Still in the lab after 45 years, chancellor’s professor emeritus Michael Roberts has received recognition for his career in reproductive biology research.
Roberts won the Marshall Medal from the UK Society for Reproduction and Fertility (SRF) in August and the Gold Medal and Honorable Membership of the Animal Reproduction Branch of the Chinese Association of Animal Science and Veterinary Medicine (CAAV) in October.
“It’s sort of a culmination of my career in reproduction,” Roberts said.
Since the mid-1970s, Roberts has studied reproductive biology including early pregnancy in cattle and sheep to stem cells models to exploring the causes of preeclampsia.
Roberts received the Marshall Medal largely for his groundbreaking research on interferon tau, a protein secreted by the embryos of cattle, sheep, and other ruminants, which is responsible for signaling to the mother that she is pregnant. In the absence of this signal, the pregnancy fails.
Roberts received the Gold Medal and Honorable Membership of the Animal Reproduction Branch for his long-term efforts in promoting academic cooperation with Chinese researchers in the field of animal reproduction science, including the training of young Chinese scientists.
Currently, Roberts’ lab is using various stem cell models to study the development of the human placenta and the origins of placental diseases, such as early-onset preeclampsia. This disease is life-threatening and initiated in the very earliest stages of a human pregnancy, although only first manifested late in the second trimester.
Even after so many discoveries, Roberts isn’t stopping when there’s still so much left to find.
At 24 weeks pregnant, a baby can hear the mother’s lullabies. At 30 weeks, her belly is a little over a foot large. At 40, the hospital bag is already packed and ready to go.
But imagine delivering only two weeks after the bump starts showing.
Preeclampsia makes induced birth necessary as life-threatening symptoms start 20 weeks into pregnancy, and delivery is the only cure. There is a lack of ways to detect it, and it’s difficult to ethically study the early stages of human reproduction. But what if it was possible to rewind the process to see when the source of the disorder took hold?
Different cellular models of the placenta might be that time machine researchers need to study early pregnancy disorders.
The Michael Roberts lab at Bond Life Sciences Center combines the knowledge and practices of three cellular models to learn more about early pregnancy and diseases.
“We can use these different models to study placental infection with viruses like Zika virus and, of course, COVID because there’s still a controversy as to whether COVID is a hazard in early pregnancy,” principal investigator Michael Roberts said. “And my suspicion is it probably is.”
The placenta is the brand-new organ generated by the embryo — the baby — before any of its other organs develop to give the baby nutrients and support as the embryo grows.
Megan Sheridan, postdoctoral fellow working with the Roberts lab, works on a project to combine 2D and 3D models to see how Zika and Dengue virus interact with the placenta and affect early pregnancy.
“[Complications] occur but you don’t necessarily know that until the end of pregnancy when the baby is delivered,” Sheridan said. “We really want to kind of go back in time and try to determine what’s going wrong in early pregnancy.”
Modeling early placental development is vital to see the beginning of disease complications, but the challenge is to get an accurate glimpse while not putting a healthy pregnancy at risk.
“It’s hard to get a good model to do research on that,” said Jie Zhou, postdoctoral fellow in the Roberts lab. “So that’s why we are working on different stem cells and trying to build up the best model to work on.”
So, the Roberts lab uses the BAP model. By working with a hospital, the lab first takes fibroblast cells from discarded umbilical cords after the baby is born. These fibroblast cells can be collected from mothers experiencing a normal pregnancy or pregnancies associated with complications, like preeclampsia. Then, as Sheridan puts it, they add a “cocktail of genes” to turn the cells into induced pluripotent stem cells. From there, the lab adds BAP — a mixture of growth factors and inhibitors that turn the stem cells into trophoblast cells.
Now the lab is back at the beginning of pregnancy except in a Petri dish of cells. In pregnancy, these trophoblast cells line the outside of the embryo.
This last model inches even closer to an early placenta. These 3D organoids float around inside a jello-like substance called Matrigel where they self-organize into a placental-like structure.
Together the two models give them a full picture. The 3D model gives a clue into how multiple cell types interact with each other while the 2D model allows researchers to see how a single cell type responds.
Since no model is perfect, the Roberts lab is combining their BAP model with protocols and growth conditions from the other two models to create a foundation for their experiments. Now researchers can start asking deeper questions.
While nothing is quite like a real womb, the Roberts lab will continue working backward.
“All of these models, put together, are really useful because we can kind of use them to their fullest potential and systematically assess which one might represent a certain disease or best answer a certain research question,” Sheridan said.
Answering the unsolved questions is a lifetime commitment for fifth year Ph.D. candidate Rowan Karvas in the Roberts Lab at Bond LSC and Laura Schulz’s lab at the medical school in the Obstetrics and Gynecology department.
Originally from St. Louis, Karvas came to Mizzou and found her keen for science through her undergrad research working on adult muscle cells, but it wasn’t until she became a technician in a radiation oncology research lab at Washington University when she realized she wanted to continue research throughout her life.
“I remember a moment when a grad student, Danny Stark, and I were isolating quail embryos,” Karvas said. “We opened them up and I saw their beating tube hearts and all the details. Just looking under the microscope at them was so fascinating to me, I realized that I wanted to keep doing biological research.”
Karvas believes asking questions is what we often forget to do as a society, and in a scientific world with unlimited questions, she knows the one she’d most like to answer.
“I would like to solve pre-eclampsia,” Karvas said. “It’s a disease that’s most likely been with us since we have been human, and it is a disease that deserves to be solved.”
Karvas works on two projects researching human placental development. The pregnancy disease pre-eclampsia often goes unnoticed until later in pregnancy, but causes dangerously high blood pressure, kidney damage, and a placenta that is underdeveloped and has not invaded the maternal endometrium efficiently.
Karvas was eager to work on this problem and so she started grad school two months early.
“This disease if often very deadly for women and in the most severe forms causes death,” Karvas said. “It is the leading cause of maternal fatality in the developing world and is becoming a problematic issue in the states. There are no rock solid genetic, physiologic factors, or environmental stimulus that accurately predicts who will get this disease.”
And that’s why Karvas spends her time researching how and when pre-eclampsia develops during pregnancy.
In Karvas’s first research project, she is looking at modifications to the genetic code that could be responsible for pre-eclampsia and her second project is finding the answer to the question, “at what stage of pregnancy does our cell model represent?”
When Karvas isn’t in the lab you can find her aiding to bridge the gap between clinical scientists and basic science researchers as president of Interdisciplinary Reproduction and Health Group Trainees. The new group involves graduate students and post-doctoral researchers from animal sciences to biochemistry, all coming together to further explore reproductive science.
“It makes me happy and it is very satisfying to start the group and be a part of the groundwork for its continuation,” Karvas said. “Fostering these relationships with people you may have not met otherwise is important.”
When Karvas isn’t running her group or in the lab, you can find her playing the clarinet. Before discovering her love for science she wanted to be a professional performer.
“It is an opportunity to use the other part of my brain,” Karvas said. “I get to shut off the science part and bring on the musical part.”
Roberts honored for breakthrough discovery in reproductive biology 30 years ago
By Eleanor C. Hasenbeck | Bond Life Sciences Center
In 1987, Michael Roberts published a groundbreaking discovery that changed the world of reproductive biology research.
Roberts and members of his lab discovered that a type of protein, an interferon, impacted how the bodies of animals such as sheep, goats and cows, recognized an embryo early in pregnancy. Previously thought to only be a part of a cell’s immune system response, this new signaling role changed the field.
In honor of his lab’s groundbreaking discovery, Roberts recently curated a section of six reviews examining the history of the discovery and current research that has built on it for the November issue of the journal Reproduction.
The discovery revealed an unknown in the reproductive systems of the ruminant family of animals, including sheep, goats, cows and deer. When an embryo first begins developing, before it’s placenta even attaches to the uterus, it releases interferons. Only present for a few days, these proteins signal to the mother’s body that the embryo is there. It triggers the response that keeps the animal from going into heat, basically shifting the animal’s hormones from breeding mode to pregnancy mode.
If the embryo doesn’t release interferons, the mother miscarries. Placing interferons in sheep that were not pregnant made the animals pseudopregnant, a false pregnancy in which no fetus is present.
Scientists at the time knew something made the mother’s body recognize the embryo, but they were not sure what. The discovery of interferon-tau was a mystery solved. That this ‘something’ was an interferon was also a surprise. Before Roberts and his co-discoverer, Fuller Bazer, found interferon-tau, researchers thought that interferons only function was in the immune system. Other interferons help the body recover from viral infections, like cold and influenza, Roberts said. The discovery that the protein also played a role in pregnancy caused some hubbub. It even caught the attention of The New York Times, Roberts said.
“It opened up a whole new area,” he said. “We all the sudden understood how these animals got pregnant, so people went off in all sorts of directions with it.”
The discovery of interferon-tau created opportunities for more research in how ruminant’s unique reproductive systems evolved. Other studies focused on using interferon-tau to improve livestock fertility, but ultimately this interest fizzled out as researchers found fertility treatments for cows were cost-ineffective for producers and unappealing to the public.
The discovery of interferon-tau earned Roberts and his co-discoverer the Wolf Prize in agriculture in 2002. Some consider the prize an equivalent to the Nobel Prize since the Nobel prize does not regularly honor agriculturalists.
After the discovery of interferon tau, Roberts found another protein that impacts pregnancy, which formed the basis of a pregnancy test for cows. Roberts said it’s now a multi-million dollar product in the cattle industry.
Today, Roberts’ lab has moved to other developmental research. He started studying human placentas. His work focuses on preeclampsia, a condition which impacts 5-10 percent of all pregnancies and is caused by the placenta. Roberts’s lab has also developed new lines of pluripotent pig stem cells which are helping scientists learn how to regenerate eye and heart tissue. At age 77, he is still funded and active.
“#IAmScience because it’s extraordinary knowing that a small step towards a treatment could positively impact someone’s life down the road.”
Megan Sheridan doesn’t let anything slow her down.
From presenting at the Society for the Study of Reproduction’s Trainee Research Competition last week—and winning first place—to finishing up her thesis while working in Dr. Michael Roberts’ lab, she’s always juggling multiple projects. Sheridan is finishing up a Ph.D in biochemistry and hopes to graduate in December 2017 or May 2018, depending on how quickly she finishes writing her thesis.
“I was lucky enough to pick up a project studying Zika virus infections early in pregnancy,” she said. “It was one of those perfect timing moments, and we ended up getting some pretty exciting results off the bat. Now I’m really inspired by the direction my thesis work is going and find that my projects are very different but that makes things exciting.“
Sheridan’s thesis focuses on using stem cells as a model for early placenta development and how preeclampsia and viral infections like Zika impact a pregnancy. Preeclampsia is a condition during pregnancy that causes high blood pressure and protein in the urine. The disease likely occurs in the first trimester, but the symptoms don’t evolve until the 2nd or 3rd trimester. To study it, Sheridan uses stem cells generated from umbilical cords of babies born to mothers experiencing preeclampsia or a normal pregnancy, and then uses those cells to determine what defects in the placenta might contribute to the disease preeclampsia.
“I would like to learn as much as possible about the placenta and human pregnancy,” she said. “There are so many unknowns in this area of research because you can’t access the placenta during a pregnancy without disrupting the pregnancy. There are many complications that effect the mother and baby, and if more was known about normal placenta development in pregnancy, then we may be able to better understand and prevent some of those complications.”
Sheridan completed her undergraduate degree at MU, and urges undergraduates to get started in research early, as she believes it gives students a stronger foundation for graduate school. She also believes that mistakes are part of the research process, and wasn’t afraid to share one that she made early on in the Ph. D program.
“I remember in my very first rotation as a graduate student I was learning how to transfect cells with DNA so we could do a reporter assay. We were in the process of adding all the reagents, and between the student I was working with and myself we got confused about who added what,” she laughed. “Somehow, we never added the DNA- an integral part of the transfection! So a week later when we were analyzing the data, we noticed there were no values at all.”
After graduation, Sheridan hopes to experience living outside of Missouri for her postdoc placement. She’d like to stay in academia, and looks forward to continuing to research and teach.
Perhaps one day she’ll even return to MU and Bond LSC!