Murphy’s worm studies may lead to new treatments to stop aging
by Kitta MacPherson
Coleen Murphy is no daydreamer.
Yet, this practical-minded biologist possesses the boldest of visions, one she insists is rooted in solid science. It may be technologically possible, she believes, to someday stall aging sufficiently so that people can live in their adult prime bodies until they die.
“Why not?” she says, half-defiantly, the trace of a twinkle in her eye.
As an assistant professor in the University’s Department of Molecular Biology and at the Lewis-Sigler Institute for Integrative Genomics, Murphy wouldn’t be caught dead saying she is doing anything as dreamy as discovering the fountain of youth. She is an award-winning scientist working in the competitive world of molecular biology, and her specialty is hermaphroditic worms.
But her work examining the life cycle of roundworms known as
C. elegans is taking her into uncharted territory. Understanding the genetic mechanisms controlling the beginning and end of a lifeform’s reproductive capability could lead to learning how to exert control over it. What if reproductive life could be extended indefinitely? Can other signs of aging — memory loss, slackening muscles, even wrinkling skin — be similarly undone?
“She’s a pioneer,” said Virginia Zakian, the Harry C. Wiess Professor in the Life Sciences at Princeton, who studies the parts of chromosomes that may play a role in the prevention of cancer. “She has discovered that there are aspects of aging in humans that can be modeled in this hermaphroditic worm.”
“Coleen is totally fearless,” said her colleague, Manuel Llinás, an assistant professor of molecular biology at Prince-ton who has known Murphy since they were postdoctoral fellows together at the University of California-San Francisco. Their labs are now one floor apart. “She has taken her research into avenues that are virtually unexplored in any organism, and she is applying her ideas to the worm because it is such a fantastic genetic tool,” he added.
It’s a long way from Kansas, where she grew up, with a father who was a Ph.D. biochemist and a biologist mother who possessed a master’s degree and ran the county public health system. Murphy planned on becoming a chemical engineer. As an undergraduate at the University of Houston, which she attended on a scholarship, Murphy was pulled toward biological research while studying for her protein chemistry and genetics classes. In those courses, the students were taught from primary sources — real research papers, not textbooks.
“It was kind of a revelation,” Murphy said. To look at the original ideas of scientists, words that had not been digested and interpreted by someone else, was empowering and exciting. The thought that the authors had done experiments “with their own two hands” and could therefore explore the mysteries of nature was deeply appealing, she said. “I knew I could connect the dots too and extend the boundaries of knowledge,” she said. “I wanted to do that. It had never occurred to me before that this was possible.”
Molecular biology beckoned to her as a field with many mysteries begging to be solved. “There are lots of questions that haven’t yet been asked, and the answers to these are accessible,” she said. “That’s amazing. The idea that you could do this and learn something new was overwhelming to me.”
Murphy knew that Cynthia Kenyon was asking interesting questions. The professor of biochemistry at the University of California-San Francisco was studying the aging process. Kenyon had wagered that, like so much else in biology, aging was probably not a randomly and haphazardly chosen development, but was most likely controlled by genes.
Kenyon also knew that some of the most important discoveries in science have come not from studying people themselves, but from watching simpler creatures, such as bacteria, yeast, mice and roundworms. They often share universal mechanisms of life at the molecular level. Kenyon chose the microscopic roundworm C. elegans as her model organism.
Murphy joined Kenyon’s lab in 2000 as a postdoctoral fellow, just after earning her Ph.D. at Stanford University. She turned up a few years after Kenyon’s group had discovered that a tiny change in the worms’ daf-2 (short for “dauer formation”) gene, which directs the production of DAF-2, the worm’s insulin receptor, doubled the worms’ lifespans. Though she didn’t yet know how to use it, Murphy proposed using a cutting-edge technique known as DNA microarray technology to examine the genetics further. Kenyon put her to work with those techniques. Murphy’s friend from graduate school, Joe DeRisi, gave her advice and training and, best of all, let her use his equipment.
Microarray technology allows the rapid study of large numbers of genes. It helps determine how a cell can control the expression of large numbers of genes simultaneously. Murphy was able to make a whole genome-wide microarray for 20,000 genes almost singlehandedly.
She also learned to use RNA interference technology, another powerful new technique that worked extraordinarily well in the genome of roundworms. Silencing the function of a gene in this way sometimes can allow a researcher to infer what the function of that gene may be.
In June 2003, the lab, led by Murphy’s work, reported that it could identify which genes became more or less active as a result of the mutation of the daf-2 gene.
The alteration enhances the activity of genes that fight infection and control metabolism as well as genes that control the cell’s response to stress, and it dampens the action of specific genes that shorten life. Like a switch, daf-2 ramps up or slows down the activity of a host of different genes. Murphy was the first author on papers that followed in journals such as Nature and Science.
With that work finished, Murphy was itching to go off and try something new. But she decided to wait a year to think through what should come next. “It was very important for me because it meant I moved from doing what was the next obvious thing to going beyond that,” she said. “It occurred to me it might be more interesting to ask some new questions. After all, what is it about aging that really intrigues us?”
A new direction
When Murphy arrived at Princeton four years ago to continue her work on C. elegans, she knew she would take it in a different direction. She has moved away from studying death and is focusing on the processes, such as reproductive ability, that decline with age.
Her keen sense of timing and selection of topics is indicative of her immense talent, according to Llinás. “Coleen is good at identifying what the crucial next steps are for a burgeoning field and has done exceedingly well at positioning herself at the right point in time and bringing the right technologies to a field as it has become necessary,” Llinás said.
She has already won the kinds of early career awards that are the mark of an up-and-coming scientist. Among them, she was named a Distinguished Young Scholar in Medical Research for 2008 by the W.M. Keck Foundation, a leading supporter of pioneering medical research, science and engineering. She also was among 31 scientists named recipients of the 2008 National Institutes of Health (NIH) Director’s New Innovator Awards.
She also enjoys teaching immensely. As the Richard B. Fisher Preceptor in Integrated Genomics, she led undergraduates this year in an intensive course where she combined leading-edge techniques with research.
Denrick Cooper was so inspired by Murphy that he developed his senior thesis around his research in her lab. He also presented his work on Alzheimer-like conditions in roundworms at a scientific conference earlier this year. “I was able to get my first real research experience in Professor Murphy’s lab,” said Cooper, who wants to go on to earn an M.D.-Ph.D. degree. “And I found that I really like it. It’s great to have the ability to learn information firsthand.”
It is also highly instructive to work with such a bold thinker, her students say. “People tend to be more comfortable with sitting on the ideas that they have been instilled with — it takes much more and is sometimes even painful to challenge old beliefs or to switch old ways of thinking,” said Shijing Luo, a graduate student in Murphy’s lab. “However, science will never evolve without doing so. I think this habit of critical thinking is what I have learned most from Coleen, and I will definitely benefit a lot from it.”
In Murphy’s space on the first floor of the modernistic, light-filled Icahn Laboratory, undergraduate students, graduate students, postdoctoral fellows and a handful of staff members spend much of their time peering through microscopes and staring at whitish specks on the slides. These are the microscopic nematodes or roundworms that have already been of enormous use to science.
The bacteria-gobbling worms, which are about 1 millimeter long, live in temperate soil environments like gardens and compost heaps. Nobel laureate Sydney Brenner began his study of their molecular and developmental biology in 1974. They come in two varieties, hermaphrodites and males. Hermaphrodites — which have both male and female reproductive organs — predominate.
Scientists like to study them because they are cheap to breed and can be frozen. Though multi-cellular, the worms are simple enough to be studied in great detail. They are transparent, allowing scientists to watch their development in such detail that they have been able to track the fate of every cell produced at birth.
C. elegans are one of the simplest organisms that exist with a nervous system. Scientists, as a result, have already mapped out every neuron in their bodies. They were the first multicellular organisms to have their genomes completely sequenced.
They can be surprisingly complex. They have been found to experience the same symptoms humans experience when they quit smoking. They are hardy too: C. elegans specimens on board the Challenger Space Shuttle survived its tragic crash in February 2003.
They have yielded a rich bounty to science. At least three Nobel Prizes have been awarded to researchers working on C. elegans. Scientists at Princeton and other leading universities worldwide have formed “worm clubs” to discuss the latest developments. Murphy met her husband, Zemer Gitai, an assistant professor of molecular biology at Princeton, in the worm club at the University of California-San Francisco.
Murphy likes roundworms because their life cycles make it easy to study them for aging issues. They live for about two weeks. It takes two and a half days for them to grow from egg to adult. Then they reproduce for about four days (the hermaphrodites produce both sperm and eggs and fertilize themselves). If their life span or reproductive cycle is doubled through genetic manipulation, they can still be monitored in a reasonable amount of time for a scientist’s purposes.
In her lab, Murphy, staff members and students are examining three questions. They are continuing her earlier work, studying how gene expression in worms changes as a result of mutations in key genes associated with aging, like the daf-2 gene. They are examining whether cognitive decline with age can be measured in worms. The Keck grant, which will be for up to $1 million over the next five years, will support Murphy’s efforts to identify the genes critical for the maintenance of higher neuronal activities, in particular, learning and memory, during aging.
Lab members also are looking at whether reproductive life in worms can be extended. Murphy’s New Innovator Award from the NIH will support these efforts with $1.5 million in direct costs over five years. Research team members will be studying the causes of reproductive aging and help identify candidates for the treatment and prevention of age-related reproductive decline and maternal age-related birth defects.
This work already has led them to discover a genetic pathway in roundworms that doubles the span of their reproductive lives and produces eggs that lack the genetic problems often seen in the eggs of aging mothers. Such work could ultimately lead to a drug that could help women.
Murphy views this as a breakthrough. If the results can be translated to humans so that the reproductive lives of female humans could be extended and the quality of their eggs maintained as they age, that could avoid lots of medical intervention, she said. Women are often forced to make difficult personal and career decisions based on their reproductive age, she said.
“I don’t think women should have to think about it at all,” she said. “Men don’t have to.”
Murphy and Gitai are the parents of a son who is almost 2, and she considers herself fortunate to have been able to combine motherhood with professional success. She is also quite glad to be married to another scientist.
“We understand each other so well,” she said. “When I say I’ll be done in an hour, he knows that means three hours!”