Researchers identify key cause of pregnancy sickness and a potential way to prevent it

A team of researchers from the United States, United Kingdom and Sri Lanka have collected extensive evidence showing the cause of pregnancy sickness: a hormone known as GDF15.

Peer-Reviewed Publication

KECK SCHOOL OF MEDICINE OF USC

 

A new USC and University of Cambridge study finds that a hormone produced by the fetus – and a mother’s sensitivity to the hormone – are the cause behind nausea and vomiting of pregnancy, which, in its more extreme form can put the mother and fetus at risk.

The findings, which appear today in Nature, suggest that pre-pregnancy exposure to the hormone might mitigate symptoms in some women.

Nausea and vomiting have long been a forgone conclusion for expectant mothers, affecting 80% of women at some point during pregnancy. An additional 2% experience an extreme form called hyperemesis gravidarum (HG) that can lead to weight loss, dehydration and hospitalization. But little has been known about the cause. Recently, a growing body of evidence has linked the symptoms to GDF15, a hormone produced in the placenta that increases substantially during pregnancy. 

The new study supports the causal role of GDF15 in pregnancy sickness and reveals the role a woman’s sensitivity to the hormone has in determining the severity of her symptoms. Women exposed to lower levels of GDF15 before pregnancy experience more severe symptoms. 

“We now know that women get sick during pregnancy when they are exposed to higher levels of the hormone GDF15 than they are used to,” said Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine and the paper’s first author.

Women who are more sensitive to the hormone get the sickest, said Professor Sir Stephen O’Rahilly, MD, co-director of the Wellcome-Medical Research Council Institute of Metabolic Science at the University of Cambridge, who led the collaboration. “Knowing this gives us a clue as to how we might prevent this from happening.”

Lowering GDF15 is one way to potentially address pregnancy sickness—and the present study provides the first human evidence that it is likely safe to do so. Another way to reduce symptoms involves exposing women to GDF15 prior to pregnancy, to “prime” or prepare them for elevated levels of the hormone once they become pregnant.

“This study provides strong evidence that one or both of those methods will be effective in preventing or treating HG,”Fejzo said. 

Mounting evidence for GDF15

Fejzo, O’Rahilly and their team used a wide variety of approaches to clarify the link between GDF15 and pregnancy sickness, including patient genetic analyses and blood tests, studies of human cells and mice.

One key piece of evidence relates to the finding that a rare mutation in the gene that codes for GDF15 leads to abnormally low levels of the hormone throughout the body, putting women at greater risk of getting HG during pregnancy, when they are suddenly exposed to more of the hormone than they are accustomed to. But if their fetus also inherits the low-GDF15 mutation, research suggests the mother may be less likely to develop HG.

“For the first time, this interaction between mother and fetus helps explain why some women get HG during some—but not all—of their pregnancies,” Fejzo said, although additional research is needed to confirm the findings.

Along similar lines, the researchers found that patients with beta thalassemia, an inherited blood disorder that causes chronically high levels of GDF15, are largely protected against HG, as well as milder forms of pregnancy sickness.

The research team also used an animal model to explore whether exposing mothers to GDF15 before pregnancy could help prevent pregnancy sickness. Mice exposed to a high dose of GDF15, similar to levels seen in pregnancy, showed appetite loss indicative of nausea. But mice that were first exposed to a low “priming dose” of GDF15 did not show the same appetite loss after the high dose of GDF15.

For the first time in humans, the study also provides evidence that having lower GDF15 levels during a pregnancy can be safe, Fejzo said. In pregnancies where both the mother and fetus had the low-GDF15 mutation, babies were born normal and healthy, suggesting that lowering GDF15 levels during pregnancy may be another safe way to prevent HG.

Preventing pregnancy sickness

The next step for the research team is to test whether priming women with GDF15 exposure prior to pregnancy can reduce nausea and vomiting or even prevent HG. Fejzo is now applying for funding to test whether metformin, a drug that increases GDF15 levels, is safe for use in patients who have a history of HG.

The researchers also hope to test an additional class of drugs that may help with HG by blocking GDF15 from binding to its receptor in the brain. Several such drugs are already in clinical trials for cachexia (a complex metabolic condition that causes extreme weight loss) and for cancer patients with nausea and vomiting.

Fejzo, who has firsthand experience with HG, said these findings offer hope for women who like her have experienced severe illness during pregnancy.

“Hopefully, now that we understand the main cause of HG, we’re a step closer to developing effective treatments to stop other mothers from going through what I, and many other women, have experienced,” she said.

About this research

In addition to Fejzo and O’Rahilly, the study's other authors are Victoria Cortessis, Patrick Mullin, Emmy Jin, Alyssa Kam and Nicholas Mancuso from the Keck School of Medicine of USC; Kimber McGibbon, from the Hyperemesis Education and Research Foundation; Nuno Rocha, Irene Cimino, Sam Lockhart, Clive Petry, Richard Kay, Keith Burling, Paul Barker, Amy George, Sung Gong, Emma Cook, Debra Rimmington, Kara Rainbow, Dominic Withers, Fiona Gribble, Giles Yeo, Brian Lam, Vladimir Saudek, Ieuan Hughes, Ken Ong, John Perry, Amy Sutton-Cole, Miriam Baumgarten, Steve Charnock-Jones, Anthony Coll, Claire Meek and Gordon Smith from the University of Cambridge; Nirmani Yasara and Sachith Mettananda from the University of Kelaniya, Sri Lanka; Anuja Premawardhena from North Colombo Teaching Hospital, Kadawatha, Sri Lanka; Archie Campbell and Caroline Hayward from the University of Edinburgh, Ozren Polasek from the University of Split; Gannie Tzoneva from Regeneron Genetics Center; and Paul Welsh and Naveed Sattar from the University of Glasgow.

This work is supported primarily by the Medical Research Council UK and National Institute for Health and Care Research UK (SOR). Additional funding sources are detailed in the publication.

 

Disclosure: Marlena Fejzo is a paid consultant for Materna Biosciences, Inc., NGM Biopharmaceuticals, and a Board member and Science Advisor for the Hyperemesis Education and Research Foundation.

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JOURNAL

Nature

DOI

10.1038/s41586-023-06921-9. 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Gdf15 linked to maternal risk of nausea and vomiting during pregnancy

ARTICLE PUBLICATION DATE

13-Dec-2023

COI STATEMENT

DSC-J reports non-financial support from Roche Diagnostics Ltd, outside the submitted work; G.C.S.S. reports personal fees and non-financial support from Roche Diagnostics Ltd, outside the submitted work; DSC-J and GCSS report grants from Sera Prognostics Inc, non-financial support from Illumina Inc, outside the submitted work. G.C.S.S. has been a paid consultant to GSK (preterm birth) and is a member of a Data Monitoring Committee for GSK trials of RSV vaccination in pregnancy. NS and PW has received grant funding from Roche diagnostics paid to their institution for biomarker work inclusive of GDF-15 measurements. JRBP is an employee and shareholder of Adrestia Therapeutics Ltd. KMG is a paid consultant for BYOMass Inc. CLM has received research funding and equipment at reduced cost from Dexcom Inc. GT is a full-time employee of Regeneron Genetics Center and receives salary, stock and stock options as compensation. FMG has received research grant support from Eli-Lilly and Astra Zeneca outside the scope of this current work. MSF is a paid consultant for Materna Biosciences, Inc., NGM Biopharmaceuticals, and a Board member and Science Advisor for the Hyperemesis Education and Research Foundation. SO has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, Astra Zeneca, NorthSea Therapeutics and Courage Therapeutics. Part of the work in this paper is the subject of a pending patent application relating to therapy for hyperemesis gravidarum filed by Cambridge Enterprise Limited (GB application No. 2304716.0; Inventor: Professor Stephen O’Rahilly). SL and NR are named creators on this patent. All other authors declare no competing interests.

Use of e-cigarettes and cigarettes during late pregnancy among adolescents

JAMA Network Open

Peer-Reviewed Publication

JAMA NETWORK

About The Study: The findings from this study using 2016-2021 data on 10,000 adolescents in the U.S. suggest that pregnant adolescents increasingly used e-cigarettes, with the highest use among white adolescents. Results from this analysis found that, unlike cigarette use, e-cigarette use during late pregnancy was not statistically significantly associated with an increased risk of small-for-gestational-age birth among adolescents. Due to the uncertainty of this nonsignificant association, future research could benefit from a larger sample size. 

Authors: Xiaozhong Wen, M.D., Ph.D., of the State University of New York at Buffalo, is the corresponding author. 

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamanetworkopen.2023.47407)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

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About JAMA Network Open: JAMA Network Open is an online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication. 

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JOURNAL

JAMA Network Open

 

What happens in the brain while daydreaming?

Observations in mice hint at role of daydreams in remodeling the brain

Peer-Reviewed Publication

HARVARD MEDICAL SCHOOL

At a glance:

• During quiet waking, brain activity in mice suggests the animals are daydreaming about a recent image.
• Having daydreams about a recently viewed image predicted how the brain would respond to the image in the future.
• The findings provide a clue that daydreams may play a role in brain plasticity.

You are sitting quietly, and suddenly your brain tunes out the world and wanders to something else entirely — perhaps a recent experience, or an old memory. You just had a daydream.

Yet despite the ubiquity of this experience, what is happening in the brain while daydreaming is a question that has largely eluded neuroscientists.

Now, a study in mice, published Dec. 13 in Nature, has brought a team led by researchers at Harvard Medical School one step closer to figuring it out.

The researchers tracked the activity of neurons in the visual cortex of the brains of mice while the animals remained in a quiet waking state. They found that occasionally these neurons fired in a pattern similar to one that occurred when a mouse looked at an actual image, suggesting that the mouse was thinking — or daydreaming — about the image. Moreover, the patterns of activity during a mouse’s first few daydreams of the day predicted how the brain’s response to the image would change over time.

The research provides tantalizing, if preliminary, evidence that daydreams can shape the brain’s future response to what it sees. This causal relationship needs to be confirmed in further research, the team cautioned, but the results offer an intriguing clue that daydreams during quiet waking may play a role in brain plasticity — the brain’s ability to remodel itself in response to new experiences.

“We wanted to know how this daydreaming process occurred on a neurobiological level, and whether these moments of quiet reflection could be important for learning and memory,” said lead author Nghia Nguyen, a PhD student in neurobiology in the Blavatnik Institute at HMS.

An overlooked brain region

Scientists have spent considerable time studying how neurons replay past events to form memories and map the physical environment in the hippocampus, a seahorse-shaped brain region that plays a key role in memory and spatial navigation.

By contrast, there has been little research on the replay of neurons in other brain regions, including the visual cortex. Such efforts would provide valuable insights about how visual memories are formed.

“My lab became interested in whether we could record from enough neurons in the visual cortex to understand what exactly the mouse is remembering — and then connect that information to brain plasticity,” said senior author Mark Andermann, professor of medicine at Beth Israel Deaconess Medical Center, and professor of neurobiology at HMS.

In the new study, the researchers repeatedly showed mice one of two images, each consisting of a different checkerboard pattern of gray and dappled black and white squares. Between images, the mice spent a minute looking at a gray screen. The team simultaneously recorded activity from around 7,000 neurons in the visual cortex.

The researchers found that when a mouse looked at an image, the neurons fired in a specific pattern, and the patterns were different enough to discern image one from image two. More important, when a mouse looked at the gray screen between images, the neurons sometimes fired in a similar, but not identical, pattern, as when the mouse looked at the image, a sign that it was daydreaming about the image. These daydreams occurred only when mice were relaxed, characterized by calm behavior and small pupils.

Unsurprisingly, mice daydreamed more about the most recent image — and they had more daydreams at the beginning of the day than at the end, when they had already seen each image dozens of times.

But what the researchers found next was completely unexpected.

Throughout the day, and across days, the activity patterns seen when the mice looked at the images changed — what neuroscientists call “representational drift.” Yet this drift wasn’t random. Over time, the patterns associated with the images became even more different from each other, until each involved an almost entirely separate set of neurons. Notably, the pattern seen during a mouse’s first few daydreams about an image predicted what the pattern would become when the mouse looked at the image later.

“There’s drift in how the brain responds to the same image over time, and these early daydreams can predict where the drift is going,” Andermann said.

Finally, the researchers found that the visual cortex daydreams occurred at the same time as replay activity occurred in the hippocampus, suggesting that the two brain regions were communicating during these daydreams. 

To sit, perchance to daydream

Based on the results of the study, the researchers suspect that these daydreams may be actively involved in brain plasticity.

“When you see two different images many times, it becomes important to discriminate between them. Our findings suggest that daydreaming may guide this process by steering the neural patterns associated with the two images away from each other,” Nguyen said, while noting that this relationship needs to be confirmed.   

Nguyen added that learning to differentiate between the images should help the mouse respond to each image with more specificity in the future.  

These observations align with a growing body of evidence in rodents and humans that entering a state of quiet wakefulness after an experience can improve learning and memory.

Next, the researchers plan to use their imaging tools to visualize the connections between individual neurons in the visual cortex and to examine how these connections change when the brain “sees” an image.

“We were chasing this 99 percent of unexplored brain activity and discovered that there’s so much richness in the visual cortex that nobody knew anything about,” Andermann said.

Whether daydreams in people involve similar activity patterns in the visual cortex is an open question, and the answer will require additional experiments. However, there is preliminary evidence that an analogous process occurs in humans when they recall visual imagery.

Randy Buckner, the Sosland Family Professor of Psychology and of Neuroscience at Harvard University, has shown that brain activity in the visual cortex increases when people are asked to recall an image in detail. Other studies have recorded flurries of electrical activity in the visual cortex and the hippocampus during such recall.

For the researchers, the results of their study and others suggest that it may be important to make space for moments of quiet waking that lead to daydreams. For a mouse, this may mean taking a pause from looking at a series of images and, for a human, this could mean taking a break from scrolling on a smartphone.

“We feel pretty confident that if you never give yourself any awake downtime, you’re not going to have as many of these daydream events, which may be important for brain plasticity,” Andermann said.

Authorship, funding, disclosures

Additional authors on the paper include Andrew Lutas, Oren Amsalem, Jesseba Fernando, Andy Young-Eon Ahn, Richard Hakim, Josselyn Vergara, Justin McMahon, Jordane Dimidschstein, and Bernardo Sabatini.

The research was supported by a National Defense Science and Engineering Fellowship, a Howard Hughes Medical Institute Gilliam Fellowship, the National Institutes of Health (F32 DK112589; DP2 DK105570; DP1 AT010971-02S1; R01 MH12343), a Davis Family Foundation award, a McKnight Scholar Award, a Harvard Mind Brain Behavior Interfaculty Initiative Faculty Research Award, the Harvard Brain Science Initiative Bipolar Disorder Seed Grant, and by Kent and Liz Dauten.

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JOURNAL

Nature

DOI

10.1038/s41586-023-06810-1 

ARTICLE TITLE

Cortical reactivations predict future sensory responses

ARTICLE PUBLICATION DATE

13-Dec-2023

 

New embryo-like model simulates early human blood production

Peer-Reviewed Publication

UNIVERSITY OF PITTSBURGH

 

IMAGE: 

HEX-EMBRYOID MODEL SHOWING EARLY BLOOD CELLS (GREEN) THAT HAVE FORMED INSIDE OF BLOOD VESSELS (RED) SURROUNDED BY YOLK SAC MESODERM CELLS (BLUE) THAT SUPPORT THESE TISSUES.

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CREDIT: MO EBRAHIMKHANI AND JOSHUA HISLOP

University of Pittsburgh researchers have developed a new embryo-like model derived from adult cells that replicates key features of early human development, including the generation of blood cells.

Described today in Nature, the new heX-Embryoid model provides a unique window into early human development, which has been shrouded in mystery because of ethical and technical challenges of studying this period of life. HeX-Embryoids, which do not use fetal tissue and cannot develop into an embryo, could enhance research on genetic diseases and infertility and make cells to replace or repair tissues for regenerative medicine applications.

“Human embryos — unlike those in other species, including some of our closest primate relatives — embed themselves into the uterine wall to proceed with development. Because the embryo is smaller than the tip of a sewing needle and hidden from view, these early stages are difficult to study,” said senior author Mo Ebrahimkhani, M.D., associate professor in the Department of Pathology, the Pittsburgh Liver Institute and the Department of Bioengineering at Pitt. “Our embryo-like model will unlock this ‘black box’ of human development, which could help solve the mystery of why about 60% of pregnancies fail in the first two weeks — before the mother even misses a menstrual period — and pave the way for new therapies.”

Remarkably, the heX-Embryoid models formed structures similar to the first sites to produce blood cells that support the developing embryo called blood islands. The researchers also detected progenitors of red blood cells, platelets and different types of white blood cells.  According to Ebrahimkhani, the generation of blood cells is a key advance of this embryo model that pushes the field forward.

“We were able to model something extremely similar to the earliest stages of blood production in humans,” said Ebrahimkhani, who is also a member of the Pittsburgh Liver Research Center and the McGowan Institute of Regenerative Medicine of Pitt and UPMC. “This is exciting because there are extensive possibilities to apply this model to better understand how blood is formed and develop better methods for growing cells for blood transfusions, novel cell therapies and hematopoietic stem cell transplants.”

To develop heX-Embryoids, the researchers started with induced pluripotent stem cells (iPSCs), which are generated from adult cells that have been reverted to a state where they can develop into any other cell. Then they programmed the iPSCs with a genetic circuit that directs early tissue development, which is only switched on by a chemical called doxycycline. When these engineered iPSCs are mixed in a lab dish with standard iPSCs and induced by adding doxycycline, the engineered cells grow and trigger the standard iPSCs to organize into three-dimensional structures that resemble certain features of an embryo.

In normal embryonic development, cells repeatedly sort and divide to eventually form distinct sections: the trophoblast, which will become the placenta, an extra-embryonic cell layer that produces the nutrient-providing yolk sac and the embryonic layer that will give rise to the embryo itself and the amniotic sac that protects the developing embryo. 

Like an embryo, heX-Embryoids have embryonic tissue and a yolk sac structure. The tissue remains anchored to the lab dish as it grows, forming a large sheet of yolk sac with dozens of embryoids sitting side by side.

“The yolk sac doesn’t contribute directly to making cells that form the embryo, but it’s a really important tissue because it’s responsible for nourishment and influencing where the head and tail of the embryo will be positioned,” said lead author Joshua Hislop, a graduate student in Ebrahimkhani’s lab at Pitt. “Other embryo-like models have had very limited differentiation of yolk sac tissue, so our model offers a unique opportunity to robustly follow this structure and study events like blood development.”

HeX-Embryoids do not contain the placenta-forming trophoblast layer, and the yolk sac is open, not a closed cavity. The lack of these features prevents embryoids becoming a true embryo or having the potential to be implanted to develop completely. 

Because heX-Embryoids are derived from reprogrammed adult skin cells, they could theoretically be made from any individual, allowing researchers to study diverse genetic backgrounds.

An important advantage of the heX-Embryoid system over other embryo-like models is that it self-organizes as it grows from the two-dimensional lab dish, uses standard growth media and is switched on by a single chemical, rather than relying on a complicated cocktail of growth factors that can be difficult to replicate. According to Ebrahimkhani, this unique approach means that heX-Embryoids can be easily stored, shipped and grown in different labs with a high level of efficiency. 

“For a model to be adopted by the scientific community and do its job of contributing to new discoveries, it must be efficient,” said Ebrahimkhani. “For example, it will be very difficult to make progress in researching miscarriage if the model itself fails most of the time. Our heX-Embryoid model overcomes this problem.”

Other authors on the study were Kamyar Keshavarz F., Rayna Schoenberger, Ryan LeGraw, Jeremy Velazquez, Ph.D., Tahere Mokhtari, Mohammad Naser Taheri, Matthew Rytel, Simon Watkins, Ph.D., Donna Stolz, Ph.D., and Samira Kiani, M.D., all of Pitt; Qi Song, Ph.D., Amir Alavi, Ph.D., and Ziv Bar-Joseph, Ph.D., all of Carnegie Mellon University; Susana Chuva de Sousa Lopes, Ph.D., of Leiden University Medical Center; and Berna Sozen, Ph.D., of Yale University.

This research was supported by the National Heart, Lung, and Blood Institute (R01 HL141805), the National Science Foundation (#2134999), the National Institutes of Health (1R01GM122096, OT2OD026682, 1U54AG075931, 1U24CA268108, T32 EB001026 and 1S10OD019973-01), the National Institute of Biomedical Imaging and Bioengineering (EB028532), the Pittsburgh Liver Research Center (NIHNIDDK P30DK120531), the Pitt Department of Pathology startup fund, the Pitt Center for Biological Imaging and the Pitt Flow Cytometry Core facilities. 

 

Top-down view of circular heX-Embryoid model showing the interface of engineered induced pluripotent stem cells (iPSCs) forming the green outer layer and non-engineered iPSCs forming the inner layer where processes that mimic early embryonic organization will occur. The cells surrounding this circular area are similar to the embryonic yolk sac.

CREDIT

Mo Ebrahimkhani and Joshua Hislop

JOURNAL

Nature

DOI

10.1038/s41586-023-06914-8 

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Modeling Post-Implantation Human Development to 1 Yolk Sac Blood Emergence

ARTICLE PUBLICATION DATE

13-Dec-2023

 

DNA discovery opens door to personalised medicine for Indigenous Australians

Peer-Reviewed Publication

AUSTRALIAN NATIONAL UNIVERSITY

 

IMAGE: 

DR HARDIP PATEL. PHOTO: JAMIE KIDSTON/ANU

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CREDIT: CREDIT: JAMIE KIDSTON/ANU

The most comprehensive analysis of Indigenous Australians’ genomes collected to date has revealed an “abundance” of DNA variations – some of which have never been reported anywhere else in the world – paving the way for new, personalised treatments that address health inequities for Aboriginal and Torres Strait Islander peoples.

A team of Australian researchers, led by scientists from The Australian National University (ANU), found DNA differences between Indigenous Australians living in the Tiwi Islands and Indigenous peoples living in the Australian desert is equivalent to comparing the genetic information of someone from Bangladesh to the United Kingdom.

The researchers detected hundreds of thousands of ‘structural gene variants’ that affect large segments of DNA. These variants occur naturally in different individuals of a population, make up most of the genetic differences between individuals, and may be linked to genetic disease in some families.

“The DNA sequencing shows for the first time this level of DNA variation observed anywhere else in the world outside of Africa, reflecting Aboriginal and Torres Strait Islander peoples’ deep cultural and linguistic diversity and long-standing connection to the Australian continent,” Dr Hardip Patel, from ANU, said.

“Some of the DNA variations we discovered appear to be exclusively found in Indigenous Australians, while others appear to be found only in one out of the four Indigenous communities that we consulted and worked with.

“Previously we’ve had to try to utilise the DNA of non-Indigenous populations to help diagnose and treat disease among Indigenous Australians, which has proven difficult and is often less reliable. But now we have a new, more accurate and personalised genomic dataset to build off.”

Led by the National Centre for Indigenous Genomics (NCIG) at ANU, research teams examined the DNA of 160 Indigenous Australians from four Aboriginal communities in the Central Desert, Far North Queensland and two islands off the coast of the Northern Territory.

It’s hoped the research will improve health outcomes for Indigenous Australians by enabling tailored treatments for a range of conditions including diabetes, coronary disease and cancer – all of which disproportionately impact Indigenous peoples compared to the rest of the Australian population.

“Aboriginal people have long said you can’t treat us the same because we are so different. Having scientific proof to show this is true is remarkable,” ANU Associate Professor Azure Hermes, a proud Gimuy Walubara Yidinji woman and deputy director of NCIG, said.

“Clinicians must realise treatment options for Indigenous Australians can’t be viewed through a one-model-fits-all lens. We are not a single genetic group and can’t be lumped into one category.”

Dr Ira Deveson, from the Garvan Institute of Medical Research, said: “we identified more than 160,000 structural gene variants, which is more than any previous population-level, long-read study to date.”

“The research team discovered at least 300 structural variants in each individual that appear to be unique to Indigenous Australians.”

A genome is equivalent to an instruction manual for the body. It is a blueprint that contains all the genetic information we need to grow, develop, function and respond to the environments in which we live.

Genomics medicine harnesses an individuals’ genetic information to develop personalised prevention and treatment strategies for a range of health conditions, as well as rare genetic disease.

“The code embedded in our genome is unique to each individual – it’s what makes us different to other human beings. Variations within our genetic code can not only explain the way we look but can sometimes impact our risk of developing certain diseases,” Dr Patel said.

“We still don’t understand why Aboriginal people are more prone to health conditions such as kidney disease, diabetes, coronary disease, cancer and other conditions. But genomics might be an important piece of the puzzle that helps unlock some of these answers.”

Associate Professor Hermes said the project is also about giving Indigenous communities oversight of how their genetic information is used by science.

“Our goal is to work with and empower Indigenous Australians to take ownership of their genetic information and show them the power of genomics and the health benefits it can deliver,” Associate Professor Hermes said.

“It’s taken us almost eight years to get to this point and has only been made possible because of guidance by Indigenous communities, careful consultation, building relationships with communities and understanding their priorities and protocols.”

NCIG houses a biobank of 7,000 blood samples from 35 Aboriginal communities across Australia. The centre is working in collaboration with Indigenous communities to figure out the best ways to care for and return these samples.

"At ANU we have established a plan for communities to decide the future use and management of these important blood samples and the data that can be generated from them,” Associate Professor Hermes said.

“This is an important step toward long-lasting reconciliation with Indigenous Australians.”

The research is published in two separate papers in Nature. This work was led by ANU in collaboration with The University of Melbourne and the Garvan Institute of Medical Research, as well as other institutions across the country.

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JOURNAL

Nature

DOI

10.1038/s41586-023-06831-w 

METHOD OF RESEARCH

Case study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Indigenous Australian genomes show deep structure and rich novel variation

ARTICLE PUBLICATION DATE

13-Dec-2023

 

Using next-gen CRISPR tool, Gladstone scientists create unprecedented molecular map of human immune response

Nature study represents a major stride for human genetics; findings will accelerate the development of new and better therapies for cancer and autoimmune diseases.

Peer-Reviewed Publication

GLADSTONE INSTITUTES

 

IMAGE: 

CARL WARD, PHD, A POSTDOCTORAL RESEARCHER IN THE MARSON LAB AT GLADSTONE INSTITUTES, WAS CO-FIRST AUTHOR OF THE LANDMARK STUDY IN NATURE, ALONG WITH FELLOW CO-FIRST AUTHOR RALF SCHMIDT, MD, A MEDICAL FELLOW AT THE MEDICAL UNIVERSITY OF VIENNA WHO IS A FORMER POSTDOCTORAL RESEARCHER AT GLADSTONE. HERE, WARD SPEAKS WITH ZEV ARMOUR-GARB, A STUDENT INTERN IN THE MARSON LAB.

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CREDIT: GLADSTONE INSTITUTES, 2023

SAN FRANCISCO—December 13, 2023—In a study of historic scale, scientists at Gladstone Institutes have created an intricate map of how the immune system functions, examining the detailed molecular structures governing human T cells using the next-generation CRISPR tool known as base editing.

Their findings, published in Nature, uncover detailed information that could help overcome the limitations of today’s immunotherapies and identify new drug targets for a wide range of diseases, including autoimmune diseases and cancer.

Led by Gladstone Senior Investigator Alex Marson, MD, PhD, the team dove deep into the DNA of T cells, pinpointing specific nucleotides—the basic units of genetic information in DNA—that influence how immune cells respond to stimuli. In all, they scrutinized more than 100,000 sites across nearly 400 genes found in functioning human T cells.

Nucleotides serve as the basic code for constructing proteins in cells, so by identifying these specific units of DNA the scientists now have clarity into exact locations within proteins that tune immune responses critical for health. The results serve as a bullseye, marking sites that can be targeted with future immune-modulating drugs.

“We’ve created astoundingly precise and informative maps of DNA sequences and protein sites that tune actual human immune responses,” says Marson, who is also director of the Gladstone-UCSF Institute of Genomic Immunology and the Parker Institute for Cancer Immunotherapy at Gladstone Institutes. “Our mapped sites provide insights into mutations found in patients with immune disorders. The enormous genetic dataset also works as a sort of cheat sheet, explaining biochemical code that will help us program future immunotherapies for cancer, autoimmunity, infections, and beyond.”

T cells play a central role in immune response and regulation, making them of keen interest to scientists looking to solve complex diseases such as cancer or immune disorders. For the past decade, the Marson lab and others have established the gene-editing technology CRISPR to study how primary immune cells work. For this study, the team went a step further, leveraging a newer CRISPR-based technology known as base editing to make more targeted changes to hundreds to thousands of DNA sites across individual genes—painting a much more nuanced picture at high-resolution.

Because the study was conducted using primary T cells sourced from human blood donors, results hold great clinical relevance, noted Ralf Schmidt, MD, co-first author of the paper. Schmidt, a medical fellow at the Medical University of Vienna, is a former postdoctoral researcher at Gladstone Institutes.

“This study is zooming into the genetic basis of immune cell functions,” Schmidt says. “We can now interrogate T cells at nucleotide resolution, generating blueprints for drug development, diagnostics, and further scientific endeavors.”

With immense pools of data generated from the more-than-100,000 sites on T cells, computational genomics became a critical piece of the study. Carl Ward, PhD, a Gladstone postdoctoral researcher and co-first author, led the team’s efforts in this area, keying in on important measures of cell function to create what he hopes can serve as an indispensable resource for immunologists and drug developers alike.

“We can now assign functions to specific mutations that had been a mystery,” Ward says. “Our detailed functional maps also can be combined with existing datasets and AI tools to amplify our discoveries and predict new avenues of investigation.”

Ward notes that the new Nature study is just the beginning of a new chapter of immune cell discoveries: “Our tools for solving disease are going to get better and better,” he says. “We’re nearing a point where we can use these maps to design therapies that can tune up the T cell function for cancer treatments or tune it down to treat autoimmune disease.”

About the Study

The paper, “Base editing mutagenesis maps functional alleles to tune human T cell activity,” was published in Nature on December 13. In addition to Alex Marson, Ralf Schmidt, and Carl Ward, authors are: Rama Dajani, Zev Armour-Garb, Mineto Ota, Vincent Allain, Rosmely Hernandez, Galen Xing, Laine Goudy, Charlotte Wang, Yan Yi Chen, Chun Jimmie Ye, Luke A. Gilbert, Justin Eyquem, Jonathan K. Pritchard, and Stacie E. Dodgson.

About Gladstone

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.

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JOURNAL

Nature

ARTICLE TITLE

Base editing mutagenesis maps functional alleles to tune human T cell activity

ARTICLE PUBLICATION DATE

13-Dec-2023

 

New study sheds light on how the brain learns to seek reward

Rewards don’t just reinforce a specific action—they quickly change the whole pattern of how we behave

Peer-Reviewed Publication

ALLEN INSTITUTE

 

IMAGE: 

ALLEN INSTITUTE/GABRIEL RODRIQUEZ

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CREDIT: ALLEN INSTITUTE/GABRIEL RODRIQUEZ

By Jake Siegel

Imagine you’re teaching a dog to play fetch. You throw a ball, and your dog sprints after it, picks it up, and runs back. You then reward your panting pup with a treat. But now comes the real trick for your dog: figuring out which part of that sequence earned the treat. Scientists call this the 'credit assignment problem' in the brain. It's a fundamental question about understanding which actions are responsible for the positive outcomes we experience.  

Dopamine, a key chemical messenger in the brain, is known to play a crucial role in this process. But exactly how the brain links specific actions to dopamine’s release has remained unclear.

A study published today in Nature by scientists at the Allen Institute, Columbia University’s Zuckerman Mind Brain Behavior Institute, the Champalimaud Centre for the Unknown and Seattle Children’s Research Institute sheds new light on this mystery. It reveals how dopamine not only signals a reward but also guides animals to home in on the specific behaviors that lead to these rewards through trial and error.

Intriguingly, the research also shows that the brain's reward system can swiftly and dynamically alter the full range of an animal’s movements and behaviors. This highlights a sophisticated learning strategy where behaviors are not just reinforced, but actively shaped and fine-tuned through experience, said Rui Costa, D.V.M, Ph.D. , the study’s senior author.

"When you reinforce behavior, we often think it's just that action,” said Costa, the president and CEO of the Allen Institute. “But no: you're changing the entire behavioral structure. And what was really surprising was how rapid it was."

 

Decoding how dopamine shapes learning

To uncover those insights, the team collaborated with engineers and neuroscientists at the Champalimaud Centre for the Unknown to develop a novel “closed loop” system that could link specific actions by mice to real-time dopamine release. The researchers outfitted mice with wireless sensors to track their movements within a simple controlled space. They then fed this data into a machine learning algorithm, which categorized these actions into distinct groups. The researchers then used optogenetics, a method for controlling neurons with light, to stimulate dopamine neurons once the mice performed predefined “target actions.”

They found that mice swiftly changed their behavior in response to dopamine release. Initially, they not only increased the frequency of the target action, but also of similar actions and those that occurred a few seconds before the dopamine release. Meanwhile, actions dissimilar to the target rapidly decreased. Over time, this refinement became more precise, with the mice increasingly focusing on the exact action that led to dopamine release.

The study also examined how mice learn a series of actions, unveiling a key process similar to rewinding time to understand what leads to a reward. When actions triggering dopamine occurred further apart, the mice learned more slowly. This shows that longer waits between actions make it harder for mice to connect the sequence with the reward. In essence, actions right before the reward are quickly grasped and improved upon, while earlier actions are refined more gradually. This ‘rewinding’ process strengthens the behavior and helps the mice progressively identify which precise actions and sequences yield the reward.

The findings could impact diverse fields like education and artificial intelligence (AI), said lead author Jonathan Tang, Ph.D. , an assistant professor at University of Washington Medicine – Pediatrics, Seattle Children’s Research Institute. For example, allowing for exploration, mistakes, and gradual refinement in the classroom may be more in line with our brain's innate learning processes.

In AI, the insights could lead to more sophisticated and efficient learning systems. By better replicating biological learning processes, we could create AI that is better at adapting to new data and situations.

This study offers deeper insight into how our brains learn and adapt through trial and error—whether you’re a scientist or a pup.

“We take a lot of stuff for granted about how things work, including credit assignment,” said Tang, who started the research with Costa while at Columbia University. “But it’s when you really start diving in that you realize the complexity. This is why people do science: to home in on the truth of the matter.”

 

About the Allen Institute

The Allen Institute is an independent, 501(c)(3) nonprofit research organization founded by philanthropist and visionary, the late Paul G. Allen. The Allen Institute is dedicated to answering some of the biggest questions in bioscience and accelerating research worldwide. The Institute is a recognized leader in large-scale research with a commitment to an open science model. Its research institutes and programs include the Allen Institute for Brain Science, launched in 2003; the Allen Institute for Cell Science, launched in 2014; the Allen Institute for Immunology, launched in 2018; and the Allen Institute for Neural Dynamics, launched in 2021. In 2016, the Allen Institute expanded its reach with the launch of The Paul G. Allen Frontiers Group, which identifies pioneers with new ideas to expand the boundaries of knowledge and make the world better. For more information, visit alleninstitute.org.

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Media Contact
Peter Kim, Sr. Manager, Media Relations
peter.kim@alleninstitute.org

 

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JOURNAL

Nature

DOI

10.1038/s41586-023-06941-5 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Dynamic behaviour restructuring mediates dopamine-dependent credit assignment

ARTICLE PUBLICATION DATE

13-Dec-2023