In this interview, Dr. Stephen Lye, the Interim Director of the Lunenfeld-Tanenbaum Research Institute at Sinai Health, talks to NewsMedical about how AI and DNA sequencing can be used for understanding pregnancy complications.
Please introduce yourself and your role at the Lunenfeld-Tanenbaum Research Institute at Sinai Health? What inspired your career – both in science and in maternal health?
My name is Dr. Stephen Lye, and I am the interim director of the Lunenfeld-Tanenbaum Research Institute at Sinai Health, which is part of the University of Toronto. My interest in maternal child health can be attributed to when I undertook my post-doctoral training in London, Ontario.
I am originally from Bristol, England, but I moved to Canada to do this post-doctoral training in a hospital setting. The experience of being in a hospital and talking to clinicians as a basic scientist gave me a better understanding of how integral maternal health is to long-term health and well-being. This idea was partly borne of the integration of basic science with clinical practice, which I think is very powerful.
As a research area, maternal health can be both underfunded and under-recognized. However, more technologies, such as AI and DNA sequencing, are being used in recent years to understand pregnancy complications further. Why is it so important to continue raising awareness of pregnancy complications?
Something that may not be immediately apparent is that a pregnancy carried to term involves two human beings – the pregnant patient and the baby. The health of the father is also relevant. It is now known that how an individual develops in utero and early infancy plays a critical role in establishing their lifelong health and well-being.
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If optimal, the pregnancy environment will help that individual to be healthy and reduce the risk of illnesses in later life.
Conversely, suppose that an individual is exposed to risks in utero. In that case, a challenge can be posed to their health trajectories, whether that is because of maternal ill health, such as preeclampsia, or whether the individual is born prematurely.
This can result in a greater risk of non-communicable diseases such as cardiovascular disease and diabetes, as well as a risk to full intellectual development and pose difficulties for that individual to form optimal social relationships.
A research framework termed Developmental Origins of Health and Disease examines these connections.
As a result, science and government have become increasingly interested in the links between maternal health and child health and how, in pre-conception, the parents’ health can impact embryo development, fetal development, and child development in areas like cardiovascular disease and diabetes.
Despite this increase in medical advancement, there’s been no reduction in the occurrence of pre-term birth. Why is this, and what impact does pre-term birth have on infants and moms?
The reality is that the diseases of aging adults have garnered increased attention in recent years, whether we are talking about cancer, diabetes, cardiovascular disease, or dementia. This increased support could be partly political: older people are at the most risk of those disorders, and it is generally older people working in government funding and setting budgets for healthcare.
The idea of the developmental origins of health and disease is gaining traction. Currently, though, where the funding is based is where researchers are. In this vein, there are far more researchers in cancer, cardiovascular disease, and diabetes than in reproductive health and development issues.
Stephen Lye at ICG17 – Understanding Pregnancy Complications with AI and DNA Sequencing
There are typically fewer researchers in specific fields like mine, and much greater collaboration is needed to make changes happen.
At my own institution, Sinai Health in Toronto, within the larger institute, where researchers are involved in cancer, neurodegenerative diseases, and cardiovascular diseases, we also have an infant health research group. This allows us to connect with those individuals and ensure we can identify some of the cutting-edge science and technologies.
You are currently a senior investigator at Sinai Hospital in Canada. Can you tell us a bit more about the laboratory you work in and some of the current research in which you are involved?
The laboratory that I lead focuses on pregnancy complications. We are interested in examining the mechanisms responsible for preeclampsia and pre-term birth. Through this understanding, we seek more efficient and earlier diagnoses of which women are more likely to have those conditions to intervene.
We are also focused on developing interventions or therapeutics that can be applied once we have understood more about the disease. It is vital, in my opinion, to focus not only on mechanisms, therapeutics, or diagnostics but to recognize that these elements are all interwoven. Our group looks at each aspect to try and make a difference.
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I am interested in these aspects of science closer to the patient because I tend to enjoy the broader picture. Rather than a career focused on one particular gene or protein and understanding everything I possibly can about that element, my research interest has been more broad.
The broad research aspect allows me to focus on how relationships and correlations happen between different sectors. If I were focused on one specific area, I might not see the connections in the background. I hope this broader approach will allow me to continue benefiting patients.
Most of the diseases and disorders we are interested in are very complex. As such, they are not single-gene or even multiple-gene but have genetic and environmental components and complex natures. Broad thinking must be employed to identify pathways that might be amenable to therapeutics.
You are involved in the largest Canadian study of its kind to track the health of women and their babies. What are you hoping to learn from this, and what does this study involve?
We introduced this study to Mount Sinai Hospital, one of the hospitals in Sinai Health. A general hospital, Mount Sinai also has one of the largest reproductive and pregnancy programs in Canada. Our practice is to enroll women when they attend their first obstetrical visit after asking them if they would like to be involved in this study.
If they wish to be involved, the patient will consent to their health information being made accessible to us. When they have a blood sample or another type of sample collected for their routine clinical care, a small sample of the original is banked for research. This way, the study does not involve additional sampling, but the data is derived from their normal care.
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The only additional requirement is for the patient to complete some detailed questionnaires about their life: their lifestyle, education, home life, economic activity, and past medical history.
We hope to learn more about what factors support a healthy pregnancy through this initiative. The information generated can be passed back to new patients to help them have better outcomes.
Currently, there are close to 4,000 women enrolled in the study. Over the study, we have obtained thousands of blood samples, urine samples, and different biospecimens, and the study is at the stage where we are now following the children born.
We have followed over a thousand children to about four years of age. We examine a range of various aspects of their early development, which provide us with insights into how we can improve pregnancy outcomes as well as how we can improve outcomes for the children.
You are currently at ICG, and your earlier presentation was titled ‘RNA Sequence.’ RNA sequence identifies signatures of maternal blood that can predict imminent pre-term birth. Could you outline some of the key takeaways from this presentation?
As mentioned earlier, one of our core aims is to provide better care for women clinically diagnosed with pre-term labor. The condition known as threatened pre-term labor occurs when women start uterine contractions before ‘normal term,’ or 37 weeks of completed pregnancy.
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When threatened pre-term labor occurs, there is a risk of the baby being born pre-term. Indeed, if the delivery is too early, that baby can die because it is essentially a fetus born into an extrauterine environment. At about 24-25 weeks of pregnancy, which is a little over halfway through, such babies would be about the size of my palm.
Sadly, if born at that gestation period, many of them will die, and others might have significant disabilities that they will experience for the rest of their lives.
When a clinical diagnosis of pre-term labor is made, it is very difficult for clinicians to know whether a woman experiencing contractions will continue to experience them and go on to deliver within the next couple of days or if the contractions will cease and pregnancy will be maintained onto term. Only about 20% of women diagnosed with pre-term labor actually deliver pre-term.
Suppose the clinician is of the opinion that there is going to be a pre-term birth. In that case, it is firstly essential that the woman is kept in a hospital, hospitalized, or transferred from a community hospital to a hospital that has a neonatal intensive care unit.
This is important since high standards of care and capability are needed for looking after a premature baby, which is costly to the healthcare system. Often, particularly in countries like Canada, which are sparsely populated, this means that women will be transported long distances away from home.
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The next step is that the patient will be either treated with drugs to try and stop the labor or given hormones to mature the baby’s organ systems and hopefully allow that baby to survive. If the patient is in real pre-term labor, these methods are all perfectly suitable, but the reality is that 80% of them are not.
We have tried to develop a new test to better identify women that are in real labor and will deliver within the next 48 hours and those that are in forced labor and could instead be sent home.
Threatened pre-term labor is the second largest cause of being hospitalized during pregnancy other than giving birth. This takes up many healthcare resources and can cause women to have treatments they do not necessarily need.
Are you hopeful that RNA sequencing could predict imminent pre-term birth? If so, what impact would this have on women, their children, and healthcare?
We had some pulmonary data of gene expression signatures in the blood of women experiencing threatened pre-term labor. These gene expression signatures were predictive of whether women would deliver or not.
cDNA microarrays were old technology deployed before sequencing came in. Its sensitivity and specificity were good, but it was not good enough to turn into a commercial test. When RNA sequencing came in and became cost-effective enough to do on a large scale, it allowed us to conduct the study we did before again and get much more resolution on the gene expression signatures.
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In our current study, we have performed nearly 1000 RNA sequences – RNA sequencing on 1000 samples. This work has increased the sensitivity and specificity of our signatures.
If all the current signatures in new populations can be validated, these can likely be used to develop a commercial test. This project is one that my own hospital jointly funds, BGI, and Genome Canada, which is through a program called the Genomic Applications Partnership Program, our genomics funding agency in Canada.
It is essential to work closely with companies interested in pregnancy. Most companies are afraid of what might happen if a problem occurs, so they steer clear of pregnancy. BGI has had some experience in pregnancy and newborn health due to their newborn screening tests. If we successfully generate a screening test through the research program, this could be introduced into their line of products.
Are you hopeful that the field of maternal health will soon see better outcomes with continued research, funding, and innovation? Could increased and improved testing generate better outcomes for pre-term birth? What more needs to be done before this can become a reality?
As an optimist, I would say we strive for and achieve positive outcomes for women. We are also trying to develop a similar type of test that will predict in early pregnancy whether a woman is likely to have a pre-term birth in addition to this screening test in development. In addition, other colleagues are developing the same approach to other pregnancy complications like preeclampsia.
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There is a great deal of activity within the pregnancy research field that can improve outcomes, particularly in diagnostics. It is more complicated to introduce a new therapeutic to women during pregnancy than to give a cancer drug where someone is at imminent risk.
Most pregnancies are uneventful and ultimately lead to the birth of a remarkable new human being. For most parents, pregnancy and childbirth are low-risk, high-reward events. For a small number – approximately 10-15% – pregnancy can be more of a rocky road and potentially have a disastrous outcome. Having a baby die in utero or during the newborn period is devastating, and this motivates us toward our goals.
As a recognized leader in the field of infant health and maternal reproductive health, what has been your proudest achievement?
When I reflect, the work that springs to mind is how the maternal immune system plays a role throughout pregnancy, which has been very exciting. From this, we have discovered that the interactions between the mothers’ immune cells and the developing placenta are critically important in forming the placenta.
In other words, as is well known, the placenta is the lifeline between the mother and the baby. The birth process also requires maternal immune cells, underlining this form of mutual communication between the mother and the baby throughout the pregnancy, which has been hugely exciting to find out.
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The other aspect that has given me the most satisfaction in my career is building groups of scientists, conditions, and investigators that can work well together. Building teams is essential, as I firmly believe that a team will have greater expertise across disciplines. Such multidisciplinary expertise is vital in understanding complex medical issues like pregnancy complications.
The third thing I am proud of is training young scientists who come into my lab as students, several of whom now hold senior positions in their own labs around the world. Those three things – the groundbreaking research we have done, the teams we have built, and the trainees who have furthered their careers in the field – have brought me great fulfillment.
What are the next steps for you and your career?
We aim to expand the research and innovation in the pre-term birth area. One element of this is the screening tests that we hope to develop further and lead to commercial products. Thanks to some early-stage therapeutics, there is also the potential to reduce pre-term birth in high-risk women. We are working to move those closer to human clinical studies.
Finally, we also have a large study in four different countries: India, China, South Africa, and Canada. I am mainly involved in the South African study, in which we are looking at interventions that start pre-conception.
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In this study, to see whether we can improve pregnancy health, women are enrolled before they have a baby so that we can follow them through pregnancy and their child’s infancy.
The study also aims to improve women’s health before they get pregnant, allow them to have healthier pregnancies, and enable their children to have better starts in life. Currently, about 24,000 women are being enrolled, which is going to be exciting over the next few years.
Omix is VGI’s vision for their company. What does Omix mean to you as a scientist?
My priority is utilizing Omix to improve the lives of individuals, which in our case refers to women during pregnancy and their children during infancy.
The core of the vision is to make these expensive and large-scale technologies more affordable and accessible to more people. Our partnership with BGI takes us some way along that route. Simply having the technical capability without understanding the biology or having access to the patients is not viable, sustainable, or valuable; instead, partnerships are essential, as are collaborations.
What are you looking forward to most at the conference, or what have you enjoyed most so far?
I have enjoyed hearing about the science that I am not necessarily familiar with. For instance, we have heard much about metabolomics and meta-genomics and how the microbiome is vital for mental and physical health. It has also been intriguing to learn more about population genomic studies research in the Baltics. This data can also help inform the rest of our work, which is invaluable.
About BGI
BGI Genomics is the world’s leading integrated solutions provider of precision medicine, now serving customers in more than 100 countries.
They provide academic institutions, pharmaceutical companies, health care providers, and other organizations with integrated genomic sequencing and proteomic services and solutions across a broad range of applications spanning:
They have almost 20 years of genomics experience helping customers achieve their research goals by delivering rapid, high-quality results using a broad array of cost-effective, cutting-edge technologies, including their own innovative DNBSEQ™ sequencing technology.
