February 27, 2017
Elizabeth Winzeler BA ’84 brings fresh approaches to the fight against an ancient disease.
Family lore has it that when she was a child, Elizabeth Winzeler BA ’84 contracted malaria.
It happened the year the family spent in Malaysia, where her father worked as an anthropologist. “Diagnostics weren’t great back then,” she says, so it was never confirmed, but the disease was rampant in Southeast Asia at the time; if you had the telltale fever, aches, and nausea, people assumed that malaria was the cause. Winzeler was only 4 and has no memory of it, but says, “Everyone said I had it.”
Although that brush with malaria didn’t directly influence her future career choice, it’s possible that it planted a small seed.
Winzeler has dedicated her research laboratory at the University of California at San Diego—and her career as a scientist—to eliminating the disease.
Plasmodium—the parasite that causes malaria—has ravaged human populations for thousands of years and continues to evade eradication. A cunning and nimble opportunist, it hijacks mosquitoes and humans to perpetuate its proliferation, manipulates its own genome to hide from the human immune system, and increasingly outsmarts the traditional drugs used to fight it. Although the last two decades have seen progress against it, malaria still sickens more than 200 million people and kills nearly half a million of them—mostly young children—every year.
It’s a formidable adversary. But in Winzeler, the tenacious parasite may have met its match. A creative and unconventional thinker herself, Winzeler has brought new ideas to the fight and accelerated the discovery of anti-malarial compounds, including two promising new drugs now in human clinical trials. According to Dr. Timothy Wells, chief scientific officer of Medicines for Malaria Venture (MMV), a Geneva, Switzerland–based organization that promotes international efforts to develop new drugs, “Elizabeth’s work has transformed the field.”
Catching the Fever
Winzeler found her way to Lewis & Clark College by way of Reno, Nevada, where her family settled after living in Malaysia. She enrolled as an art major and focused most of her attention on sculpture and wood carving, until a class with then Professor of Physics Robert Deery in her senior year changed her trajectory. “His classes are where I started to understand that I liked math,” she says. “He was a very creative, dynamic teacher, and he’s probably the reason I went into science.” Adding a second major, she graduated with degrees in both art and natural sciences, two disciplines that she believes are highly complementary. “Creativity is just as important in science as it is in art,” says Winzeler.
I think those who are most successful in science are creative people who can combine ideas from a broad range of experiences to make new discoveries.
“I think those who are most successful in science are creative people who can combine ideas from a broad range of experiences to make new discoveries. My liberal arts education not only expanded my horizons and helped convince me to go into a scientific career— it also prepared me to be a creative scientist.”
After college, a family friend took note of Winzeler’s blossoming quantitative side and offered her an opportunity to learn computer programming as part of her team at the Bureau of Labor Statistics in Washington, D.C. Winzeler became a proficient programmer there before returning to school to earn a master’s degree in biochemistry at Oregon State University and a PhD in developmental biology at Stanford University. She worked in bacterial genetics as a PhD student at Stanford, then gravitated back toward computer programming, and ended up working in genetics and genomics as a postdoctoral fellow. Eventually, she was able to combine all of her skills, experiences, and interests in the work she does now —“and that,” she says, “is what you get from a liberal arts education.” Parasite Interrupted Winzeler’s focus on malaria grew out of a general interest in diseases of the developing world and a specific interest in parasites. She is especially intrigued by the life cycle of malaria parasites, which require both mosquito and human hosts to complete different parts of their development.
The parasites change forms as they interact with humans and mosquitoes. They migrate through the body and can remain dormant for years. And they just have a very interesting developmental trajectory.
“The parasites change forms as they interact with humans and mosquitoes,” she says. “They migrate through the body and can remain dormant for years. And they just have a very interesting developmental trajectory.”
Searching for ways to interrupt that trajectory and break the cycle of mosquito-to-human-to-mosquito transmission has become her life’s work. It has taken her from the Genomics Institute of the Novartis Research Foundation and the Scripps Research Institute to UCSD, where she has been since 2012. Her lab at UCSD now employs 15 postdoctoral, graduate, and undergraduate researchers and collaborates with hundreds of partners worldwide to develop new therapies aimed at treating—and potentially eliminating—malaria.
“We’ve eradicated diseases, such as smallpox, before,” says Winzeler. “But malaria is more challenging.” A significant barrier is the parasite’s ability to alter its genome so that humans don’t build immunity to it. Drug resistance is another challenge: in many parts of the world, the parasite is becoming resistant to the current—actually very old—drug arsenal.
Most of the medicines used to treat malaria today are based on quinine and artemisinin, two natural remedies that have been in use for 500 to 2,000 years. Aside from resistance, says Winzeler, “The problem with these medicines is that they eliminate the symptoms, but they don’t eliminate all the parasites. Our goal is to create completely new classes of medicines that not only treat the symptoms, but also function like vaccines to prevent people from acquiring the parasites or transmitting them to other people.”
Toward that end, she says, “We’ve been fairly successful.” Her lab discovered the precursor molecules that led to two new medicines currently in human clinical trials, including the first new medicine to be registered for the treatment of malaria in 20 years. Both drugs show great promise for preventing the disease. Their discovery was made possible by a novel process that Winzeler developed while at Novartis.
A Game-Changing Approach
Up until about 10 years ago, explains MMV’s Timothy Wells, the general approach to drug discovery for infectious diseases was to study the parasite’s genome to find its Achilles heel, and then to scrutinize individual chemical compounds to try to target that point. “Elizabeth took a very different approach,” he says. “She transformed the entire field from that reductionist approach to a more holistic one that looks at the whole organism and basically asks the parasite what its weaknesses are.”
She transformed the entire field from a reductionist approach to a more holistic one that looks at the whole organism and basically asks the parasite what its weaknesses are.Timothy WellsChief Scientific Officer of Medicines for Malaria Venture
The problem with the old approach, says Winzeler, was that it was very slow; it was very expensive; and it depended a lot on random luck. As automation and informatics came into play, she began to wonder: why don’t we just screen everything and see what kills the parasite?
Winzeler set out to develop an automated cellular assay, or screening process, that would be able to test large numbers of chemical compounds directly against live parasites. “It seems obvious today, now that it’s gained widespread acceptance in many fields,” she says, “but at the time it was considered quite radical.” Many told her that it couldn’t be done—not with the sensitivity and precision that would be required for validated, reproducible, and useful results. “If you want something done,” says Wells, “just tell Elizabeth that it can’t be done, and she’ll prove you wrong every time.”
Elizabeth Winzeler BA ’84
- BA 1984, Lewis & Clark College (art, natural sciences)
- MS 1990, Oregon State University (biophysics, biochemistry)
- PhD 1996, Stanford University (developmental biology)
- 2012–present, professor of pediatrics, Division of Pharmacology and Drug Discovery, University of California at San Diego
- 2012–present, director of translational research, UCSD Health Sciences Center for Immunity, Infection & Inflammation
- 2010–12, associate professor, Department of Genetics and Department of Immunology & Microbial Science, The Scripps Research Institute
- 2007–12, department head, Department of Cellular Biology, Genomics Institute of the Novartis Research Foundation Select Awards and Grants:
- 2016, Grand Challenges Explorations phase II grant, Bill & Melinda Gates Foundation
- 2014, Bailey K. Ashford Medal for distinguished achievements in tropical medicine
- 2011, National Institutes of Health grant for malaria research
- 2004, W.M. Keck Foundation, Distinguished Young Scholar in Medical Research award
- Fellow, American Academy of Microbiology
The process, now known as ultra-high-throughput screening, uses sensitive robotic instruments to dispense miniscule droplets of chemical compounds, about the size of a pinhead, and live malaria parasites into tiny wells on a 1,536-well plate. After 72 hours, the plates are analyzed to identify “hits” where compounds have had an effect on the parasites’ growth. Computers then analyze all the data to single out the compounds with the most anti-malarial promise. “If we see several versions of a compound appearing over and over again as ‘active,’” says Winzeler, “it gives us confidence that the compound has real potential and is worth exploring further.”
Once she developed the assay and verified its quality, Winzeler and her team were able to screen through the entire Novartis library of about 1 million compounds in just two months. “Not only did she get it to work,” says Wells, “but she got other people to pick up the technology. Today, we have about 15 new compounds in various stages of clinical development, and most of them came either as direct products of her work or from other people picking up on her work.”
Since moving to UCSD, Winzeler and her team have screened at least another million compounds, dissected over 100,000 mosquitoes to obtain parasite material for the assay, and continued to run screens for major pharmaceutical companies and other organizations. “Every compound that researchers can get their hands on,” says Winzeler, “ultimately gets sent to us.”
After completing her first large-scale screen, Winzeler had another radical thought. “Wouldn’t it be awesome,” she said to herself, “if we could share our data so everyone could use it to try to stimulate drug discovery?” As a neglected disease that hits hardest in the poorest countries, where resources and profit incentives for drug discovery are scant, malaria is an ideal case for open-source drug discovery.
Winzeler talked to her colleagues at Novartis, and to Wells at MMV, and the idea took hold. She published her screening method, and within two years, groups at Novartis, GlaxoSmithKline, and St. Jude Children’s Research Hospital all released their data publicly. In addition, MMV sent a greatest-hits collection of the 400 most active compounds to hundreds of scientists around the world. “All together,” says Winzeler, “about 20,000 compounds with anti-malarial activity have been placed on the internet for anyone to use. It has stimulated a lot of research.”
More recently, Winzeler’s lab has leveraged genome sequencing to make a number of important discoveries about the parasite’s drug-resistance genes, and is turning its attention to other stages in the organism’s life cycle. “I’m very interested in the liver stage,” says Elizabeth, “because this is the way to prevent malaria.” Since the parasite can hide out in the liver for years, it can cause a relapse at any time. “That’s a serious barrier to eradication,” she says. “If we don’t find medicines that work against this dormant liver stage, we could put a lot of effort into controlling the disease in a population and have it all undone by a single relapse that reintroduces the disease years later.” Winzeler’s efforts in this area, and others, are now largely funded by the Bill & Melinda Gates Foundation, which shares her commitment to eradicating the disease.
Many challenges remain, but due to better prevention and control, deaths from malaria have fallen by 60 percent since 2000. Within the scientific community, there is talk of eradication in our lifetime. “I believe it can happen,” says Winzeler. “With the advances in communication, identification, and new classes of medicines, I’m optimistic.”
Without question, her work has made an impact. “Elizabeth and her colleagues have not only delivered new compounds that kill the parasite, but have shown us how they work,” says Wells. “She has a paper in Science every year—hardly anyone achieves that. Anybody can have one or two good ideas, but to produce a continuous stream of good ideas, as she does, is quite uncommon.”
Asked about her hopes for the future, Winzeler says, “It would be amazing if some of the medicines we create could actually be used to help get rid of malaria.” Indeed. When you consider that the malaria parasite conscripts only the females of the anopheles mosquito to carry out its proliferation, it would feel like poetic justice—a sort of evening of the score—for a woman to bring it to its end.
Ellisa Valo is a freelance writer in Oregon City. This article originally appeared in the winter 2017 issue of The Chronicle,