Polina Lishko, a Ukrainian-born physiologist whose work at the University of California, Berkeley, has already led to the development of promising new non-hormonal contraceptives for women and could lead to male or unisex contraceptives, has been chosen to receive a 2020 MacArthur “genius” Award.
The award comes with $625,000 in funding over five years, which Lishko, an associate professor of molecular and cell biology, will use to continue her work on reproductive physiology, including how sperm navigate the reproductive tract and the effects of aging on the female reproductive system. She was among 21 fellows announced today by the MacArthur Foundation.
“In the past several years, I have submitted numerous grant applications, because our lab was in this challenging budgetary situation, and when they called initially and told me I had been awarded a MacArthur fellowship, my first reaction was, ‘Well, that is a mistake, I haven’t applied,'” she laughed. “Of course, you do not apply; somebody nominates you.”
Though bursting with the good news, Lishko was allowed to tell only one person, her husband. Her two children and her lab colleagues were left in the dark.
A UC Berkeley associate professor of molecular and cell biology, Lishko studies sperm and ovarian cells to understand the cellular steps that allow sperm to swim through the reproductive canal to find and fertilize the eggs. By focusing on the ion channels dotting the cell membranes of sperm cells, she has identified several potential drugs that can interfere with sperm movement and prevent fertilization without the use of hormones, which have side effects in many women.
Her discoveries have been licensed by a startup, YourChoice Therapeutics, that hopes to market a non-hormonal contraceptive that women could use during intercourse and potentially also a contraceptive that would be used by men. Though she was a co-founder of the company, she has since left the startup to focus on her UC Berkeley research.
Although Lishko said there is an urgent need for better contraceptives to prevent unwanted pregnancies without unwanted side effects, she has become increasingly frustrated by her inability to draw federal funding for the work. Much of her research on contraceptives has been supported by private funds, including a recent Bakar Fellowship through UC Berkeley and the Male Contraceptive Initiative (MCI). She had begun to despair, she said, that few people are interested in how normal human reproduction works on the cellular, molecular and genetic levels. Such basic research could have implications for women who are delaying starting families until their late 30s, hoping to rely on technological means, such as in vitro fertilization, to get pregnant.
“The MacArthur fellowship is a life-changer. Psychologically, it is a huge boost – not only for me, but for the team, as well, because it shows a recognition of the importance of the field of reproductive physiology,” Lishko said. “All the years of being constantly rejected for federal funding took a little negative toll; I was thinking, ‘Ok, no one cares.'”
She also worried that her mentees, seeing her struggle for funding, would decide to get out of the field. Several did. But Lishko persisted. As she emphasizes to her students when teaching mammalian physiology, reproduction is essential to the survival of every species.
“It is amazing that this award exists. It was a huge surprise, but also a huge appreciation: The community basically tells you that your work is important,” she said. “That is probably one of the most gratifying things any researcher can experience.”
Lishko, 46, grew up in Kyiv, Ukraine, the child of two chemists, both of whom worked at Taras Shevchenko National University of Kyiv.
“My childhood was spent in chemistry laboratories,” she said. “Of course, I was safely excluded from all the combustible and toxic chemicals.”
Lishko graduated from the same university with a specialist degree in 1996 and entered graduate school at the Bogomoletz Institute of Physiology of the National Academy of Sciences of Ukraine, from which she received a Ph.D. in biophysics in 2000. Her thesis was on the regulation of ion channels in neurons, for which she learned patch-clamp techniques, which are used to measure the minute electrical currents in single cells. Ion channels allow charged particles to enter cells, triggering a huge variety of cellular activities.
Lishko and her husband, Yuri Kirichok, whom she met and married in graduate school, subsequently moved to Harvard University for postdoctoral positions. When Kirichok was appointed an assistant professor at UC San Francisco in 2006, Lishko was hired by UCSF as a specialist and, at the same time, collaborated with Kirichok to adapt patch-clamp techniques to work on human sperm cells, the smallest cells in the body.
“Sperm cells, for decades, had been considered the only cells incapable of applying this technique to,” she said, “Sperm cells are the smallest cell in the human organism and vigorously motile. Since you need to catch a cell with a glass pipette, form a tight seal and record electrical currents from the cell, it was considered to be technically impossible.”
While at Harvard, Kirichok achieved success with mouse sperm cells, which are twice as large as human sperm cells. At UCSF, while Kirichok turned his focus to mitochondria – the powerhouses of the cell – Lishko continued to focus on the ion channels of human sperm and succeeded in capturing and studying them with the patch-clamp technique. She continued this work after taking up a faculty position at UC Berkeley in 2012, and has since successfully studied the sperm of bulls, boars, monkeys, rats and horses, all of which are much different from human sperm.
Her research led in 2016 to the discovery of a switch – a protein receptor on sperm cells – that triggers the power kick that sperm use to penetrate and fertilize a human egg. In 2018, when she found two natural chemicals that block this receptor, she co-founded YourChoice Therapeutics to develop them into a contraceptive.
Last year, in work conducted with Kirichok, they discovered a drug that has a different effect on sperm: It short-circuits the mitochondria and drains away so much energy that the sperm are no longer able to swim upstream to the egg. The drug, already approved by the Food and Drug Administration for treating tapeworm and considered extremely safe, is also being developed by the company as a potential contraceptive.
“When we give sperm cells this compound, they start to slow down, and they cannot overcome the viscous mucous in the reproductive canal,” she said. “It’s like salmon going upriver, and there’s a huge dam they cannot get through. The idea for a human contraceptive is the same: It will go in the female reproductive tract, where it will affect sperm cells without killing the sperm and without being absorbed by the cells lining the tract.”
Recently, she has begun collaborating with researchers at the Buck Institute for Research on Aging, in Novato, California, to understand the relationship between aging ovaries and neurodegenerative diseases, like Alzheimer’s disease. This work was spurred by the finding that girls who have delayed menarche – the first occurrence of a period – and women with early menopause have increased risk of these diseases. Because hormones like progesterone and estrogen, which are produced by the ovaries and plummet at menopause, are known to affect the filtering of cerebrospinal fluid, Lishko is exploring whether early menopause lowers the filtering of toxins in the brain and contributes to neurodegeneration in older women.
“We are looking at this very interesting mechanism – that steroid hormones can directly influence production of cerebrospinal fluid – and we want to understand how, and whether we can pharmacologically facilitate this process to help,” she said.
She also is an adjunct associate professor with the Buck’s Center for Reproductive Longevity and Equality, which funds research on ovarian aging and its impact on women’s health. Lishko’s goal is to find ways to delay aging of the reproductive system in women of child-bearing age.
Lishko admits to being chagrinned at the term “genius” award, which the MacArthur Foundation uses to describe the annual awards.
“All who work in science have very big brain potential. It is too arrogant to say we are geniuses; every person is a genius in a certain way,” she said. Nevertheless, she added, “this is a landmark, I would say, in my career development and an award that also recognizes the importance of reproductive biology.”