Publisher Health

Previously underexplored immune cell populations have been mapped across multiple tissues in development and adulthood to provide new insights into how our immune system works.
Two new papers from the Wellcome Sanger Institute, the University of Cambridge and collaborators have created open-access atlases of the immune cells in the human body. One study focuses on the early development of the immune system and the localisation of immune cells across several tissues. The other study looks at immune cells in multiple tissues from adult individuals, providing a framework for prediction of cell type identity and insights into immunological memory.
These studies are part of the international Human Cell Atlas (HCA) consortium, which is aiming to map every cell type in the human body as a basis for both understanding human health and for diagnosing, monitoring, and treating disease. An open, scientist-led consortium, HCA is a collaborative effort of researchers, institutes, and funders worldwide, with more than 2,300 members from 83 countries across the globe.
Published today (12 May 2022) in Science, both studies explore the similarities and differences of immune cells across different tissues, which are understudied, compared to those circulating in the blood. Knowing more about immune cell traits and reactions in these tissues at different stages of life could help future research into therapies that aim to produce or enhance an immune response to fight disease, such as vaccinations or anti-cancer treatments.
These papers are two of four major studies published in Science this week, which have created comprehensive and openly available cross-tissue cell atlases. The complementary studies shed light on health and disease, and will contribute towards a single Human Cell Atlas.
The human immune system is made up of many different types of cells that can be found throughout the body, all playing crucial roles. They not only fight off pathogens when they appear, but remember them so they can be eliminated in the future.

Research from the University of Michigan Rogel Cancer Center could provide a new approach to treating an aggressive form of breast cancer.
A study led by Duxin Sun, Ph.D., found that targeting the immune microenvironment in lymph nodes and tumors simultaneously led to long-term tumor remission in mice models of metastatic triple negative breast cancer. Further, using nanoparticles to deliver these immune-altering drugs increases treatment efficacy. These results appear in Science Translational Medicine.
Immunotherapy combined with chemotherapy has been long approved as standard treatment option for triple negative breast cancer but only shows a limited response in patients. Many believe that the tumor immunosuppressive microenvironment is one of the main contributing factors for the poor responses in those with TNBC.
Sun, Charles R. Walgreen Jr. Professor of Pharmacy and Professor of Pharmaceutical Sciences at the U-M College of Pharmacy, says that previously developed immunomodulators work well in animal models, but fail in clinical trials. He and his team wanted to come up with a better approach that would treat TNBC patients long-term that could withstand the rigor of clinical trials. To do this, they had to look beyond just the tumor microenvironment to the lymph nodes.
“People don’t pay enough attention to the lymph node microenvironment,” Sun said. “But it’s equally important. The lymph nodes play a crucial role in initiating the progression and metastasis of cancer.”
Sun and his team, with co-senior author Wei Gao, Ph.D., investigated strategies to modulate both the tumor and lymph node microenvironments to improve treatment response. Based on 15 years of experience, Sun knew that one type of nanomedicine could be used to deliver immune modulators to these microenvironments to alter their macrophages — a type of white blood cell of the immune system that combats pathogens, like cancer cells.

A study published by researchers from Mayo Clinic Cancer Center at Mayo Clinic in Florida and Case Western, Cleveland Medical Center, investigates the reasons for decreasing remission rates for patients with non-Hodgkin lymphoma treated with chimeric antigen receptor-T cell therapy (CAR-T cell therapy). The study is published in Cancer Discovery.
“CAR-T cell therapy is a promising treatment for non-Hodgkin lymphoma, especially for patients who have relapsed or those who have not responded to prior therapies,” says Tae Hyun Hwang, Ph.D., a researcher at Mayo Clinic Cancer Center in Jacksonville, Florida.
However, Dr. Hwang says that recent long-term follow-up data suggest that the success rate of CAR-T cell therapy for patients with non-Hodgkin lymphoma may be decreasing. “Lasting remission in this setting ranges from 30% to 40%,” so it is critical to identify a predictive biomarker to measure CAR-T cell resistance so we can better match patients with effective therapy,” says Dr. Hwang.
“The overall goal of our research is to support precision oncology care. Novel therapeutic strategies will help us improve the efficacy of CAR-T cell therapy for patients with non-Hodgkin lymphoma,” says David Wald, M.D., Ph.D., of Case Western, Cleveland Medical Center, the study’s co-author,
“Our team hypothesized there would be distinct molecular patterns in CAR-T cells between patients who responded to treatment and patients who did not respond,” says Dr Hwang. He says the team used innovative computational and experimental approaches to identify these patterns.
Researchers generated single-cell RNA and protein sequencing data for CAR-T cells before they were administered to patients and again at multiple points after being infused in patients. Dr. Hwang says this work generated more than 133,000 single-cell expression profiles that researchers used to develop and apply computational approaches to dissect single-cell level RNA or protein expression patterns of CAR-T cells associated with treatment response.
Using these computational approaches, the team found that a gene called TIGIT — a T cell — was highly expressed in post-infusion CAR-T cells from patients who did not respond to CAR-T cell therapy. The team also validated that TIGIT drives CAR-T cell exhaustion and dysfunction, and they discovered that blocking TIGIT with CAR-T cell therapy could improve treatment efficacy in an in vivo study.
“If our findings can be validated in prospective clinical trials, our TIGIT blocking strategy with CAR-T cell therapy may improve current CAR-T cell therapy responses in patients with non-Hodgkin lymphoma and may also improve patient survival,” says Dr. Hwang.
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The bark of the Galbulimima belgraveana tree, found only in remote rainforests of Papua New Guinea and northern Australia, has long been used by indigenous people for both healing and ceremony. A tea brewed from the bark not only induces a dreamlike state but is said to ease pain and fever. To probe these effects, researchers have isolated more than 40 unique chemicals from the tree bark but have struggled to reproduce the compounds in the lab or study their biology.
Now, Scripps Research scientists have developed a method to synthesize one of these chemicals known as GB18. Their approach, described online in the journal Nature on May 12, 2022, includes a new type of reaction that could be useful in synthesizing other chemicals. It also let them produce enough GB18 to study its effects on human brain cells and discover that the chemical binds to opioid receptors — the same molecules targeted by many painkillers. While opioid painkillers activate these receptors, however, GB18 turns them off — a function that some researchers hypothesize could be useful in treating depression and anxiety.
“This goes to show that Western medicine hasn’t cornered the market on new therapeutics; there are traditional medicines out there still waiting to be studied,” says senior author Ryan Shenvi, PhD, a professor of chemistry at Scripps Research. “Our hope is that we can turn GB18 into a useful medicine.”
In the 1950s, Galbulimima belgraveana caught the attention of Australian researchers, who began isolating and studying its chemicals, called GB alkaloids. Some GB alkaloids were found to decrease smooth muscle spasm. Some increased heart rate, whereas others decreased it. A structural outlier, GB18, affected mouse behavior and appeared to be psychotropic. But without the ability to recreate the compounds in the lab, it was difficult to further pursue their potential therapeutic value.
While some members of the Shenvi lab recently worked out ways to synthesize other GB alkaloids — described in Science in March 2022 — Scripps graduate student Stone Woo tackled GB18. Its structure was particularly tricky, with a chemical ring tucked in a hard-to-access pocket, like a mug handle attached to the inside of a cup instead of the outside. Woo discovered a series of chemical steps, however, that could produce the desired structure, exactly mimicking the structure of GB18 found naturally in Galbulimima belgraveana bark.
“Stone was able to devise this beautiful choreography for bringing together small chemicals to assemble the complex constellation that is GB18,” explains Shenvi. “He developed a way to build this ring motif that is unprecedented.”
The method that Woo devised, in fact, let him control which side of GB18 the ring could be tacked on to — an innovation with implications for creating variants of GB18 as well as for carrying out other chemical syntheses involving similar rings.
“The way we were able to efficiently assemble these molecular connections could prove useful in other contexts,” says Woo.
Once the researchers had a means to synthesize GB18, they produced enough of it to use in screening experiments conducted through the National Institute of Mental Health Psychoactive Drug Screening Program, run by Professor Bryan Roth of UNC Chapel Hill. These screens revealed that GB18 bound to two different opioid receptors in the brain. These receptors had never before been identified as targets of any GB alkaloids and represent the first new receptors linked to Galbulimima belgraveana activity in more than 35 years.
Now, the researchers are further studying the exact biological impact of GB18’s binding to the opioid receptors. While opioid drugs involved in the ongoing overdose epidemic will activate these receptors, GB18 seems to shut them off. Shenvi says that may make GB18 useful as an antidepressant or anti-anxiety drug, but more work is needed to adapt it to human use.
Shenvi and Woo are the only authors of the study “Synthesis and target annotation of GB18.” A provisional patent for GB18 has been filed by both authors.
This work was supported by funding from the National Institutes of Health (R35GM122606; S10 OD025208), the National Science Foundation (CHE 1856747) and the Skaggs Graduate School.
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Imagine sitting at a meeting where the shape of the table and your place at it might impact how you get along with the other members. Cells also communicate with their nearest neighbors, and in embryos, nothing is left to chance in the ‘seating plan’ for the first few cells. However, questions remain about the how this process is controlled and how it can influence the overall growth of an organism.
Building on their previous studies on the development of worm eggs, researchers from Kyoto University Kanagawa Institute of Technology, and the National Institute of Genetics have now precisely modeled the shape of eggshells to show how the space in the egg and the contours of the shell direct the relative positions of cells in the growing embryo. Their findings may provide a theoretical basis for directing the development of stem cells into larger tissues and organs.
Lead author Professor Sungrim Seirin-Lee of Kyoto University’s Institute for the Advanced Study of Human Biology (WPI-ASHBi) said, “We had found that when Caenorhabditis elegans embryos reached the 4-cell stage, there are five patterns that the cells arrange themselves in the spaces of the egg. But the T-reverse arrangements we found did not match our previous calculations based on the attraction of the cells and the aspect ratio of the eggs. We realized something was missing from our model.”
When looking under a microscope at eggs of the worm Caenorhabditis elegans, the team previously noticed that in eggs with a longer shape, the first four cells arranged in a line; in contrast, if the shell was round, the cells would bunch up. They also identified an unexplained ‘T-reverse’ pattern in some eggs, where three cells bunch up, making a gap shaped like a T, with one cell in a line at the end.
The team hypothesized that the formation of this pattern, might be controlled by variations in the eggshell contours. To test this, they applied a more sophisticated ‘phase-field’ mathematical model that could more precisely account for the actual egg shape measured from worms. This new model successfully reproduced the previous findings and now also accounts for the unexplained T-reverse arrangement. The findings show for the first time that the previously ignored local contours of the egg affect the cell patterns.
In the new way of looking at the embryo, it turns out that it is actually the “space inside the egg” that is a key factor driving the cell patterns. To test this concept further, the researchers examined the eggs of worms that were genetically modified to allow more space for the cells inside. With extra room, the first four cells preferred to spread out in a line rather than bunching up.
Seirin-Lee said, “Worm eggshells are often treated as a simple oval shape but the actual shape may be closer to a capsule in some cases. We now understand how important geometric constraints and space are for directing cells, and this concept also applies to human cells. We hope this work will lead us to a better handle on artificially controlling cell differentiation and extend the capabilities of stem cell techniques.”
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Our gut is home to countless bacteria, which help us to digest food. But what exactly do the microorganisms do inside the body? Which enzymes do they produce, and when? And how do the bacteria metabolise health-promoting foods that help us avoid disease?
To obtain answers to such questions, researchers at the Department of Biosystems Science and Engineering at ETH Zurich in Basel modified bacteria such that they function as data loggers for information on gene activity. Together with scientists from University Hospital of Bern and the University of Bern, they have now tested these bacteria in mice. This is an important step towards using sensor bacteria in medicine in the future for applications such as diagnosing malnutrition and understanding which diets are good for an individual.
Immune system becomes data logger
The data logger function was developed over the past few years by researchers led by Randall Platt, Professor of Biological Engineering at ETH Zurich. To do this, they employed the CRISPR-Cas mechanism, which is a type of immune system present naturally in many bacterial species. If the bacteria are attacked by viruses, they can incorporate snippets of the viral DNA or RNA into a section of their own genome called the CRISPR array. This lets the bacteria “remember” viruses with which they have had contact, allowing them to fight off a future viral attack with greater speed.
To put this mechanism to use as a data logger, the researchers didn’t concern themselves with DNA snippets of viral intruders, but focused on something else: the mechanism can be exploited such that the bacteria incorporate snippets of their own messenger RNA (mRNA) into the CRISPR array. mRNA molecules are the blueprint that cells use to manufacture proteins. As such, mRNA snippets can reveal which genes are being used to build proteins for executing cellular functions.
To make the method effective, the scientists introduced the CRISPR array of the bacterial species Fusicatenibacter saccharivorans into a strain of the intestinal bacterium Escherichia coli, which is regarded as safe in humans and available as a probiotic. The transfer included the blueprint of an enzyme called reverse transcriptase, which is able to transcribe RNA into DNA. This enzyme also transcribes the information in the mRNA into DNA form, which along with accompanying CRISPR-associated proteins is necessary for incorporating the DNA snippet into the CRISPR array.

Genetic studies have revealed many genes linked to both common and rare disease, but to understand how those genes bring about disease and use those insights to help develop therapies, scientists need to know where they are active in the body. Research on single cells can help achieve this goal, by surveying gene activity in specific cell types. Scientists need to profile all cell types and compare them across organs in the body to learn about the full range of human diseases, but this is difficult to do with existing methods.
Now researchers at the Broad Institute of MIT and Harvard have developed a robust experimental pipeline that can profile many more cell types from more tissues than can be studied with other techniques, as well as machine learning methods to put this data together and query the resulting map, or atlas. The team used it to pinpoint specific cell types from various tissues involved in multiple diseases. Their approach will enable other large-scale studies of diverse cell types and comparisons across tissues, including cells from frozen tissue that can be collected from many patients. This work opens up a wealth of samples stored in research collections around the globe for this kind of single-cell analysis, and also brings scientists a huge step closer towards their goal of a human cell atlas that catalogs every cell type in the human body, in a large number of individuals from diverse backgrounds.
Previous single-cell studies have mostly focused on one tissue type at a time, to create tissue-specific maps. Using their new pipeline, the team built a massive atlas of hundreds of thousands of cells across multiple tissues in the body. This allowed them to uncover unexpected new functions and gene expression programs for several cell types, such as muscle cell programs being expressed in lung connective tissue cells. The findings also revealed genetic similarities among cells in different tissues, and linked certain cell types to specific diseases for the first time.
The atlas is the first cross-tissue atlas to be based on measurements of gene activity within individual cell nuclei, which allowed the team to capture a greater variety of cell types than existing methods that measure gene expression from the whole cell.
The researchers say their atlas will spur many new studies on health and disease, and have openly shared it with the scientific community through the GTEx portal and the Broad’s Single-Cell Portal.
This study is part of the international Human Cell Atlas (HCA) consortium, which is aiming to map every cell type in the human body as a basis for both understanding human health and for diagnosing, monitoring, and treating disease. An open, global, scientist-led consortium, HCA is a collaborative effort of researchers, institutes, and funders worldwide, with more than 2,300 members from 83 countries across the globe.

Researchers from King’s College London have published a review of care for women with pre-eclampsia in the New England Journal of Medicine.
Pre-eclampsia is a condition that affects up to 4% of women during pregnancy, and up to 8% of women during their lifetime. It includes high blood pressure (hypertension) and damage to a number of her body’s organ systems, and remains one of the two main causes of death for pregnant and recently-pregnant women worldwide — about 46,000 young women a year. Up to half a million women lose their babies to pre-eclampsia every year.
In this invited review, researchers from King’s College London Professor Laura Magee, Professor Kypros Nicolaides, and Professor Peter von Dadelszen, have provided a state-of-the-art summary of current knowledge of, and best practises for caring for women with, pre-eclampsia. This review also consists of significant findings published within the past five years.
There are important insights into how pre-eclampsia develops, how best to identify women at risk and how to respond to those risks to prevent pre-eclampsia, how to diagnose pre-eclampsia and provide ongoing care — including assessing risks and reducing those risks by controlling blood pressure and timing birth, and how to provide follow-up to women if they have had pre-eclampsia.
The findings are particularly significant for pregnant women living in low-economically developed countries.
Lead author, Professor Laura Magee from King’s College London, who is the co-president of the International Society for the Study of Hypertension in Pregnancy, states, “In this review of advances in our knowledge over the past five years, we have focussed on individualising the care of women with pre-eclampsia by carefully integrating concepts concerning the prediction, prevention, diagnosis, and management of pre-eclampsia during pregnancy and in the long term.”
Senior author, Peter von Dadelszen from King’s College London, said: “This paper is very timely for two reasons. First, this is World Pre-eclampsia Month — a time during which we focus our attention on this dangerous condition. Second, the paper emphasises the particular risks borne by pregnant women living in, or having immigrated from, less-developed countries — more than 99% of related mum and baby deaths occur in less-developed countries.”
Renowned King’s College London obstetrician and scientist, Professor Kypros Nicolaides added: “The future is bright. We are confident that current research should provide new insights into sub-types of pre-eclampsia, improve its prediction and management, and enable individualised care during and after pregnancy.”
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About one in 20,000 infants is born with what’s called a congenital giant nevus — a huge, pigmented mole that may cover much of the face and body. Due to the mole’s appearance and its risk of later developing into skin cancer, many patients decide to have their children undergo extensive surgery to remove the entire lesion, which can cause large and permanent scars. Researchers led by investigators at Massachusetts General Hospital (MGH) recently created multiple preclinical models of this condition and used them to show that several drugs can be applied to the skin to cause the lesions to regress, and one topical drug also protected against skin cancer. Their findings are published in the journal Cell.
“The goals of our study were to develop a series of animal models designed to elucidate key biological features of these lesions, and to test nonsurgical drug treatments to skin, aiming to cause the nevus cells to recede, thereby removing the need for surgical treatments,” says senior author David E. Fisher, MD, PhD, director of the MGH Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center.
The models included mice engineered to express a gene called NRAS that contains a mutation known to cause most congenital giant nevi in humans, as well as mice with transplanted skin grafts containing human congenital giant nevi. Fisher and his colleagues used these models to analyze different phases of these nevi to better understand how they form and develop. Also, when the scientists used the models to test topical applications of single or combination drugs that block signaling pathways known to be activated by NRAS mutations, they found that some of the treatments led to significant nevus regressions. In addition, a drug that stimulates a type of inflammatory reaction after topical application to the skin caused the nevi to fully regress after three treatments. The therapy also offered complete prevention against formation of skin cancers in the mice.
“These findings will hopefully set the stage for additional refinements aimed to directly test such skin treatments on patients with congenital giant nevi,” says Fisher. “This work will include additional studies of safety, potential further enhancements of efficacy, and more analysis of underlying mechanisms. The overall goals are to prevent melanoma in these patients and also to avoid the disfigurement challenges from these lesions.”
Additional study authors include Yeon Sook Choi, Tal H. Erlich, Max von Franque, Inbal Rachmin, Jessica L. Flesher, Erik B. Schiferle, Yi Zhang, Marcello Pereira da Silva, Alva Jiang, Allison S. Dobry, Mack Su,Sharon Germana, Sebastian Lacher, Orly Freund, Ezra Feder, Jose L. Cortez, Suyeon Ryu, Tamar Babila Propp, Yedidyah Leo Samuels, Labib R. Zakka, Marjan Azin, Christin E. Burd, Norman E. Sharpless, X. Shirley Liu, Clifford Meyer, William Gerald Austen, Jr., Branko Bojovic, Curtis L. Cetrulo, Jr., Martin C. Mihm, Dave S. Hoon, Shadmehr Demehri, and Elena B. Hawryluk.
This work was supported by the National Institutes of Health and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
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