ageing, a nationally representative sample of the English population aged at least 50 between 2002 and 2018.
Researchers combined this with the frailty index, which captures broad age-related declines in functional ability and physical and mental health.
The sample had an average age of 67 years and an average frailty index score of 0.15 (on a scale of 0 to 1, with 1 being maximum frailty).
Researchers found that frailty index scores increased more rapidly across all genders and socio-economic groups during the study period but it was particularly noticeable in the oldest people.

Frailty levels dropped in the 2000s but experienced a steep increase in the 2010s, when the UK government introduced a wave of public spending cuts in response to the 2008 global financial crisis, with all ages losing improvements that had been made.
For the oldest, the improvements were lost entirely, and they were frailer than those of the same age living in the prior decade, experts say.
The researchers did not examine why public sector cuts might cause these changes, but they say the findings correspond with the flattening of life expectancy seen in the 2010s, with higher mortality rates particularly seen in the eldest.
Dr Carys Pugh, Research Fellow at the University of Edinburgh, said: “A key implication of this research should be a recognition that public spending reductions likely have negative impacts on health and, in turn, mortality, particularly amongst the oldest in society. Frailty normally increases with age but as we emerge from the pandemic and into a cost of living crisis, any new austerity measures need careful consideration given their potential impact on long-term health, especially among the eldest who appear particularly vulnerable.”

The drugs used to treat erectile dysfunction may also be associated with a reduced risk of Alzheimer’s disease, according to a study published in the February 7, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study does not prove that erectile dysfunction drugs reduce the risk of Alzheimer’s disease. It only shows an association.
Erectile dysfunction drugs, which work by dilating blood vessels to allow more blood to flow through, were first developed to treat high blood pressure. A new study suggests that the drugs may be tied to a reduced risk of Alzheimer’s disease.
“Although we’re making progress with the new treatments for Alzheimer’s disease that work to clear amyloid plaques in the brain for people with early stages of the disease, we desperately need treatments that can prevent or delay the development of Alzheimer’s disease,” said study author Ruth Brauer, PhD, of the University College London in the United Kingdom. “These results are encouraging and warrant further research.”
The study involved 269,725 male participants with an average age of 59 who were newly diagnosed with erectile dysfunction. Participants did not have any memory or thinking problems at the start of the study. They were then followed for an average of five years. The study compared the 55% of the participants who had prescriptions for erectile dysfunction drugs to the 45% who did not have prescriptions.
During the study, 1,119 people developed Alzheimer’s disease.
Among the participants taking erectile dysfunction drugs, 749 developed Alzheimer’s disease, which corresponds to a rate of 8.1 cases per 10,000 person-years. Person-years represent both the number of people in the study and the amount of time each person spends in the study. Among those who did not take the drugs, 370 developed Alzheimer’s disease, which corresponds to a rate of 9.7 cases per 10,000 person-years.
Once researchers adjusted for other factors that could affect the rate of Alzheimer’s disease, such as age, smoking status and alcohol consumption, they found that people who took erectile dysfunction drugs were 18% less likely to develop Alzheimer’s than people who did not take the drugs.
The association was strongest in those who were issued the most prescriptions over the study period.
“More research is needed to confirm these findings, learn more about the potential benefits and mechanisms of these drugs and look into the optimal dosage,” Brauer said. “A randomized, controlled trial with both male and female participants is warranted to determine whether these findings would apply to women as well.”
The study was based on prescription records. A limitation of the study is that researchers did not have information on whether participants actually filled the prescriptions and used the drugs.

Published1 hour agoShareclose panelShare pageCopy linkAbout sharingBy Anna Collinson and Sophie HutchinsonBBC NewsFamilies who say their children were harmed by a hormonal pregnancy test feel they have been “airbrushed” from a scheme proposing financial help.Primodos was given to more than a million women in the UK in the 1960s and 70s.The scheme by the Patient Safety Commissioner recommends urgent monetary support for patients damaged by an epilepsy drug and pelvic mesh implants.The Commissioner is urging ministers to support Primodos families.Women were prescribed two Primodos pills to detect if they were pregnant. If there was no pregnancy, it would trigger a period.The tests were withdrawn from the market in 1978 and families have argued for decades that it was responsible for birth defects, miscarriages and stillbirths.The manufacturer, Schering, now part of Bayer, has always denied a link and last year a Court judge ruled there was no new evidence linking the tests with foetal harm. In 2020, the First Do No Harm review of Primodos, pelvic mesh implants and the anti-epilepsy drug sodium valproate, found avoidable harm had been caused by failures in the healthcare and regulatory system affecting tens of thousands of lives.This led to a government apology and the appointment of England’s first Patient Safety Commissioner, who is tasked with giving patients a voice.However, the first major report by the Commissioner, Dr Henrietta Hughes, has only looked into financial redress for those damaged by pelvic mesh implants and sodium valproate, which she says should be provided by the government urgently.The report states the terms of reference did not include the issue of hormone pregnancy tests and that this was a decision taken by the Department of Health. Marie Lyon gave birth to a daughter with limbs that were not fully formed, after being prescribed Primodos. She has been campaigning for nearly 50 years. “The fact that we were excluded from this report is devastating, because it’s as if the families don’t matter,” she says. “The Primodos families have been airbrushed.””Mums like me all feel guilty, we took those tablets and our children were damaged, or they died.Image source, Marie Lyon”At the moment we’re looking after the physical and mental needs on our own. We don’t get anything from the state. There’s no help.”Dr Hughes says she hopes her recommendations will act as a blueprint for redress for any harmed group of patients: “There are so many examples where the views and voices of patients aren’t immediately listened to and acted upon.”I hope that the government will be able to use the information in the report to identify those who have been harmed and then look for ways of supporting them, and that would include Primodos families.”The Commissioner’s ten recommendations are now being considered by governments across the UK.More on this storyHealth scandal victims need payouts soon – reportPublished10 hours agoJudge throws out damages claims over pregnancy testsPublished26 May 2023Anger at slow progress over mesh scandalPublished8 July 2021The patients fighting for answers for decadesPublished7 July 2020Hundreds suing NHS over vaginal implantsPublished18 April 2017Related Internet LinksThe Hughes Report – Patient Safety CommissionerThe BBC is not responsible for the content of external sites.

Researchers in a Johns Hopkins Children’s Center-led study that used genetic material from human blood and lab-grown brain cells say they have made progress in developing a blood test to identify disease-associated changes in the brain specifically linked to postpartum depression and other psychiatric and neurological disorders.
The research findings, published Jan. 11 in Molecular Psychiatry, focused on identifying the “footprints” of brain cell-derived mRNAs in blood circulating outside the brain. These blood extracellular vesicles carry brain-specific pieces of genetic material that potentially allow researchers to detect disease-associated changes in gene activity inside the brain.
Extracellular vesicles (EVs), fatty sacs of genetic material essential to communication among cells, carry messenger RNA (mRNA) and are released by every tissue in the body, including the brain.
The new research was inspired, investigators say, by results of a study published in September 2022, in which Johns Hopkins Medicine scientists discovered EV communication is altered in pregnant women who go on to develop postpartum depression after giving birth.
“We only detected placenta-specific EVs during the pregnancy, and not after birth. This was a proof of concept, that we can detect EVs that are coming from a specific tissue or organ,” explains Sarven Sabunciyan, Ph.D., an assistant professor of pediatrics at the Johns Hopkins University School of Medicine, and the paper’s senior author.
First, using the human placenta as a model, the investigators identified 26 placental mRNAs that are present in maternal blood only during pregnancy and not following birth, proving that mRNAs from specific tissues are found in EVs in circulating blood. Then, using lab-grown human brain tissue derived from stem cells (brain organoids), researchers found that EV mRNAs that are released from these brain tissues reflected the changes occurring inside the tissues. Sabunciyan and his team conclude that it is possible to gather biological information about normally inaccessible tissues, such as the placenta and the brain, by examining EV mRNAs circulating in blood.
They were able to identify mRNAs that are specifically expressed in the brain using data from the Human Protein Atlas — a Swedish-based database of human proteins in cells, tissues and organs — and the Genotype-Tissue Expression Project, which has extensively cataloged mRNA levels in human tissues.

Further analysis of those mRNA genetic pathways showed that the brain-specific mRNAs in blood EVs were involved in particular brain functions, and were significantly enriched for genes already associated with brain disorders that involve mood, schizophrenia, epilepsy and substance abuse.
The research team says this analysis suggests that these mRNAs are likely to be ideal biological markers for identifying such conditions.
“This is very exciting, because right now, there isn’t a blood marker for disorders affecting the brain, says Lena Smirnova, Ph.D., an assistant professor in the Department of Environmental Health and Engineering at the Johns Hopkins Bloomberg School of Public Health and co-author of the paper. Essentially, these conditions are diagnosed by clinical interviews between patients and providers.”
Researchers also discovered 13 brain-specific mRNAs in the blood that were found to be associated with postpartum depression. To determine the extent to which blood EV mRNAs reflect transcription in the brain, researchers compared mRNAs isolated from cells and EVs in a brain organoid model. They found that although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular expression changes in the brain via EV mRNA levels.
The goal is to develop a simple blood test to detect changes such as higher or lower levels of blood EV mRNAs directly linked to changes in the brain associated with mental disorders without having access to the brain itself, says Sabunciyan.
Eventually, Sabunciyan adds, the availability of such blood tests could enable detection of early signs of mental health emergencies, such as suicidal behavior. The ability to identify patients who are at risk of having a psychiatric episode would enable the care team to intervene and possibly prevent negative outcomes.

In future studies, they plan to use lab-grown brain samples to identify similar biomarkers to develop tests for autism spectrum disorder.
The researchers caution that the differences identified with respect to depression may be linked only to postpartum depression because the study was conducted using samples only from female participants.
Along with Sabunciyan and Smirnova, authors are Sergio Modafferi and Charlotte Schlett from Johns Hopkins; Lauren Osborne from Weill Cornell Medicine; and Jennifer Payne from University of Virginia.
The study was funded by grants from the National Institutes of Health under award numbers NIH-NIMH R01 MH112704, NIH-NIMH 1K23 MH110607 R01ES034554.
No authors declared conflicts of interest under Johns Hopkins University School of Medicine policies.

Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, in collaboration with the Broad Institute of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in Nature, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.
“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author Rajat Gupta, MD, of the Divisions of Genetics and Cardiovascular Medicine at Brigham and Women’s Hospital. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”
The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at the Broad Institute of MIT and Harvard, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.
In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devasting vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the TLNRD1 gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that TLNRD1 may be involved in both CAD, a common disease, and CCM, a rare one.
Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into TLNRD1 can lead to better forms of genetic testing and risk stratification.
This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.
“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”
Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.
“It was remarkable that this unbiased, systematic approach? — in which we deleted all candidate CAD genes in a single experiment? — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz, PhD, assistant professor of genetics at Stanford Medicine.

Scientists at the UC San Francisco (UCSF) and Northwestern Medicine may have found a way around the limitations of engineered T cells by borrowing a few tricks from cancer itself.
By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potency to engineered T cells. Inserting a gene encoding this unique mutation into normal human T cells made them more than 100 times more potent at killing cancer cells without any signs of becoming toxic.
While current immunotherapies work only against cancers of the blood and bone marrow, the T cells engineered by Northwestern and UCSF were able to kill tumors derived from skin, lung and stomach in mice. The team has already begun working toward testing this new approach in people.
“We used nature’s roadmap to make better T cell therapies,” said Dr. Jaehyuk Choi, an associate professor of dermatology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine. “The superpower that makes cancer cells so strong can be transferred into T cell therapies to make them powerful enough to eliminate what were once incurable cancers.”
“Mutations underlying the resilience and adaptability of cancer cells can super-charge T cells to survive and thrive in the harsh conditions that tumors create,” said Kole Roybal, associate professor of microbiology and immunology at UCSF, center director for the Parker Institute for Cancer Immunotherapy Center at UCSF, and a member of the Gladstone Institute of Genomic Immunology.
The study will appear in Nature Feb. 7.
A solution hiding in plain sight
Creating effective immunotherapies has proven difficult against most cancers because the tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit. Often, tumors hijack the body’s immune system, causing it to defend the cancer, instead of attacking it.

Not only does this impair the ability of regular T cells to target cancer cells, it undermines the effectiveness of the engineered T cells that are used in immunotherapies, which quickly tire against the tumor’s defenses.
“For cell-based treatments to work under these conditions,” Roybal said, “we need to give healthy T cells abilities that are beyond what they can naturally achieve.”
The Northwestern and UCSF teams screened 71 mutations found in patients with T cell lymphoma and identified which ones could enhance engineered T cell therapies in mouse tumor models. Eventually, they isolated one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.
“Our discoveries empower T cells to kill multiple cancer types,” said Choi, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This approach performs better than anything we’ve seen before.” Their discoveries can be incorporated into treatments for many types of cancer, the scientists said.
“T cells have the potential to offer cures to people who are heavily pretreated and have a poor prognosis,” Choi said. “Cell therapies are living drugs, because they live and grow inside the patient and can provide long-term immunity against cancer.”
In collaboration with the Parker Institute for Cancer Immunotherapy and Venrock, Roybal and Choi are building a new company, Moonlight Bio, to realize the potential of their groundbreaking approach. They are currently developing a cancer therapy that they hope to begin testing in people within the next few years.

“We see this as the starting point,” Roybal said. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”
The research was supported by the Parker Institute for Cancer Immunotherapy, NIH grants (grants F30 CA265107, T32 CA009560, 1DP2AI136599-01 and DP2 CA239143), Cancer Moonshot grant U54 CA244438, the Mark Foundation for Cancer Research, the Bakewell Foundation, and UCSF Helen Diller Family Comprehensive Cancer Center.
Roybal and Choi are inventors on patents related to these discoveries and are co-founders and equity holders in Moonlight Bio.