CSHL and global collaborators map Solanum pan-genome

Peer-Reviewed Publication

Cold Spring Harbor Laboratory

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As part of a landmark study, African eggplant crops (inset) cultivated from a field in Mukono, Uganda (left) underwent trait analysis at Uplands Farm in Cold Spring Harbor, NY (right).

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Credit: Lippman lab/CSHL

About 75 percent of the world’s food comes from 12 plants. Scientists estimate up to 30,000 species are edible. Not only does this bottleneck jeopardize our food supply if a major crop is impacted by drought or disease—it also limits our choices at the grocery store. For years, breeders have struggled to expand food selection. Part of the reason is a problem familiar to biologists. The same methods of selecting for advantageous traits can produce different results in related species. Now, Cold Spring Harbor Laboratory (CSHL) has unearthed a likely solution to the predictability issue.

CSHL researchers and colleagues around the globe have sequenced dozens of complete genomes for the plant genus that includes tomatoes, potatoes, and eggplants. In a process they deem “pan-genetics,” the biologists use their new, high-quality pan-genome to map the genes behind specific traits of agricultural significance across the genus, and target those genes to create desirable mutations. Their research reveals the importance of understanding the evolution of paralog genes—those that arise through gene duplication—in predicting genome editing outcomes. CSHL Professor & HHMI Investigator Zachary Lippman led the study. “There’s a lot of wonderful food crops out there,” he says. “How many of them have not received the attention they would benefit from, compared to ‘major’ crops?”

Researchers have studied gene duplication for decades. But how paralogs relate to physical changes across species has not been deeply studied—until now. Lippman collaborated with colleagues on four continents to fill this gap. Importantly, their biggest breakthroughs didn’t come from plants in Lippman’s backyard. Instead, it was African eggplant. A tomato relative indigenous to the sub-Saharan region, African eggplant varies highly in fruit shape, color, and size.

Lippman and longtime collaborator Michael Schatz at Johns Hopkins University turned to a breeder in Uganda to exchange ideas and expertise. Mapping tens of thousands of paralogs, the team identified a previously unknown gene in African eggplant that affects fruit size. The paralog has the same function in tomatoes. The team, involving Joyce Van Eck from the Boyce Thompson Institute and Matthias Benoit from INRAE, discovered they could influence tomato size by editing it.

“Reciprocal exchange between indigenous and major crops creates new, predictable paths for better breeding,” says Benoit. “This is key to boost the diversity and resilience of the food system.”

“Crop diversity benefits nutrition, choice, and health,” Lippman adds. Determining how related paralogs function across species could help improve crop yields, flowering times, and food selection. In other words, it’s a win-win-win for scientists, farmers, and consumers everywhere.

 

This map illustrates the approximate central growing locations and agricultural uses of 22 indigenous crops included in the Solanum pan-genome.

 

These images highlight the remarkable diversity of plant shoots and fruits among just one subset of Solanum species in the pan-genome.

Credit

Lippman lab/CSHL

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Journal

Nature

DOI

10.1038/s41586-025-08619-6a 

Article Title

Solanum pan-genetics reveals paralogues as contingencies in crop engineering

Article Publication Date

5-Mar-2025

 

Scientists discover how aspirin could prevent some cancers from spreading

UK Research and Innovation

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Mice with breast tumours developed metastatic cancer in their lungs (visible as dark deposits), whereas this was prevented in mice lacking ARHGEF1 - a key protein involved in suppression of T cell immunity by the clotting factor Thromboxane A2. 

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Credit: Copyright: Jie Yang

Scientists have uncovered the mechanism behind how aspirin could reduce the metastasis of some cancers by stimulating the immune system, in a new study primarily funded by the Medical Research Council.

In the study, published in Nature, the scientists say that discovering the mechanism will support ongoing clinical trials, and could lead to the targeted use of aspirin to prevent the spread of susceptible types of cancer, and to the development of more effective drugs to prevent cancer metastasis.

The scientists caution that, in some people, aspirin can have serious side-effects and clinical trials are underway to determine how to use it safely and effectively to prevent cancer spread, so people should consult their doctor before starting to take it.

Studies of people with cancer have previously observed that those taking daily low-dose aspirin have a reduction in the spread of some cancers, such as breast, bowel, and prostate cancers, leading to ongoing clinical trials. However, until now it wasn’t known exactly how aspirin could prevent metastases.

In this study, led by researchers at the University of Cambridge, the scientists say their discovery of how aspirin reduces cancer metastasis was serendipitous.

They were investigating the process of metastasis, because, while cancer starts out in one location, 90% of cancer deaths occur when cancer spreads to other parts of the body.

The scientists wanted to better understand how the immune system responds to metastasis, because when individual cancer cells break away from their originating tumour and spread to another part of the body they are particularly vulnerable to immune attack. The immune system can recognise and kill these lone cancer cells more effectively than cancer cells within larger originating tumours, which have often developed an environment that suppresses the immune system.

The researchers previously screened 810 genes in mice and found 15 that had an effect on cancer metastasis. In particular, they found that mice lacking a gene which produces a protein called ARHGEF1 had less metastasis of various primary cancers to the lungs and liver.

The researchers determined that ARHGEF1 suppresses a type of immune cell called a T cell, which can recognise and kill metastatic cancer cells.

To develop treatments to take advantage of this discovery, they needed to find a way for drugs to target it. The scientists traced signals in the cell to determine that ARHGEF1 is switched on when T cells are exposed to a clotting factor called thromboxane A2 (TXA2).

This was an unexpected revelation for the scientists, because TXA2 is already well-known and linked to how aspirin works.

TXA2 is produced by platelets - a cell in the blood stream that helps blood clot, preventing wounds from bleeding, but occasionally causing heart attacks and strokes. Aspirin reduces the production of TXA2, leading to the anti-clotting effects, which underlies its ability to prevent heart attacks and strokes.

This new research found that aspirin prevents cancers from spreading by decreasing TXA2 and releasing T cells from suppression. They used a mouse model of melanoma to show that in mice given aspirin, the frequency of metastases was reduced compared to control mice, and this was dependent on releasing T cells from suppression by TXA2.

Professor Rahul Roychoudhuri, from the University of Cambridge, who led the study, said: “Despite advances in cancer treatment, many patients with early stage cancers receive treatments, such as surgical removal of the tumour, which have the potential to be curative, but later relapse due to the eventual growth of micrometastases – cancer cells that have seeded other parts of the body but remain in a latent state.

“Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there’s a unique therapeutic window of opportunity when cancer cells are particularly vulnerable to immune attack. We hope that therapies that target this window of vulnerability will have tremendous scope in preventing recurrence in patients with early cancer at risk of recurrence.

Dr Jie Yang, who carried out the research, at the University of Cambridge, said: “It was a Eureka moment when we found TXA2 was the molecular signal that activates this suppressive effect on T cells. Before this, we had not been aware of the implication of our findings in understanding the anti-metastatic activity of aspirin. It was an entirely unexpected finding which sent us down quite a different path of enquiry than we had anticipated.”

“Aspirin, or other drugs that could target this pathway, have the potential to be less expensive than antibody-based therapies, and therefore more accessible globally.”

In the future, the researchers plan to help the translation of their work into potential clinical practice by collaborating with Professor Ruth Langley, of the MRC Clinical Trials Unit at University College London, who is leading the Add-Aspirin clinical trial, to find out if aspirin can stop or delay early stage cancers from coming back. Professor Langley, who was not involved in this study, commented: “This is an important discovery. It will enable us to interpret the results of ongoing clinical trials and work out who is most likely to benefit from aspirin after a cancer diagnosis.

“In a small proportion of people, aspirin can cause serious side-effects, including bleeding or stomach ulcers. Therefore, it is important to understand which people with cancer are likely to benefit and always talk to your doctor before starting aspirin.”

The research was principally funded by the Medical Research Council, with additional funding from the Wellcome Trust and European Research Council.

The Add-Aspirin clinical trial is funded by Cancer Research UK, the National Institute for Health and Care Research, the Medical Research Council and the Tata Memorial Foundation of India.

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Journal

Nature

DOI

10.1038/s41586-025-08626-7 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity

Article Publication Date

5-Mar-2025

 

Compound harnesses cannabis’ pain-relieving properties without side effects

Mouse study points to an effective alternative to opioids

WashU Medicine

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Researchers at WashU Medicine and Stanford University developed a compound that relieves pain in mice but doesn't affect the brain, thereby avoiding mind-altering side effects and abuse potential. The custom-designed molecule, derived from cannabis, may provide an alternative to opioids for treating chronic pain. The compound is illustrated here in cyan, nestled within a protein (green and purple) involved in sensing pain.

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Credit: Tasnia Tarana

Treatment for chronic pain still relies heavily on opioids. While effective, they are highly addictive and potentially deadly if misused. In the quest to develop a safe, effective alternative to opioids, researchers at Washington University School of Medicine in St. Louis and Stanford University have developed a compound that mimics a natural molecule found in the cannabis plant, harnessing its pain-relieving properties without causing addiction or mind-altering side effects in mice.

While more studies are needed, the compound shows promise as a nonaddictive pain reliever that could help the estimated 50 million people in the U.S. who suffer from chronic pain. The study is published March 5 in Nature.

“There is an urgent need to develop nonaddictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years,” said the study’s senior author Susruta Majumdar, PhD, a professor of anesthesiology at WashU Medicine. “The custom-designed compound we created attaches to pain-reducing receptors in the body but by design, it can’t reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn’t addictive because it doesn’t act on the brain’s reward center.”

Opioids dull the sensation of pain in the brain and hijack the brain’s reward system, triggering the release of dopamine and feelings of pleasure, which make the drugs so addictive. Despite widespread public health warnings and media attention focused on the dangers of opioid addiction, numerous overdose deaths still occur. In 2022, some 82,000 deaths in the U.S. were linked to opioids. That’s why scientists are working so hard to develop alternative treatments for pain.

“For millennia, people have turned to marijuana as a treatment for pain,” explained co-corresponding author Robert W. Gereau, PhD, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the WashU Medicine Pain Center. “Clinical trials also have evaluated whether cannabis provides long-term pain relief. But inevitably the psychoactive side effects of cannabis have been problematic, preventing cannabis from being considered as a viable treatment option for pain. However, we were able to overcome that issue.”

The mind-altering properties of marijuana stem from natural molecules found in the cannabis plant referred to as cannabinoid molecules. They bind to a receptor, called cannabinoid receptor one (CB1), on the surface of brain cells and on pain-sensing nerve cells throughout the body.

Working with collaborators at Stanford University, co-first author Vipin Rangari, PhD, a WashU Medicine postdoctoral research associate in Majumdar’s laboratory, designed a cannabinoid molecule with a positive charge, preventing it from crossing the blood-brain barrier into the brain while allowing the molecule to engage CB1 receptors elsewhere in the body. By modifying the molecule such that it only binds to pain-sensing nerve cells outside of the brain, the researchers achieved pain relief without mind-altering side effects.

They tested the modified synthetic cannabinoid compound in mouse models of nerve-injury pain and migraine headaches, measuring hypersensitivity to touch as a proxy for pain. Applying a normally non-painful stimulus allows researchers to indirectly assess pain in mice. In both mouse models, injections of the modified compound eliminated touch hypersensitivity.

For many pain relievers, particularly opioids, tolerance to the medications over time can limit their long-term effectiveness and require higher doses of medication to achieve the same level of pain relief. In this study, the modified compound offered prolonged pain relief – the animals showed no signs of developing tolerance despite twice-daily treatments with the compound over the course of nine days. This is a promising sign that the molecule could be used as a nonaddictive drug for relief of chronic pain, which requires continued treatment over time.

Eliminating the compound’s tolerance resulted from the bespoke design of the compound. The Stanford collaborators performed sophisticated computational modeling that revealed a hidden pocket on the CB1 receptor that could serve as an additional binding site. The hidden pocket, confirmed by structural models, leads to reduced cellular activity related to developing tolerance compared to the conventional binding site, but it had been considered inaccessible to cannabinoids. The researchers found that the pocket opens for short periods of time, allowing the modified cannabinoid compound to bind, thus minimizing tolerance.

Designing molecules that relieve pain with minimal side effects is challenging to accomplish, said Majumdar. The researchers plan to further develop the compound into an oral drug that could be evaluated in clinical trials.

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Journal

Nature

DOI

10.1038/s41586-025-08618-7 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

A cryptic pocket in CB1 drives peripheral and functional selectivity

Article Publication Date

5-Mar-2025

 

Should I stay or should I go? Brain switchboard found

Neuroscientists discover how the brain switches strategy between persevering in a goal, trying something new, or giving up

Sainsbury Wellcome Centre

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The balance between different behavioural states is compromised in a variety of prevalent neuropathological conditions.

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Credit: Sainsbury Wellcome Centre

Researchers have revealed neural circuits in the brainstem that are crucially involved in implementing decisions by controlling three fundamental behavioural states or strategies: perseverance, exploration and disengagement. The circuits revealed in this study in mice may help to further understand a number of neuropsychiatric conditions including obsessive-compulsive disorder (OCD), autism and major depressive disorder.

The research, published today in Nature, outlines how scientists at the Sainsbury Wellcome Centre at UCL studied a midbrain area called the median raphe nucleus (MRN) in mice. They tested the function of neural circuits in the MRN under different conditions and revealed how animals switch between states.

“For all living beings, survival depends on the ability to adapt their goals. Animals must constantly decide whether to persevere in their current goal, explore alternative options, or disengage altogether. We wanted to understand the neural circuits that drive these behavioural strategies and enable animals to maintain or switch between them. The need to maintain the correct balance between these strategies is common across the animal kingdom, so the underlying neural circuits are likely to be evolutionarily conserved and subcortical,” explains Mehran Ahmadlou, Senior Research Fellow in the Hofer Lab at SWC and first author on the paper.

To explore how the brain controls behavioural strategies, the researchers used both instinctive, naturalistic tasks, where the animals did not need any previous knowledge, as well as learned tasks in which animals acted on prior knowledge of where to expect a food reward. Using optogenetic manipulations, calcium imaging, and neural circuit tracing, the researchers revealed three cell types in the MRN with complementary functions.

“Manipulating the neural activity of specific cell types in the median raphe strongly biased the animals’ behaviour in similar ways in both instinctive and learned behavioural paradigms. Three types of neurons in the median raphe could between them drive decisions on whether to stick to what you are doing, try something else, or give up altogether”, explains Professor Sonja Hofer, Group Leader at the SWC and corresponding author of the study.

“We found that suppression of GABAergic neurons causes perseverance in a current or familiar goal; activation of glutamatergic neurons drives exploration of alternative options; and suppression of serotonergic neurons in the median raphe nucleus causes the animal to disengage,” Mehran Ahmadlou expands further.

“We were really surprised to find that the three main cell types in this small brain structure had three fundamentally different but complementary functions with such strong control over the animals’ behaviour,” continued Hofer.

The researchers also uncovered that the median raphe receives information about whether an experience is positive or negative from two further brain regions, the lateral hypothalamus and the lateral habenula, and these signals in turn can drive perseverance in a goal or disengagement from it.

Together these findings establish the MRN as a central behavioural switchboard for decision-making, uniquely positioned to flexibly control behavioural strategies.

The neural circuits revealed in this study may help to further understand a number of neuropsychiatric conditions. For instance, an overly high drive to persist in familiar actions and repetitive behaviours can be observed in OCD and autism, while pathological disengagement and lack of motivation is one symptom of major depressive disorder. Changes in the firing rate of specific median raphe cell types could therefore contribute to certain aspects of these conditions.

“It is possible that in some mental disorders specific median raphe neurons could have pathological firing rates. For example, very low activity of serotonergic neurons specifically in the median raphe nucleus could contribute to a depressive phenotype. This is interesting as most of the more effective treatments for depressive disorders are indeed centered around the neurotransmitter serotonin. But these drugs are unspecific, slow and do not work for everybody. A better understanding of the brain mechanisms underlying healthy and pathological behavioural phenotypes can hopefully provide a basis for the development of new, more specific treatments,” concludes Hofer.

This research was funded by the Sainsbury Wellcome Centre Core Grant from the Gatsby Charity Foundation and Wellcome (GAT3755 and 219627/Z/19/Z) and a European Research Council Starting Grant (HigherVision 337797).

Source:

Read the full paper in Nature: ‘A subcortical switchboard for perseverative, exploratory, and disengaged states’ DOI: 10.1038/s41586-025-08672-1

Media contact:

For more information or to speak to the researchers involved, please contact:

April Cashin-Garbutt,  Head of Research Communications and Engagement, Sainsbury Wellcome Centre
E: a.cashin-garbutt@ucl.ac.uk T: +44 (0)20 3108 8028

About the Sainsbury Wellcome Centre

The Sainsbury Wellcome Centre (SWC) brings together world-leading neuroscientists to generate theories about how neural circuits in the brain give rise to the fundamental processes underpinning behaviour, including perception, memory, expectation, decisions, cognition, volition and action. Funded by the Gatsby Charitable Foundation and Wellcome, SWC is located within UCL and is closely associated with the Faculties of Life Sciences and Brain Sciences. For further information, please visit: www.sainsburywellcome.org

Distinct cell types in MRN, inhibitory neurons (GABAergic; blue), excitatory neurons (glutamatergic VGluT2+; green), and serotoninergic neurons (orange), differentially control perseverative, exploratory and disengaged states.

Credit

Sainsbury Wellcome Centre

Journal

Nature

DOI

10.1038/s41586-025-08672-1 

Method of Research

Experimental study

Subject of Research

Animals

Article Title

A subcortical switchboard for perseverative, exploratory, and disengaged states

Article Publication Date

5-Mar-2025