Publisher Health

The largest U.S. report of elective fertility preservation outcomes to date found that 70 percent of women who froze eggs when they were younger than 38 — and thawed at least 20 eggs at a later date — had a baby.
Led by experts at NYU Grossman School of Medicine and the NYU Langone Fertility Center, the new finding was based on 15 years of “real life” frozen egg thaw outcomes for women who had delayed childbearing and faced natural, age-related fertility decline.
Published online May 18 in Fertility and Sterility, the study also found that considerable number of the women studied had more than one child through egg preservation. In total the study reports 211 babies from egg freezing.
In comparison, and using fresh eggs or embryos from women trying to conceive, at age 40 fewer than 30 percent undergoing in vitro fertilization (IVF) become pregnant and fewer than 20 percent gave birth to live babies as a result, according to statistics gathered by the Centers for Disease and Prevention from the nation’s nearly 500 fertility clinics. Egg freezing and thawing at a later date provides a higher pregnancy success rate than using fresh embryos during assisted reproductive technology, say the study authors.
“Our findings shed light on the factors that track with successful births from egg freezing, which include careful screening of embryos to be thawed and implanted,” says study lead author Sarah Druckenmiller Cascante, MD, fellow in the Division of Reproductive Endocrinology and Infertility, within the Department of Obstetrics and Gynecology at NYU Langone. “A better understanding of the live birth rate from egg freezing for age-related fertility decline is necessary to inform patient decision-making.”
“Importantly, our study is based on actual clinical experience,” adds Cascante, “rather than mathematical modeling with limited data, which is most of what has been published on the chance of births from egg freezing thus far.” The number of U.S. women having children at older ages has been increasing for three decades, with evidence that the trend will continue. Birth rates have declined for women in their 20s and jumped for women in their late 30s and early 40s, according to the U.S. Census Bureau. The average age at first birth has risen from 19 years old in 1984 to 30 years old in 2021 and is higher in many metropolitan areas.

CRISPR has ushered in the era of genomic medicine. A line of powerful tools has been developed from the popular CRISPR-Cas9 to cure genetic diseases. However, there is a last-mile problem — these tools need to be effectively delivered into every cell of the patient, and most Cas9s are too big to be fitted into popular genome therapy vectors, such as the adenovirus-associated virus (AAV).
In new research, Cornell scientists provide an explanation for how this problem is solved by nature: they define with atomic precision how a transposon-derived system edits DNA in RNA-guided fashion. Transposons are mobile genetic elements inside bacteria. A lineage of transposon encodes IscB, which is less than half the size of Cas9 but equally capable of DNA editing. Replacing Cas9 with IscB would definitively solve the size problem.
The researchers used cryo-electron microscopy (Cryo-EM) to visualize the IscB-ωRNA molecule from a transposon system in high resolution. They were able to capture snapshots of the system in different conformational states. They were even able to engineer slimmer IscB variants, by removing nonessential parts from IscB. 
“Next-generation fancy applications require the gene editor to be fused with other enzymes and activities and most Cas9s are already too big for viral delivery. We are facing a traffic jam at the delivery end,” said corresponding author Ailong Ke, professor of molecular biology and genetics in the College of Arts and Sciences. “If Cas9s can be packaged into viral vectors that have been used for decades in the gene therapy field, like AAV, then we can be confident they can be delivered and we can focus research exclusively on the efficacy of the editing tool itself.”
CRISPR-Cas9 systems use an RNA as a guide to recognize a sequence of DNA. When a match is found, the Cas9 protein snips the target DNA at just the right place; it’s then possible to do surgery at the DNA level to fix genetic diseases. The cryo-EM data gathered by the Cornell team show that the IscB-ωRNA system works in a similar way, with its smaller size achieved by replacing parts of the Cas9 protein with a structured RNA (ωRNA) which is fused to the guide RNA.  By replacing protein components of the larger Cas9 with RNA, the IscB protein is shrunken to the core chemical reaction centers which snip the target DNA.
“It’s about understanding the molecules’ structure and how they perform the chemical reactions,” said first author Gabriel Schuler, a doctoral student in the graduate field of microbiology. “Studying these transposons gives us a new starting point to generate more powerful and accessible gene editing tools.”
It is believed that transposons — mobile genetic elements — were the evolutionary precursors to CRISPR systems. They were discovered by Nobel Laureate Barbara McClintock ’23, M.A. ’25, Ph.D. ’27.
“Transposons are specialized genetic hitchhikers, integrating into and splicing out of our genomes all the time,” Ke said. “The systems inside bacteria in particular are being selected constantly — nature has basically tossed the dice billions of times and come up with really powerful DNA surgical tools, CRISPR included. And now, by defining these enzymes in high resolution, we can tap into their powers.”
As small as IscB is compared to CRISPR Cas9, the researchers believe they will be able to shrink it even smaller. They’ve already removed 55 amino acids without affecting IscB’s activity; they hope to make future versions of this genome editor even smaller and hence even more useful.
Better understanding the function of the companion guide RNA was another motivation behind the study, said co-first author Chunyi Hu, a postdoctoral researcher in the Department of Molecular Biology and Genetics. “There’s still a lot of mystery — like why do transposons use an RNA-guided system? What other roles this RNA may be playing?”
 One challenge that yet remains for the researchers is that while the IscB-ωRNA is extremely active in test tubes, it was not as efficient at altering DNA in human cells. The next step in their research will be to use the molecular structure to explore the possibilities they have identified for the cause of the low activity in human cells. “We have some ideas, a lot of them actually, that we are eager to test in the near future,” Schuler said.
The research was funded by grants Ke received from the National Institutes of Health. Schuler is supported by the Department of Defense through the National Defense Science and Engineering Graduate Fellowship Program. The Cryo-EM work was assisted by the Cornell Center for Materials Research and the Brookhaven National Laboratory. 
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Materials provided by Cornell University. Original written by Linda B. Glaser, courtesy of the Cornell Chronicle. Note: Content may be edited for style and length.

Last summer, Northwestern University researchers introduced the first-ever transient pacemaker — a fully implantable, wireless device that harmlessly dissolves in the body after it’s no longer needed. Now, they unveil a new, smart version that is integrated into a coordinated network of four soft, flexible, wireless, wearable sensors and control units placed around the upper body.
The study will be published Friday (May 27) in the journal Science. The work was led by Northwestern’s John A. Rogers, Igor R. Efimov and Dr. Rishi Arora.
The sensors communicate with each other to continuously monitor the body’s various physiological functions, including body temperature, oxygen levels, respiration, muscle tone, physical activity and the heart’s electrical activity.
The system then uses algorithms to analyze this combined activity in order to autonomously detect abnormal cardiac rhythms and decide when to pace the heart and at what rate. All this information is streamed to a smartphone or tablet, so physicians can remotely monitor their patients.
The new transient pacemaker and sensor/control network can be used in patients who need temporary pacing after cardiac surgery or are waiting for a permanent pacemaker. The pacemaker wirelessly harvests energy from a node within the network — a small wireless device that softly adheres to the patient’s chest. This technology eliminates the need for external hardware, including wires (or leads).
To enable the system to communicate with the patient, the researchers incorporated a small, wearable haptic-feedback device that can be worn anywhere on the body. When the sensors detect an issue (such as low battery power, incorrect device placement or pacemaker malfunction), the haptic device vibrates in specific patterns that alert wearers and inform them of the problem.

A new antibiotic, synthesized at The Rockefeller University and derived from computer models of bacterial gene products, appears to neutralize even drug-resistant bacteria. The compound, named cilagicin, works well in mice and employs a novel mechanism to attack MRSA, C. diff, and several other deadly pathogens, according to a study published in Science.
The results suggest that a new generation of antibiotics could be derived from computational models. “This isn’t just a cool new molecule, it’s a validation of a novel approach to drug discovery,” says Rockefeller’s Sean F. Brady. “This study is an example of computational biology, genetic sequencing, and synthetic chemistry coming together to unlock the secrets of bacterial evolution.”
Acting on eons of bacterial warfare
Bacteria have spent billions of years evolving unique ways to kill one another, so it’s perhaps unsurprising that many of our most powerful antibiotics are derived from bacteria themselves. With the exceptions of penicillin and a few other notables derived from fungi, most antibiotics were first weaponized by bacteria to fight off fellow bacteria.
“Eons of evolution have given bacteria unique ways of engaging in warfare and killing other bacteria without their foes developing resistance,” says Brady, the Evnin Professor and head of the Laboratory of Genetically Encoded Small Molecules. Antibiotic drug discovery once largely consisted of scientists growing streptomyces or bacillus in the lab and bottling their secrets to treat human disease.
But with the rise of antibiotic-resistant bacteria, there is an urgent need for new active compounds — and we may be running out of bacteria that are easy to exploit. Untold numbers of antibiotics, however, are likely hidden within the genomes of stubborn bacteria that are tricky or impossible to study in the lab. “Many antibiotics come from bacteria, but most bacteria can’t be grown in the lab,” Brady says. “It follows that we’re probably missing out on most antibiotics.”
An alternative method, championed by the Brady lab for the past fifteen years, involves finding antibacterial genes in soil and growing them within more lab-friendly bacteria. But even this strategy has its limitations. Most antibiotics are derived from genetic sequences locked within clusters of bacterial genes, known as biosynthetic gene clusters, that function as a unit to collectively code for a series of proteins. But those clusters are often inaccessible with current technologies.

Until recently, nearly all pediatric liver cancers were classified as either hepatoblastoma or hepatocellular carcinoma. However, pediatric pathologists observed that some liver tumors have histological features that do not easily fit neither of these two carcinoma models. These cancers are less likely to respond to chemotherapy and patient outcomes are poor.
First author Dr. Pavel Sumazin, associate professor of pediatrics at Baylor College of Medicine and Texas Children’s Cancer and Hematology Center, and his colleagues looked to better characterize this high-risk cancer.
The researchers examined the molecular profiles of the tumors, including genetic alterations and gene expression profiles. They found that these profiles do not fit into the hepatoblastoma (HB) or hepatocellular carcinoma (HCC) molecular categories. Instead, these tumors exhibited recurring molecular features that have been observed in both HBs and HCCs. They designated these tumors as hepatoblastomas with hepatocellular carcinoma features (HBCs).
The team also examined HBC treatments and outcomes and found that they tended to be more resistant to standard chemotherapy and have poor outcomes when not treated with more aggressive surgical approaches, including transplantation. Based on their findings, the team proposed a diagnostic algorithm to stratify HBCs and guide specialized treatment.
“Our findings highlight the importance of molecular testing to accurately classify these tumors to optimize treatment recommendations at the time of initial diagnosis,” said Dr. Dolores López-Terrada, corresponding author of the paper, professor of pathology, immunology and pediatrics at Baylor and chief of the division of genomic medicine at Texas Children’s. “Our analysis suggested that children with HBCs may benefit from treatment strategies that differ from the guidelines for patients with hepatoblastoma and hepatocellular carcinoma.”
Find all the details of this study in the Journal of Hepatology.
Sumazin and López-Terrada both are members of the Dan L Duncan Comprehensive Cancer Center at Baylor. Other authors from Baylor and Texas Children’s include Tricia L. Peters, Stephen F. Sarabia, Hyunjae R. Kim, Martin Urbicain, Emporia Faith Hollingsworth, Karla R. Alvarez, Cintia R. Perez, Mohammad Javad Najaf Panah, Jessica L. Epps, Kathy Scorsone, Barry Zorman, Sarah E. Woodfield, John A. Goss, Sanjeev A. Vasudevan, Andras Heczey, Angshumoy Roy, Kevin E. Fisher, Kalyani R. Patel and Milton J. Finegold. Howard Katzenstein, Allison F. O’Neill, Rebecka Meyers, Greg Tiao, Jim Geller, Sarangarajan Ranganathan, Arun A. Rangaswami, all members of the Children’s Oncology Group Liver Tumor Committee, as well as Rita Alaggio and Alice Pozza also contributed. They are from the following institutions: Wolfson Children’s Hospital, Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School, Primary Children’s Hospital, Cincinnati Children’s Hospital Medical Center, University of California San Francisco and Bambino Gesù Children’s Hospital.
This work was funded by the Cancer Prevention and Research Institute of Texas (RP180674), the European Union’s Horizon 2020 (826121), the Schindler Foundation and the National Cancer Institute (R21CA223140).
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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.

Practice-changing research from Cedars-Sinai Cancer shows that a combination of androgen deprivation therapy — a commonly used hormone injection — plus pelvic lymph node radiation, kept nearly 90% of clinical trial patients’ prostate cancer at bay for five years. The findings were published in the peer-reviewed journal The Lancet.
The study also shows that patients with prostate cancer who didn’t receive androgen deprivation therapy — and who did not receive pelvic lymph node radiation — had a five-year survival of 70%.
“We can now confirm that pelvic lymph node treatment used together with androgen deprivation therapy, or even used as a stand-alone treatment option, greatly improves outcomes in patients with postoperative prostate cancer,” said Howard Sandler, MD, chair of the Department of Radiation Oncology at Cedars-Sinai Cancer and senior author of the study. “These findings are an encouraging step forward, both for the medical community and for the patients and their loved ones seeking curative treatment options.”
The international, Phase III clinical trial that served as the basis of The Lancet study, enrolled 1,716 patients between March 31, 2008, and March 30, 2015. Enrollees were separated into three groups.
Group one received salvage prostate bed radiotherapy — a standard radiation targeted to the area in which the prostate used to exist before its surgical removal. These patients had a median five-year survival of 71%.
The second group received the standard radiation treatment, in combination with androgen deprivation therapy. They had a median five-year survival of 81%.

Research from the lab of Matthew Lew at Washington University in St. Louis offers entirely new ways to see the very small.
The research — two papers by PhD students at the McKelvey School of Engineering — was published in the journals Optica and Nano Letters.
They have developed novel hardware and algorithms that allow them to visualize the building blocks of the biological world beyond three dimensions in a way that, until now, wasn’t feasible. After all, cells are 3D objects and full of “stuff” — molecules — that moves around, rotates, spins and tumbles to drive life itself.
Like traditional microscopes, the work of two PhD students in the Lew lab, Tingting Wu and Oumeng Zhang, uses light to peer into the microscopic world — but their innovations are anything but traditional. Currently, when people use light in imaging, they are likely interested in how bright that light is or what color it is. But light has other properties, including polarization.
“Oumeng’s work twists the polarization of light,” said Lew, assistant professor in the Preston M. Green Department of Electrical & Systems Engineering. “This way, you can see both how things translate (move in straight lines) and rotate at the same time” — something traditional imaging doesn’t do.
“The development of new technology and the capability to see things we previously couldn’t see is exciting,” Zhang said. This unique capability to track both rotation and position at the same time gives him unique insights into how biological materials — human cells and pathogens, for instance — interact.
Wu’s research also provides a new way to image cell membranes and, in a way, to see inside of them. Using fluorescent tracer molecules, she maps how the tracers interact with fat and cholesterol molecules in the membrane, determining how the lipids are arranged and organized.
“Any cell membrane, any nucleus, anything in the cell is a 3D structure,” she said. “This helps us probe the full picture of a biological system. This enables us, for any biological sample, to see beyond three dimensions — we see the 3D structure plus three dimensions of molecular orientation, giving us 6D images.”
The researchers developed computational imaging technology, which synergizes software and hardware together, to successfully see the previously unseeable.
“That’s part of the innovation,” Lew said. “Traditionally, biological imaging labs have been tied down to whatever commercial manufacturers are making. But if we engineer things differently, we can do so much more.”
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Materials provided by Washington University in St. Louis. Original written by Brandie Jefferson. Note: Content may be edited for style and length.

Many U.S. hospitals are postponing scans used to diagnose diseases after a Covid lockdown in China hobbled the main U.S. supplier of an imaging chemical.Doctors cannot seem to pinpoint what is wrong with Michael Quintos.Mr. Quintos, 53, a Chicago resident, has constant stomach pain. He has been hospitalized, and his doctors have tried everything including antibiotics, antacids, even removing his appendix. “I still don’t feel good,” Mr. Quintos said.His doctors recommend using a CT scan with contrast, imaging that relies on a special dye often injected into patients to better visualize their blood vessels, intestines and organs like the kidney and liver.But a nationwide shortage of the imaging agents needed for the procedure — the result of the recent lockdown in Shanghai to quell a Covid outbreak — has prompted hospitals to ration these tests except in emergencies.Like thousands of others in recent weeks, Mr. Quintos cannot get an exam using the contrast dye.And an alternative may not be enough to determine how to treat his illness.“The fact you can’t figure it out tells me you need more tools to figure it out,” he said.An estimated 50 million exams with contrast agents are performed each year in the United States, and as many as half the nation’s hospitals are affected by the shortage. Some are reserving much of their supply on hand for use in emergency rooms — where quick, accurate assessments are most dire.The shortage of a vital imaging agent is the latest example of the country’s vulnerability to disruptions in the global supply chain and its overreliance on a small number of manufacturers for such critical products. The Shanghai plant shuttered by the lockdown is operated by GE Healthcare, a unit of General Electric and one of two major suppliers of the iodinated contrast materials. The company supplies its dyes, Omnipaque and Visipaque, for the United States.Lawmakers expressed concern about the scarcity of imaging agents. “In the wealthiest nation on Earth, there should be no reason doctors are forced to ration lifesaving medical scans to compensate for a shortage of material,” Representative Rosa DeLauro, Democrat of Connecticut, said in a statement. “We are seeing supply chains break down because of consolidated industries experiencing manufacturing shortages and offshoring American jobs to China.”Shortages of the dye were reported to the U.S. Food and Drug Administration earlier this month, and the agency said it was working closely with manufacturers “to help minimize the impact on patients.” Yet even though GE Healthcare said this week that the situation was improving now that the plant had reopened, the shortages and patient delays could persist well into the summer because of a lag in how quickly replenished supplies could be distributed.Senator Patty Murray, Democrat of Washington, is pressing the agency to see what steps it is taking to address the shortage, according to a statement from her office. She has also introduced legislation, with Senator Richard Burr, Republican of North Carolina, to strengthen the supply chain.“The hits just keep on coming in this pandemic in the supply chain,” said Dr. Jamie McCarthy, the chief physician executive at Memorial Hermann Health System, a large hospital group in Houston.Health officials and doctors worry that the low supply and prolonged waits for tests will exacerbate earlier delays in care caused by the pandemic, when hospitals were overrun with Covid patients, they were facing sizable backlogs to get tests and elective procedures were canceled or postponed for months. Patients who overlooked troubling new symptoms or could not get follow-up appointments have suffered deteriorating health in many cases. Some doctors report more cancer patients with advanced-stage disease as a result.“We continue to be concerned about the impact of the delayed, deferred or ignored screening over the last few years,” said Dr. William Dahut, the chief scientific officer for the American Cancer Society.The lack of contrast dye in an exam can make it more difficult to diagnose cancer, he said, and can make it harder to see if a treatment is working. “Patients could be in a situation where clinical decisions are going to be negatively impacted,” Dr. Dahut said.In addition to using contrast with a CT angiogram to determine whether patients have a blood clot or internal bleeding, doctors often rely on CT scans with contrast to spot infections, bowel blockages or cancers. Doctors are also delaying some cardiac catheterizations.The shortage does not affect people undergoing mammograms and screenings for lung cancer because they do not require the imaging agents, and some patients may be able to have an M.R.I. in place of a CT scan or have the exam performed without contrast.But for many others, the shortage leaves them in limbo. “It’s definitely causing more stress for patients,” said Dr. Shikha Jain, an oncologist in Chicago. “There are patients who are getting frustrated because scans are delayed or canceled.”How long and to what extent the shortage will affect patient care is difficult to predict. For health care workers, for whom supply shortages and the pandemic have been so relentlessly taxing, “it feels like a never-ending marathon,” she said.Health care workers walked a residential street in lockdown in Shanghai on Monday. The city’s current covid precaution has affected a plant that manufactures the dyes.Aly Song/ReutersAt Memorial Hermann, the system has “throttled back” its use of contrast for elective procedures, Dr. McCarthy said, to preserve its supplies. The daily volume of CT scans being performed with contrast is about half of what it normally is, he says.At ChristianaCare, a Delaware-based hospital group, the supply depletion problem emerged in mid-May, and “became a serious issue very quickly,” said Dr. Kirk Garratt, the medical director for the group’s heart and vascular health center and a former president of the Society for Cardiovascular Angiography and Interventions. When other area hospitals began running out of dye, they started sending patients to ChristianaCare. “It impacted our burn rate,” he said.“We’re really worried here,” Dr. Garratt said. Explaining why elective procedures were being delayed, he added: “We feel we have to make this change now to ensure we have a supply so we can keep doing the urgent care we need.”A patient who fails an exercise stress test that may indicate a heart problem but is not in imminent danger is likely to wait for a scan and be treated with medications. But if a patient enters the emergency room and is sweating, with severe chest pain, an angiogram requiring contrast dye is immediately ordered to determine whether the person is suffering a heart attack.“We either fix that now, or in a few hours it will be too late to save you,” Dr. Garratt said.Hospitals generally rely on a single supplier for their contrast agents, and many facilities may have only a week or two of supply on hand, says Dr. Matthew Davenport, vice chair of the commission on quality and safety for the American College of Radiology and a professor at Michigan Medicine.He likens the situation to the current scarcity of baby formula, where only a handful of companies serve a critical market. “There is not a lot of redundancy in the system,” Dr. Davenport said.GE Healthcare said in a statement on Monday that its supply of iodinated contrast media products was increasing, although it did not provide an estimate for when the shortage would end. “We are working around the clock to expand production and return to full capacity as soon as possible and in line with local authorities” in China, the company said.“After having to close our Shanghai manufacturing facility for several weeks due to local Covid policies, we have been able to reopen and are utilizing our other global plants wherever we can,” the statement read.GE Healthcare said the plant was operating at 60 percent capacity and would be at 75 percent within the next two weeks. It also said it had taken other steps like increasing production of the products at its plant in Cork, Ireland, and flying some shipments to the United States.The company also said it was distributing the dye to hospitals based on their historical supply needs, which doctors said could prevent large hospital systems from stockpiling excessive amounts.Bracco Imaging, the other producer based in Milan, said in a statement that it was working to deliver supplies even to hospitals that were not customers to shore up use for “critical emergency procedures,” according to Fulvio Renoldi Bracco, the company’s chief executive. In a statement, he said that Bracco had also submitted a request to the F.D.A. for the potential importation of an equivalent agent that had not been approved for use in the United States. The agency declined to comment on the request.Nancy Foster, the vice president of quality and patient safety policy for the American Hospital Association, a trade group in Washington, likened the situation to the short supply of oxygen, among other treatment machines and remedies, during the pandemic. The group has urged G.E. to share more information about the shortage.“We need to figure out how to really create a much more robust, not as lean, supply system that has some give to it,” she said.

Even the smallest marine invertebrates — some barely larger than single-celled protists — are home to distinct and diverse microbial communities, or microbiomes, according to new research from University of British Columbia (UBC) biologists.
The study underscores that a vast diversity of animals have microbiomes, just as humans do. But more surprisingly, there’s little correlation between how closely related most animals are and how similar their microbiomes are — something widely assumed to be true based on the study of humans, larger mammals, and insects.
“This says a lot about how microbiomes originated and how they evolve today,” says UBC evolutionary microbiologist Dr. Patrick Keeling, senior author of the paper published today in Nature Microbiology.
“People might intuitively think the purpose of a microbiome is to be of benefit to the host animal, and that they co-evolve together. But the bacteria could care less about helping the animal host — they have their own agenda.”
“Most animals harbour a community of bacteria that are simply good at living in animals. From this ‘professional guild’ of animal specialists likely evolved the more elaborate, co-evolving microbiomes that are well studied in humans and insects. But as we looked at a broader set of smaller marine animals, it became clear that the microbiomes of bigger creatures are likely exceptions, not the rule.”
The team found the microbiomes of the tiny creatures differ from the microbes living in the surrounding environment, and often differed from the microbiome of even closely related invertebrates.

In a first-of-its-kind experiment, researchers have identified links between 127 genes and immune diseases, providing newfound insights into the sequence and timing of gene activity during the activation of T cells, a key process in regulating the body’s immune response.
The study, led by researchers from Open Targets, the Wellcome Sanger Institute and GSK, is published today (26 May 2022) in Nature Genetics. The result of a 3 year research effort, it is the first to show that numerous disease-linked variants are active during different stages of T cell activation, providing key information to guide the development of new therapies for immune diseases such as rheumatoid arthritis, type-1 diabetes and Crohn’s disease.
T cells are a group of white blood cells that help to manage the human immune system. When T cells malfunction, they can cause severe immune deficiencies that leave patients at high risk of infection, as well as more common autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, where the body mounts an attack against its own cells.
T cell activation is the first step in the immune system’s response to infection. Mapping this activation cycle at a molecular level is crucial to understanding where it can go wrong, and at which points therapeutic interventions can influence the process. But to date, only limited snapshots of the activation sequence have been mapped, such as looking at cells at a single time point. These snapshot techniques have also been unable to capture the diversity of cell subtypes present at each stage. Previous research from Open Targets showed that certain variations in DNA associated with immune diseases are linked to the T cells’ activation process1.
In this new study, researchers at the Wellcome Sanger Institute and GSK profiled over 650,000 individual cells using single-cell RNA sequencing technology2 to map the timing of gene activity for each cell subtype in the T cell activation process. They identified genes regulated by variations in DNA that were switched on or off in each cell, from their resting state through three different time points during T cell activation.
The team identified over 6,400 genes involved in the activation process. By comparing their data with known genetic variants for 13 immune diseases, they were able to find 127 genes associated with those diseases, some of which only manifested at specific time points that have not been previously studied.
Dr Blagoje Soskic, a first author of the study from the Wellcome Sanger Institute, said: “By profiling multiple time points during T cell activation, our study emphasises that genetic regulation can be specific for a particular cell state.Crucially, we were able to associate DNA variants with changes in the activity of specific genes, in particular cell types, at various times in the activation process. This unprecedented granularity is key to better understanding T cell activation, providing more in-depth data with which to pursue new treatments for immune disorders.”
By cataloguing the genes involved in T cell activation, this work provided the first step to a deeper understanding of immune processes and how they go awry in diseases. Follow up studies will need to alter each gene individually and observe how this affects the T cell activation process to understand its exact function. This will provide critical insights into how immune processes can be affected by variations in DNA, and how immune-mediated diseases develop.
John Lepore, SVP and Head of Research at GSK, said: “This study is already informing our early discovery portfolio by providing a novel, rich data set we are actively using to select genetically-informed drug targets for further validation experiments. As a founding partner of Open Targets, GSK is pleased that studies like this one can help further our shared understanding of the intersection of human genetics and immunology so we can get ahead of disease together.”
While this study focused on genes involved in 13 immune diseases, the approach and data generated can be applied to identifying genes involved in other disorders. The authors hope that this will shed light on how diseases are related or underpinned by similar biological processes, and highlight genetic risk factors. Ultimately, this work informs drug discovery to create new and better therapies for immune-mediated conditions.
Dr Gosia Trynka, the senior author of the study from the Wellcome Sanger Institute and Experimental Science Director of Open Targets, said: “T cells are particularly dynamic cells, so being able to capture their activation process in such detail is an important achievement. Our data will provide crucial insight into key immune system mechanisms, helping us to understand which genes are affected, what might be causing disease, and what factors might be putting patients at risk. In particular, the ability to link genetic variants strongly tied to immune diseases with changes in the activity of genes during this activation is a crucial first step to developing new treatments.”