Decoding Pregnancy Sickness: Stephen O'Rahilly and Marlena Fejzo's Genetic Breakthroughs

Breaking the Wall of Pregnancy Sickness 

Winner Interview 2024: Life Sciences

Stephen O'Rahilly and Marlena Fejzo, Life Sciences winners, are dedicated to understanding and curing Hyperemesis Gravidarum, a severe form of pregnancy sickness. Their groundbreaking research has identified genetic factors and the role of the hormone GDF15 in Hyperemesis Gravidarum, leading to new prevention and treatment avenues. This interview page highlights Stephen O'Rahilly's interview responses, while Marlena Fejzo's responses are available on her interview page.

Which wall does your research or project break?

Nausea and Vomiting occurs in more than 80% of pregnancies, and is commonly severe enough to significantly disrupt working, family and social life. In 1-3 % of pregnancies, across all ethnicities and cultures, the vomiting is so severe that the pregnant woman requires intravenous rehydration. This condition, referred to as Hyperemesis Gravidarum (HG), can cause serious complications, up to and including maternal and fetal death.  The treatment of hyperemesis has, until now, has largely involved the use of empirical anti-nausea medications that are only partially effective and are mostly unlicensed. The principal barrier to developing safe and effective treatment for PS has been the almost complete ignorance of the fundamental mechanisms leading to the disorder. The research of Fejzo, O’Rahilly and colleagues has led to a very clear understanding of what appears to be the major driver of nausea and vomiting in pregnancy including HG.  We now know that PS results from the action of the hormone GDF15 on specific centres in the maternal hindbrain and that the GDF15 produced in large amounts in pregnancy comes overwhelmingly from the fetal part of the placenta. 

The severity of PS relates to two factors a) the amount of GDF15 produced by the fetal component of the placenta and b) the mother’s sensitivity to GDF15, which is substantially influenced by the amount of GDF15 in her circulation prior to becoming pregnant. In experimental animals we have shown that prior exposure to GDF15 reduces the behavioural response to a subsequent bolus of the hormone, providing an explanation of why women with higher, pre-pregnancy levels of GDF15 are at lower risk of developing HG. These findings, published in Nature earlier this year (PMID: 38092039),  provide a clear direction for the development of therapies to treat and prevent HG. We are currently exploring 1) What are the factors, including genetics, that influence the amount of GDF15 produced by the fetal placenta? 2) How exactly does desensitisation occur? Is it at the level of the target neuronal population expressing the receptor for GDF15 or is it occurring more distally in the neuronal circuits downstream of those neurons? 3) What are the other genetic factors that influence maternal risk of HG and how do they exert their influence?

What are the three main goals of your research or project?

Firstly, we want to fully understand the mechanism of Pregnancy Sickness. Our ongoing approaches to this are described in the section above.
 
Secondly,  we want to develop a safe and effective therapy for HG. In addition to our own work which causally implicates GDF15 in HG, research in primates undertaken has shown that the nausea and vomiting resulting from surges of GDF15 (e.g. after cytotoxic chemotherapy) is effectively prevented by an antibody which blocks GDF15 from acting at its receptor, GFRAL. It seems highly likely that blocking GDF15 in pregnancy has a high likelihood of being efficacious. Safety is, of course, a major concern; the tragedy that resulted from previous attempts to treat HG with thalidomide being a stark reminder of this. However, we have strong reasons to believe that blocking GDF15 action in pregnancy would be safe. 1) Nine individuals have been described who totally lack functional GDF15 or GFRAL with no apparent impact on development, health or fertility (Gurtan et al Biorxiv 2024 and personal observations) ) 2) The receptor for GDF15, is undetectable in first trimester human fetal brain. We believe that the evolution of placental production of GDF15 in higher primates (it does not occur in lower species) was likely driven by the advantages, primarily to the fetus, of influencing maternal behaviour, in order to avoid ingestion of teratogenic toxins or infected foodstuffs, which were abundant during our time as hunter gathers. In a modern food environment this “normal” function of GDF15 has become largely redundant. Both Fejzo and O’Rahilly are working with companies who have generated anti-GFRAL antibodies to plan the first clinical trials in HG
 
Finally, we will work towards reducing  the risk of HG in high-risk women.  Women who have higher GDF15 levels before pregnancy are less likely to develop HG. If we can safely increase GDF15 levels in women planning pregnancy this should reduce the risk of HG. This is of particular interest to women who have had HG in their previous pregnancy as many such women wish, but greatly fear, to have a subsequent pregnancy. In Coll AP et al Nature 2020, we reported that metformin , a widely used ant-diabetic drug with an excellent safety profile, can substantially elevate GDF15 levels. Both Fejzo and O’Rahilly are planning preventive trials of metformin in women with a previous history of HG. Importantly, as metformin is cheap and generic, this could have implications for impacting on the burden of HG in resource-poor settings.

What advice would you give to young scientists or students interested in pursuing a career in research, or to your younger self starting in science?

For young people wishing to embark on a research career, their experience as a graduate student is critical. It is really important to find a supervisor with whom you can build rapport and a mutually respectful relationship. This could be a relatively early career scientist.  Don’t be too be dazzled by the baubles of a famous PI. They may not have the time available to devote to you.

Don’t define yourself by a technique e.g. “ Hi!  I am an electrophysiologist”. By all means develop deep, domain-specific technical expertise but, in the long run, your career as a scientist will be defined by how well you ask interesting and tractable questions and how effectively you access whatever tools you need to address those questions.

Read widely in science. Major advances often happen when an approach taken in an area unrelated to your own sparks an idea about how to address your own scientific problem in a different way.

In any study you undertake, your first duty is to ensure that your data is robust and reproducible. As you mature as a scientist, you will get better at distinguishing between what is true, but relatively trivial, from what is true and genuinely interesting. Occasionally you will find out something that is both true and beautiful and/or true and practically useful. They are the times that make being a researcher the best job in the world.

What inspired you to be in the profession you are today?

As a teenager my father bought me a magazine every Friday,mostly I asked for soccer  or  rock and roll weeklies but occasionally I asked for Scientific American.  In March 1972, when I was just about to turn 14,  Roger Guillemin (who 6 years later was to win the Nobel Prize) wrote an article on hypothalamic hormones which totally captured my imagination and made me decide to be an endocrinologist when I grew up!  

What impact does your research or project have on society?

If, as we predict, our research leads to the successful treatment and prevention of severe pregnancy sickness,  this will have a huge global impact on women’s health 

What is one surprising fact about your research or project that people might not know?

In contrast to Marlena Fejzo, who has had a long-standing and  passionate commitment to solving the problem of hyperemesis gravidarum,  I came to the problem indirectly. I became interested in the hormone in GDF15 when it became clear that , although it can be made anywhere,  its receptor is  tightly restricted to a small part of the brain. That led me to ponder and start to experiment to find out its functions in health and disease and pregnancy sickness looked like a very promising area to explore. A problem can often be more readily solved if scientists working together approach it  from very different directions.

What’s the most exciting moment you've experienced over the course of your research or project?

There were several high points for me in the evolution of this scientific discovery 1. When Richard Kay, using an elegant natural label-based, mass spec experiment showed me the data that established that the vast majority of the GDF15 in maternal serum was made by fetal cells 2 When Nuno Rocha showed me the blot that proved that the rare mutation in GDF15 that Marlena had reported to be associated with a high risk of Hyperemesis was stuck in the cell and not secreted, leading us to chase down a population where we could prove that carrying this mutation resulted in very low levels in the blood outside of pregnancy 3 When Prof Sachith Mettananda, in Sri Lanka,  confirmed our hunch that women with thalassemia, who have very high levels of GDF15 pre-pregnancy,  have vanishing low levels of nausea and vomiting in pregnancy 4 When Irene Cimino showed me the data establishing that pre-treating nice with modest amounts of GDF15 greatly reduced their behavioural response to a later bolus of the hormone, thus confirming our esensitisation. hypothesis. Finally when together , with special input from Sam Lockhart, we crafted an elegant and comprehensive  description of our findings which we knew would likely be of  historic significance for women’s health.