Radically different
Researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust (CUH), and Open Targets have created a detailed cellular study of Crohn’s disease (CD), mapping how gene activity changes across more than 50 cell types in the gut. (Founded in 2014, Open Targets is a pre-competitive, public-private partnership that uses human genetics and genomics data to systematically identify and prioritize drug targets.)
Co-led by Tim Raine, MD, PhD, consultant gastroenterologist at Cambridge University Hospitals NHS Foundation Trust, the team analyzed over a million gut cells from people with Crohn’s and from healthy controls, comparing changes in the gut lining and identifying immune cells that drive inflammation. The resulting single cell RNA-sequencing (sc-RNA-seq) resource, IBDverse, characterizes each cell type and those whose activity shifts in disease, uncovering new molecular and cellular signatures of immune activity in the gut lining.
Co-first author Monika Krzak, PhD, formerly at the Wellcome Sanger Institute and now based at the Institute of Metabolic Science, University of Cambridge, said, “Crohn’s disease is complex, variable and deeply personal to every individual living with it, which is why understanding it at the level of single cells is so important. By creating this unprecedented map of more than one million gut cells, we are giving researchers around the world a powerful new tool to uncover how inflammation begins, persists and may one day be stopped. This is the kind of open science that can accelerate discoveries and bring us closer to better treatments for patients.”
Raine added, “There is an urgent need for increased understanding of the biology of Crohn’s disease if we are to develop more effective and safe medications for people living with this condition. The patients who contributed to this research have helped us build insight into the different ways that gut function and immune function are disrupted in the disease, and with the insight comes immediate new avenues for drug development and targeted therapies.”
Reported in Nature Genetics (“Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis,”) the research revealing the cell types and molecular changes involved in Crohn’s inflammation is one of two complementary studies—the other a paper recently published in Nature—built on IBDverse to investigate different aspects of the disease.
In their newly published report the team concluded, “These findings establish a comprehensive cellular and molecular framework for CD, offering insights into disease mechanisms and therapeutic opportunities.”
Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that cause chronic inflammation of the gastrointestinal tract. Over half a million people in the U.K. are estimated to be living with IBD, which includes Crohn’s disease and ulcerative colitis.
Crohn’s is a chronic condition that causes inflammation and ulcers in the digestive tract, from the mouth to the anus, often affecting the small intestine and colon. However, the authors noted, “Although inflammation is most commonly observed in the terminal ileum, CD exhibits substantial heterogeneity in disease location, severity and behavior, both between patients and within patients, over time.”
Although inflammation is most commonly observed in the terminal ileum—the final section of the small intestine—Crohn’s is found in many locations of the body and with variation in severity both between patients and within patients over time.
While therapies targeting immune cells have improved clinical outcomes for some patients, non-response to treatment remains high, with 15% of Crohn’s patients requiring surgery within five years of diagnosis. Consequently, there is an urgent need to better understand the etiology of CD in order to broaden therapeutic opportunities,” the investigators stated.
For their newly reported study the researchers took and analyzed biopsies from 111 patients with Crohn’s and a history of current or previous terminal ileitis—inflammation of the ileum—and 232 healthy volunteers. The team performed single-cell RNA sequencing to measure gene expression in individual cells. “Single-cell RNA sequencing (scRNA-seq) technologies provide a high-throughput means to dissect complex tissues at the resolution of single cells and cell types,” they noted.
By creating a comprehensive map of cellular and molecular differences in Crohn’s compared to healthy controls, the researchers established IBDverse as a result—an online data resource of over 1,185,000 cells isolated from small intestine samples. The large IBDverse dataset will serve as an open resource for future research.
Using the data, the scientists identified genes that are abnormally expressed in Crohn’s and those where expression is specific to given cell types and cellular processes.
One of the study’s most striking findings was a ‘molecular scar’ in the gut lining. Even after visible inflammation had healed, genes that help send messages to the immune system stayed switched on in the gut’s stem cells—the cells that constantly renew the lining. This suggests that an episode of inflammation leaves a lasting mark on these cells, which may shape how the gut responds to inflammation in future. In their paper the authors noted, “We uncovered epithelial changes marked by interferon-driven upregulation of major histocompatibility complex class I molecules that persisted in progenitor cells after macroscopic inflammation resolution.”
The researchers also identified a population of macrophages—immune cells that engulf and digest cellular debris—with high expression of the gene ITGA4. These cells were key drivers of inflammation through the JAK/STAT pathway, which carries signals from the cell surface to the nucleus to switch genes on and off. “ITGA4+ macrophages were identified as key inflammatory drivers, showing enriched JAK–STAT signaling and cytokine expression (interleukin-6 (IL-6), IL-12 and IL-23),” the investigators stated. Drugs that block this pathway, known as JAK inhibitors, are already used to treat IBD, which points to these macrophages as a likely target of therapies.
Co-first author Tobi Alegbe, PhD, at the Wellcome Sanger Institute and Open Targets, said “For inflammatory bowel diseases like Crohn’s and ulcerative colitis, it’s still unclear what is going wrong in the gut cells to cause inflammation. We have been able to compare gut cells of hundreds of people with and without IBD. This has given us new insight into the genes and cell types that are involved during active disease, and lays the groundwork for similar approaches to understand diseases of other major organs like eczema and asthma.”
Co-senior author Carl Anderson, PhD, at the Wellcome Sanger Institute, said “What makes this study different is that we designed replication in from the start and found that even with hundreds of patients and standardized protocols, fewer than half of the gene expression changes we detected in one cohort replicated in the other. That’s a sobering finding for the field. The biology that did replicate consistently points to the gut lining itself as a key player in Crohn’s with a molecular signature in epithelial cells that persists even after inflammation has resolved. We don’t yet know what that persistence means, but it likely influences how the gut responds to future inflammatory insults.”
The post Single-Cell RNA Sequencing Reveals Gene Activity Changes in Crohn’s Disease appeared first on GEN – Genetic Engineering and Biotechnology News.
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A Conversation with Tom Osborn, Founder of Africa’s Largest Mental Health Provider Shamiri Institute
Aaliyah Nadirah Madyun, program director at the Stavros Niarchos Foundation (SNF) Global Center for Child and Adolescent Mental Health at the Child Mind Institute, recently sat down with Tom Osborn, founder of the Shamiri Institute and an International Advisory Board member at the SNF Global Center. They discussed Osborn’s remarkable journey as a young entrepreneur.
At just 18, while studying at Harvard University, Osborn founded the Shamiri Institute, which has since grown into Africa’s largest youth mental health provider — now reaching over 100,000 young people annually and having trained and employed more than 3,000 providers. In this candid conversation, Osborn shares hard-won lessons on resilience, mentorship, and well-being. He offers advice to the SNF Global Center’s Youth Council members — many of whom are launching their own mental health initiatives in communities across Greece, Brazil, South Africa, and beyond.
AM: You founded Shamiri when you were just 18. Many members of our SNF Global Center Youth Councils are now launching their own mental health organizations. What advice would you give them?
TO: I think these past three to five years post-COVID have been quite good for mental health. There’s just more dialogue, more conversation. It’s maybe one of the best times to start working in mental health. There is a big space for young people to be leaders. On the other hand, it’s also very difficult.
AM: What kind of difficulties can young people expect to encounter?
TO: It’s very difficult for a few reasons. We normally start this work because we have a lot of passion, enthusiasm, and commitment to the cause. But that is not the day-to-day of being a social entrepreneur. It’s convincing people to partner with you, to fund you, etc., which is a completely different skill set to learn. And the second part is getting a level of comfort with failure. Because the reality is, on average, nine out of ten doors that you try to open will not open; especially when you are starting. For example, if you’re in Brazil and there are 100 other young people trying to start something, there is a finite pool of opportunities and resources. So, when you are starting, part of the initial process requires you to develop resilience and a growth mindset.
AM: Could you speak about the role mentorship has played in your journey, and how young entrepreneurs can leverage mentorship to navigate the challenges of building something from the ground up?
TO: Mentorship is really crucial. Finding folks — researchers, practitioners, or just folks in the community — who can help provide guidance as you build the skills you need to be an effective entrepreneur.
AM: How would you recommend young people go about finding a mentor? It seems like that ability, identifying and cultivating a mentoring relationship, might be a skill set in itself.
TO: In my experience, there are three pathways. In many countries we have what we call accelerators, which look for young people who literally have an idea and enthusiasm, and then take them through 10–16 weeks of bootcamp where they can learn the skills to develop their idea. So, that’s one pathway. The second pathway, which really worked for me but may sound intimidating, is direct outreach to folks who have done something similar. So, you can do some research. It doesn’t have to even be related to mental health. It can be education or some broader thing. But find someone who has built something that you admire. You will be surprised how many people are willing to support and pay it forward, because we all have benefited from the help of someone else. I created an Excel spreadsheet with a list of people who I looked up to, and I reached out to them on LinkedIn. Sometimes you can even find their email. Some people said “no”, but if you reach out to 10 or 20 people, some people will talk to you. And the third pathway is . . . increasingly we have a lot of resources like the SNF Global Center Youth Councils and international organizations that deal with mental health. You can join these organizations to expand your network.
AM: Could you share your story with us and tell us how you got started?
TO: I started when I was in University as part of a research project I was doing when I was studying psychology. I needed to do something for my thesis and in the process of doing that I applied to an accelerator. I also went to my professor and asked him, ‘Do you know anyone who could connect me with?’ In fact, he helped me write my first grant and gave me the opportunity to learn those entrepreneurial skills.
AM: Starting at such a young age, one can imagine that you must have encountered many challenges and setbacks. What were the key lessons you took away from that growth period?
TO: The reality of this work, and not to discourage people but to give a factual picture, is that there are more setbacks than there are wins. Part of the process is that you learn from the setbacks. I can give you an example of some of my own setbacks. In my first year of doing this, we tried to raise money. We applied for grants, sent out proposals, etc.; but we couldn’t raise any money. So, what I did after getting the rejection is I would email and ask, “Do you have any feedback for us about why we didn’t get the funding?” or “Can we jump on a call so you can explain what we can do better?” What I learned from that was the way I was communicating what we were doing made sense in my mind, but I wasn’t putting myself in the shoes of the person who was reviewing the proposal. I only have five to ten minutes of someone’s time. So, how can I really simplify my message? For example, my first proposal was, “Shamiri does task-shifting mental health interventions for adolescent depression, anxiety, etc.” If you are in the field, you maybe get it. But if you are somebody who is just reading grants on mental health education, you don’t really get it. Now we say, “Shamiri means thrive and we enable young people to thrive.” So that invites people to ask how we’re helping people to thrive.
AM: What is another setback that surprised you?
A second example of a failure is getting buy-in from the beneficiaries that we were trying to work with. I thought, “We have this great idea, we’ve done this research, and it works. We’re going to go to schools and they’re going to be like, ‘This is great! Come work with us.’ Teachers are going to want to work with us.” But actually, in our first three years we were trying to work with 25,000 students and we ended up working with only 1,000 students. We really struggled with getting people to sign up. The lesson from that was we were thinking more from the idea this was our product, rather than thinking, “What is the problem that I am trying to solve for this person?” To give a concrete example, there are three people we need to get buy-in from: young people in schools, teachers, and parents. Just having a great product does not mean that people are going to use it. You need to figure out what the problem is. How can I solve it? How do I communicate this to users?
AM: I can imagine that dealing with failures and setbacks is extremely hard, especially for a young person. What would you say to a young person who is currently experiencing this?
TO: Finding ways to stay grounded and healthy from a well-being perspective is really crucial. Identify what matters to you and connect with those things. And ideally if you can find a way to build a routine around that, it could help. Doing this work takes a big toll. If you don’t find ways to ground yourself and get the energy to continue with this, you may burn out.
AM: Do you have some final words for our Youth Council members and other young people reading this?
TO: Those closest to the problem are those closest to the solution. I am from Kenya, which is a really young country. The median age is 19 and 70 percent of the population is under 30. If we are to solve some of these pressing problems, including mental health, those solutions are going to have to come from young people.
The post Turning Rejection Into a Roadmap: Advice for the Next Generation of Mental Health Leaders appeared first on Child Mind Institute.