Revealing the genetics of the immune system and pregnancy

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Immune systems are complex. Previous research at the Wellcome Sanger Institute identified over 140 genes linked to immune system regulation in mice, and individual patients respond very differently to infections and treatments. Dr Emma Davenport, Group Leader at the Sanger Institute, uses computational biology to understand how genetic differences contribute to this variation.

Journey into computational genomics

Emma began her science career with an undergraduate degree in Biochemistry at the University of Oxford.

“I was interested in human genetics from an early age. I was fascinated looking at families and seeing how certain traits are inherited or how they sometimes skip a generation,” said Emma.

She decided to stay in the same research laboratory for her PhD where she explored the genetic variation in human responses to common and rare infections. Her work focused on sepsis and Common Variable Immunodeficiency disorders, which reduce a person’s level of antibodies and their ability to fight infection. Emma’s supervisor, Professor Julian Knight, shared his clinical experience and emphasised the importance of tailoring research to address problems that are important to patients such as how to improve diagnosis and treatment.

"We were lucky there was a big shift in technology during that time, which led to genome-wide data being cheaper to generate. So the team formed mini working groups, each dedicated to different datasets, spreading our expertise and helping each other. We also had a fantastic core bioinformatics facility.

“I discovered that I enjoyed analysing the research data. I had quite an interesting and unexpected journey, moving from biochemical research at a bench to spending around 90 per cent of my time on computational research. Coding had become more accessible and I taught myself online,” explained Emma.

Seeking a more immersive experience in computational biology and statistical genetics, Emma started a postdoctoral research fellowship with Professor Soumya Raychaudhuri's lab at Harvard Medical School, Boston.

“An exciting aspect of academia is the opportunities you encounter to try something different. For me, that was a big jump – moving from wet lab to dry lab, and then to a different country!”

Emma’s projects have continued to focus on genetics and the immune system.

“I've always been fascinated by how the body responds to infection. And then on the other extreme, we have autoimmunity, when a body attacks its own tissues and organs. In both cases, we know that genetics plays a role, as well as the environment.”

Dr Emma Davenport
Group Leader, Human Genetics Programme, Wellcome Sanger Institute

Functional genomics is an area of molecular biology exploring how the genome functions through gene expression and regulation, and how genes and proteins interact.

When Emma returned to the UK in 2018 she set up a computational research group at the Sanger Institute, focusing on sepsis, lupus and other inflammatory conditions.

Women’s health and pregnancy

Emma recently decided to use her expertise on infection response and immunity to understand pregnancy. Historically, women have been under-represented in medical health research. There was extensive gender bias in the male-dominated medical system and women’s reproductive health issues were especially overlooked. Researchers are trying to redress this balance and commit to greater data diversity, increasing the representation of women and other under-studied groups in society.

This research vacuum means that scientists still do not fully know how the mother’s immune system changes throughout pregnancy. A few small studies¹  have explored the peripheral immune system, which comprises immune cells that remain inactive unless a specific substance (an antigen) triggers them, versus the central nervous system’s cells that are always active. The scientists observed changes in gene expression over time. But it is difficult to infer what this would mean in larger groups of patients.

Addressing this, Emma’s team is collaborating with the Rosie Hospital, part of Cambridge University Hospitals NHS Foundation Trust, Pregnancy Outcome Prediction Study 2 (POPS2)². This exciting project will follow over 1,000 pregnant women who will have routine blood tests and ultrasounds at four time-points during their pregnancy. Extracted RNA from their blood will be sent to Emma’s team who will use bulk RNA sequencing to reveal how the mothers’ immune systems change over time. The anonymised data will be accessible to the research community via the European Genome-phenome Archive (EGA) and summary data more widely available.

"Pregnancy is a unique state where the body tolerates the foetus by reducing the immune system’s responsiveness. It may be that these changes vary between trimesters and between pregnancies, so we can explore if these differences are associated with adverse outcomes, such as preeclampsia. We also hope to use these findings to explore how to change the immune system, and aid drug discovery. For example, perhaps the immune system can be dampened intentionally to improve autoimmune conditions such as lupus," explains Emma.

Lupus is a chronic disease causing widespread inflammation across many different organs, which can cause fatigue, joint pain, skin rashes, neurological symptoms and more. It varies greatly between patients and only a limited number of treatments exist. Emma’s team is collaborating with Open Targets to improve the molecular understanding of lupus and hopefully help identify new tailored, more effective treatments that could also reduce side effects.

Sepsis and the immune system

Another severe medical condition Emma’s team is investigating is sepsis. Sepsis can arise after someone suffers an infection and the body over-responds with widespread inflammation that can lead to blood clots and leaky blood vessels. The situation can escalate rapidly, ranging from tissue damage to organ failure, and it accounts for one in five deaths globally each year³. Symptoms include fever or low body temperature, increased heart rate, rapid breathing, confusion or disorientation, extreme pain and clammy skin.

"Anyone can suffer from sepsis but it’s difficult to predict who might have the most severe reaction. In my PhD we collected blood samples from sepsis patients in intensive care to measure their gene expression. We identified two subgroups with different immune responses and outcomes related to their gene expression patterns. Our findings showed that these different immune responses could be linked to different survival rates – and thus highlight who is more at risk,” says Emma.

This finding is encouraging because it may lead to easier diagnosis of sepsis, more effective clinical trials and the development of more effective treatments.

“Ten years after my PhD thesis, I have continued collaborating with my original PhD supervisor on this subgrouping research. We are now working with Danaher Corporation to turn our gene signature into a point-of-care diagnostic test⁴ to provide precision medical care."

Technological advances have been central to this achievement. It is now possible to collect blood in an intensive care unit, extract the RNA, conduct real-time PCR on just a few genes, and view the resulting gene expression patterns. These tests can be completed within an hour, which is crucial for emergency conditions such as sepsis. Clinicians need to have the information quickly to make treatment decisions.

Now Emma’s team can identify subgroups of patients, the next step is to find the genes that are most informative and translate that into something that might improve patient care. The rapidity of the test means it could be used alongside other vital signs to monitor patients over time and assess the effectiveness of treatments. Many hospitals already have access to the necessary machines, but the process is expensive. Sepsis is a global problem and many affected countries are resource-limited, so the technology needs to become cheaper and more readily accessible.

Life at the Sanger Institute

Leading a research group involves spending significant time with your colleagues and providing ongoing coaching and support for early-career scientists.

“I’ve kept in touch with PhD students and postdoctoral researchers who have worked with me as they have progressed through their careers. If they asked me for advice, I’d suggest they stay curious and open to trying new things. Learn as much as you can from your colleagues and peers. Share your expertise and collaborate with others. Take advantage of diverse experiences and opportunities to help you grow and succeed in your career.”

Dr Emma Davenport

Emma also enjoys public engagement and outreach.

“I’ve met some impressive schoolchildren. After providing a talk for a school, a student got in touch because she’d read my papers and wanted to interview me for her extended essay. I was impressed with her fantastic questions! We have stayed in touch and she is joining my team for work experience this summer. It’s been rewarding to show her the opportunities available in medical research.”

I asked Emma to share her experience as a faculty member at the Sanger Institute.

“The best part of my day is working with the team; the people are fantastic. I enjoyed setting up my own lab because I could shape the team's culture and dynamic. We have created a supportive environment where team members help each other and learn from different projects. We have a positive and encouraging atmosphere.

“The Sanger Institute is an incredible place to start a research group. You get to start hiring and generating data rapidly because you don’t have to wait months for the outcome of grant applications. There is secure funding for some of your team members and this longevity benefits our long-term projects.”