News & Publications
The College Magazine - Summer 2008
Graham Redgrave (SF90) counsels patients while conducting research
on the neural mechanisms involved in eating disorders.
"By far, the greatest obstacle to the progress of science and to the undertaking of new tasks and provinces therein is found in this-that men despair and think things impossible."
Francis Bacon, The New Organon
Among the characteristics that unite Johnnies, across disciplines and time, are these: A burning desire to investigate theories for themselves. Boundless curiosity. A willingness to doubt even the most entrenched doctrines and ideas. Perhaps most important is a willingness to doubt themselves, to hold their judgments up to a critical light, abandon what doesn't stand up to scrutiny, and formulate new ideas.
These are traits shared by the Johnnie scientists profiled here, who attribute at least a share of their success to their experiences at St. John's, not just in the laboratory but in all aspects of the college. The "radical inquiry" at the heart of the Program prepared them to explore deep questions in their respective fields. Graham Redgrave (SF90) uses analogies to Homer along with MRI scans in his work with patients diagnosed with eating disorders. Cynthia Keppel (A84) divides her time between applied and basic science, work rooted in her fascination with nuclear physics. At the National Institutes of Health, Steven Holland &40;A79) seeks genetic links to infectious diseases. Patricia Sollars (A80) hopes her work in a tiny area of the brain may provide clues about the biological clock. And in her laboratory at the University of Chicago, Leslie Kay (SF83) learns more about the brain by studying how rats distinguish one odor from another.
In some cases, these determined inquirers have more questions than answers. But instead of finding "despair" in their dead ends, they draw satisfaction from the continuing quest.
Why do people get sick?
Graham Redgrave: Psychiatrist
When the youthful patient began to describe the alluring temptation of self-starvation and binge-eating, the psychiatrist tried a metaphor. "Have you read the Odyssey?" She nodded. "Do you remember the scene where his sailors tie him to the mast?" As the two of them continued to discuss the ways in which her psychological disorder tempted her to engage in binge-eating, he asked her: "Are you saying you feel like Odysseus, as you struggle with the impulse to overeat?"
The patient nodded. "That's right," she told Johns Hopkins University psychiatrist Graham W. Redgrave, M.D. (SF90), during a recent therapy session at Hopkins Hospital. "I can see that when I'm tempted to start gorging on doughnuts or cookies, I'm like Odysseus hearing the music of the Sirens."
Helped along by Homer's great epic poem, the discussion at the eating disorders clinic continued, as the patient told the doctor that although the "singing of the Sirens was beautiful, Odysseus knew he shouldn't listen, because if he got distracted by the music, his ship would crash on the rocks." Redgrave listened carefully—then used the metaphor to reassure that patient that it was all right to "give up" the disorder and then "go home" (like the wandering Odysseus) to a healthier way of living—a concept that the troubled patient had been struggling to accept.
For the 40-year-old Redgrave, who last year won a coveted NARSAD Young Investigator grant for his groundbreaking research on the functional neuroanatomy of anorexia nervosa, that recent conversation about Odysseus at the hospital's nationally renowned Phipps Psychiatric Clinic in Baltimore was a "fabulous example" of how the liberal arts (and especially classical philosophy and literature) can often play a helpful role in the practice of psychotherapy.
"More than anything else," says Redgrave, "a psychotherapy session is a conversation in which both participants are trying to communicate about problems related to what Freud described as 'broken meaning.'" And so, in one way or another, the challenge is always to persuade patients to lay aside these broken meanings by gradually bringing understanding and insight to them.
"In the case of that particular patient, the discussion about Odysseus was an important part of the dialogue, because it helped her achieve some useful insights about the recurring 'temptation' to engage in an eating disorder that was wrecking her life."
During the months that followed that therapy session in the fall of 2007, Redgrave says his patient "continued to make important strides in understanding the psychological issues—the areas of broken meaning—that had been key factors in causing her episodes of starvation and overeating.
"As a psychiatrist, I feel very fortunate to be able to work in a setting where I can study both the physical brain and the ideas that emerge from it," the therapist and researcher explained. "More and more, it's becoming clear to me—in my [brain] research and also in my clinical treatment of patients—that knowing how to organize the knowledge you gain in a coherent epistemological framework is absolutely essential to effective psychiatry."
Ask Redgrave to account for his passionate interest in "the links between epistemology and psychiatry," and he'll tell you that it began during his junior year in Santa Fe ... when he agreed to take on the "marvelously exciting" challenge of analyzing and then writing an essay on Plato's Theaetetus.
"That was an extraordinary experience," he recalls with a nostalgic smile, "because it forced me to think long and hard about what knowledge really is. When can you be sure you understand an idea accurately, and what should you do with the knowledge you've obtained? What's the best way to think about an idea, if you really want to grasp its essence?"
More than a decade after his graduation in Santa Fe, Redgrave says he was "just amazed" to discover—while en route to an eventual residency in general psychiatry at Hopkins—that the legendary JHU psychiatrist and co-author of the classic The Perspectives of Psychiatry, Dr. Paul McHugh, had centered his entire approach to psychotherapy on a carefully thought out epistemological framework based in large part on concepts Redgrave had first encountered in the Theaetetus.
"During my first year in medical school at Johns Hopkins, I wound up 'shadowing' a psychiatrist who was treating HIV/AIDS patients," Redgrave recalls. "This doctor was achieving some very positive results among a highly stressed, inner-city population, and I was intrigued by that. When he described his approach to patients as 'based on Dr. McHugh's system,' and then as I watched him interact with the patients and saw how effectively he communicated with them, I was struck by how clear-headed and sharply focused that approach really was.
"After a few months of working with him, I realized that the McHugh approach was a truly deep way of thinking about psychiatry, and that it was based on an epistemological system that in many ways seemed to have come straight out of Plato. That was very helpful for me, because it showed how effective psychiatry must be built on a clearly focused epistemological framework."
Born in London in 1968, Redgrave moved with his family to the Maryland suburbs of Washington, D.C., as a fourth-grader, then landed on the Annapolis campus of St. John's in the fall of 1986. A dedicated classics student in high school (he took four years of Latin and loved it), at St. John's he liked the way "the education flowed out of the continuing 'conversation' between you and your tutor and your classmates. I remember being blown away by Euclid, and by the elegance of his definitions.
"You got the sense that you were right there at the intellectual roots of Western civilization," he says, "and the conversation kept getting richer and richer. And everything we read was part of that living conversation. In many ways, I think the reason I'm so excited about doing research in psychiatry these days is because I get to participate in a similar conversation, but now it's about the brain and the mind and behavior and meaning."
After meeting his future spouse, Brooke, in Santa Fe (they're now raising three young children in the Baltimore area), Redgrave spent several years working as a computer programmer in San Francisco, then opted for med school in 1994. "I found computer science very challenging," he says today, "but psychiatry ultimately seemed much richer and more complex. What I really like about my current role at Johns Hopkins is that I'm able to conduct MRI-based research on brain function in eating disorders, while also treating illnesses like anorexia and bulimia.
"As our treatment methods continue to get better, it's a privilege to find yourself working in both arenas. Eating disorders affect millions in this country and cause immense suffering. The stakes are high, and we need every tool—including the Greek and Latin classics!—that can help us to better understand these illnesses."
Redgrave spends many of his afternoons (and more than a few of his nights) in a specially designed, state-of-the-art "imaging lab" at The Johns Hopkins Hospital. His quest: to pinpoint some of the key changes in brain function that take place during episodes of the eating disorder anorexia nervosa—a potentially lethal behavioral syndrome in which young women starve themselves as part of a pathology that often involves several different psychological factors.
In his role as a clinical psychiatrist, Redgrave treats eating-disorder patients in psychotherapy sessions that explore the psychological vulnerabilities contributing to anorexia. During these encounters, the psychiatrist employs the standard techniques of traditional psychotherapy to help patients overcome a disorder that reportedly affects up to one percent of the U.S. female population (or about 1.6 million American women).
Once he steps into his lab at the Hopkins Hospital's Phipps Clinic, however, the clinician puts on a different hat. He becomes a researcher who's more interested in the activation of brain regions than in behavior patterns among struggling patients.
Although the neuroanatomy involved in Redgrave's studies is complex, the strategy behind them can be easily understood. By using (MRI) technology to chart the flow of oxygen-carrying hemoglobin in the brains of patients with severe eating disorders, the researcher can monitor the ways in which the neurons (brain cells) respond to anorexia-related "cues" in the behavior of the test subjects. Hopefully, gaining a better understanding of the patterns of activation involved in such disorders will aid researchers in developing interventions (such as new drugs or psychotherapy techniques) that will eventually help to reduce or even prevent them.
Explains Redgrave: "By studying the change in levels of oxygenation in areas of the brain such as the dorsolateral prefrontal cortex or the insula, we can measure the activity that's taking place in neurons in women acutely ill with anorexia and compare it to healthy women.
"Studying neural mechanisms of eating disorders is a relatively new frontier in psychiatry, and the rapid evolution of imaging technology makes this an especially promising area of research. I don't think we're going to find a magic bullet for eating disorders anytime soon, but we are getting closer to understanding the basic building blocks of the disorder, which may one day help relieve the suffering of anorexia patients everywhere."
By Tom Nugent
What are the fundamental building blocks of matter?
Cynthia Keppel: Experimental Nuclear Physicist and Cancer Researcher
Cynthia Keppel (A84) enjoys a career that combines the best of both
theoretical and applied science, allowing her to work toward
better treatment for cancer while probing mysteries of the subatomic world.
At some point, every thinking being looks to the stars and wonders about the nature of the universe. Where did all of this come from? What is everything made of? What keeps everything from flying apart?
"These are probably questions that we all ask ourselves at one time or another," says Cynthia Keppel (A84). "Some of us just become a little obsessed with them."
Keppel spends her days probing questions that could keep a person busy for a lifetime—several lifetimes, perhaps. Most of them deal with the behavior of quarks, elementary particles that are bound together with gluons that form into larger particles such as protons and neutrons. "My approach to physics is very St. John's-like. I've always been most interested in the big questions," Keppel says. "There are so many basic, fundamental and compelling questions to pursue."
Keppel balances many professional roles: She holds a joint position as University Endowed Professor of Physics at Hampton University in Virginia and Staff Scientist at the Thomas Jefferson National Accelerator Facility. She also directs the Hampton University (HU) Center for Advanced Medical Instrumentation and a joint medical physics program with the Eastern Virginia Medical School, where she is leading efforts to develop advanced diagnostic and treatment tools using nuclear technology.
Keppel has a fourth job that takes top priority; she and her husband, Barry Hellman (A84), a pathologist, have three children, ages 21, 14, and 7. It's not unusual for her to be at the university laboratory in the morning, return home to "hang with the kids" in the afternoon, and head back to the laboratory for late-night research. "I think the greatest advance in my work," she quips, "has been the development of the home office."
One of her most exciting endeavors is directing the scientific and technical aspects of Hampton University's Proton Therapy Institute, a $200 million project to treat cancer patients more safely and effectively. Five proton therapy centers are currently operating in the United States. Hampton's center is under construction and scheduled to treat its first patients in August 2010. As the Scientific and Technical director, Keppel is responsible for machine operations, nuclear science, and treatment planning for the patients.
It's not news that radiation kills tumors," Keppel explains. "The trick is to kill the tumor while reducing side effects and increasing safety for those undergoing the therapy."
Traditional radiation therapy directs a photon beam to the patient, Keppel says. As force carriers, photons "interact all the way through the patient's body, even sometimes all the way through the table."
In contrast, protons deposit all of their energy into a well-defined (tumor) space and interact only minimally beforehand with healthy tissue. After careful positioning, patients are exposed to the proton beam for only about a minute, as an intense energy burst is targeted precisely to the tumor. "That translates into exactly what you want for battling cancer," she says.
Her work has had direct and beneficial medical applications, and that has been immensely rewarding for Keppel. But, at the Jefferson Lab, she spends her time exploring abstract and puzzling questions of experimental physics that first captivated her while she was a student at St. John's.
Keppel first gained experience in scientific research by working at the Naval Research Laboratory during summer and winter breaks at St. John's. She did computer modeling and imaging, gained skills in applied mathematics, and read extensively about physics. She chose American University for graduate studies primarily to work with Ray Arnold, who was among the prominent scientists making exciting discoveries in particle physics at the Stanford Linear Accelerator Center (SLAC) in California. At SLAC, it costs $100,000 a day to run an experiment on the particle beam accelerator, but Keppel managed to secure time for her experiment on resonance electroproduction, the subject of her dissertation. Resonances are extremely short-lived elementary particles (they exist for about 10-23 seconds) that are produced in proton scattering experiments.
"When you hit a nucleon, like a proton, they might do elastic scattering, like billiard balls striking each other, and stay intact. Or the electron beam can hit the proton and completely break it apart. Another thing that can happen is that the electron hits the proton, but the proton absorbs it and goes into an excited state and grows. The quarks then have to align themselves into different spin structures. That's a resonance state."
What Keppel was exploring then and continues to probe today is the question: how do quarks align themselves to remain bound in a resonance state? What force holds quarks together, and how does it differ from the force that holds nucleons together?
"The strong force that holds quarks together must somehow also be the same force responsible for holding protons and neutrons together," she explains. "For physicists, these are phenomena on vastly different scales. How do we link these things together?"
Scientists understand the force that holds quarks together through quantum chromodynamic (QCD), a quantum field theory of the strong interactions based on the exchange of force-carrying gluons between quarks and antiquarks. But the force holding nuclei together is "fraught with mystery," Keppel says. "It doesn't fall into any of our fundamental field theories."
Keppel's work straddles classical and modern science, practical and theoretical applications, and nuclear and particle physics. "Nuclear physics is like classical mechanics—it works. We can make MRI machines, smoke detectors, nuclear power and bombs. On the other hand, we know from a couple decades of experiment now that quarks and gluons are the fundamental things that everything should be made of."
But there's no bridge between nuclear and particle physics. "That's my little niche," Keppel says, "trying to find that bridge."
Physicists at the JLAB probe these questions about subatomic matter by running experiments in the Continuous Electron Beam Accelerator Facility (CEBAF). The accelerator allows Keppel and her colleagues to propel electrons at a nucleus and then study the output: data such as energy, wavelength, and geometric patterns. Getting time on the particle beam accelerator at this national laboratory is extremely competitive, says Keppel, and takes much more time than the actual experiment: "You describe what the experiment is, who your 50 to 100 collaborators are, and you write this whole thing up and present it to a Program Advisory Committee composed of internationally distinguished scientists. The committee approves only a fraction of the proposals submitted and invites researchers to present their experiment." Her St. John's education is helpful in that Keppel knows how to state her case succinctly and effectively, as well as stand up to prolonged questioning.
In one way, her analytical skills were sharpened at St. John's, but Keppel notes "there's no sugarcoating" the disadvantage Johnnies may encounter in graduate school in the sciences. "Most people who find out they want to do math, science, and engineering [at other colleges and universities] have been working so many problems, not in a global sense, but sitting there with paper and a computer, and doing lots of applied math. That is a skill on its own and thinking on its own, and it's something we don't do at St. John's," she says. "Nevertheless, we make it."
In her sophomore year—when she first settled on a career in science—Keppel seriously considered transferring to another institution; instead she listened to a "strong feeling" that she had a lot more yet to learn at St. John's. Getting comfortable with dif?cult questions in the liberal arts—posed by Hegel and Aristotle as well as Einstein and Bohr—prepared her to be a tenacious and creative researcher, still filled with wonder at the mysteries of the universe.
"In my research, we're working on questions we may not know the answers to for 20 years," she says. "One of the most valuable things I learned at St. John's was to keep at it—to keep questioning."
By Rosemary Harty
Why do people get infections?
Steven Holland, M.D.: Physician and Researcher
Even modern scientists hit road-blocks and dead-ends,
says Dr. Steven Holland, who hopes to find cures
for raffling diseases such as Job's syndrome
After a morning of hospital rounds at the National Institutes of Health, Dr. Steven Holland (A79) was up to speed on the cases of a young boy whose lungs were under attack by a mysterious fungus, a young woman with an unidentified infection causing painful skin rashes, and a woman in her 30s with a rare genetic disease that has killed four members of her family.
As Chief of the Laboratory of Clinical Infectious Diseases at NIH's National Institute of Allergy and Infectious Diseases, Holland devotes much of his time to research. But periodically he takes his turn as the consulting physician at the Institute's hospital in Bethesda, Md. For a month, he works in close contact with the medical staff who treat the sometimes stubborn, baffling and debilitating infections that have brought patients here.
The team began with an update on the condition of the 12-year-old boy. "He has fungi in his lungs, and we're working very hard to figure out what his problem is," Holland explained later. "It must be genetic and it must be profound, and we're desperate to figure it out because he's got a fatal problem."
Getting to help patients while researching the causes of their disease combines the best of two worlds for Holland. "What I get to do as a physician is to identify the problem, meet the patient, try to understand her illness at a molecular and genetic level, and try to treat it with specific, directed therapies," he explains, adding with a grin: "That's pretty fun."
The NIH is like a small city, and Holland's laboratory has a broad charge, studying everything from frightening staph infections and drug-resistant tuberculosis to preparing a defense for potential bioterrorist attacks. The welfare of each individual patient is at the heart of their work. "It's a wonderful thing to be here because patients come who have rare or undiagnosed problems, and we get to take a holistic approach that nobody else can afford to take anymore."
After graduating from St. John's, Holland earned a medical degree from Johns Hopkins University School of Medicine in 1983. He stayed at Hopkins as an intern, resident, and chief resident in internal medicine, followed by a fellowship in infectious diseases. He joined NIAID in 1989 to study the molecular biology of HIV, and in 1991 moved to the Laboratory of Host Defenses to study phagocytes and phagocyte immunodeficiencies. He's been Chief of the Laboratory of Clinical Infectious Diseases since 2004.
In medical school Holland developed an interest in working in the developing world, perhaps specializing in tropical diseases or nutrition. He eventually focused his interest on infectious diseases such as tuberculosis, largely eradicated in the U.S. but still a major killer in the developing world. "With the advent of HIV, which came up just as I was starting medical school and residency, the importance of infectious diseases to global health really became obvious," he says.
The research side of Holland's work is driven by a desire to understand why human beings are susceptible to diseases. The more interesting question to think about, Holland suggests, is: why don't more of us get sick more often? "It's been many millions of years since [humankind] began, and we've become the dominant species," he says. "It isn't because of antibiotics, it's because we've really become damn good at fighting off infections. We have found an accommodation with all the biome in the world that has, most of the time, for most of us, kept us pretty happy."
Holland examines immunodeficiency at the molecular level and at a functional level, seeking to pinpoint the reasons individuals develop rare diseases. He has a driving interest in genetic causes of disease because "so much of immunity is genetic."
At any one time, his laboratory runs dozens of clinical protocols dealing with infectious disease. One seeks to find the genetic cause of mycobacterial infections, which are similar to TB. Everyone is exposed to mycobacteria in air, water and dirt. Infection is extremely rare except in severe cases of HIV, in patients with profound immune defects, and a third group that Holland is investigating: North American and Western European women who are post-menopausal, Caucasian, and thinner and taller than their peers. "This is a new disease we're studying, and it must have some genetic basis," Holland says. "It's got ethnicity and morphological restriction, and we're very interested in trying to definitively characterize it and identify the genes responsible."
When he first began studying these patients, Holland was convinced he would find a genetic defect in their immune system that was responsible for their lung disease. Holland's new working thesis is that these patients have normal immune systems, but share some genetic flaw in the lung surface itself. His research team now includes a lung specialist as well as infectious disease and immunology specialists. "Part of the fun in doing science is every now and then being able to say how wrong you were," Holland says. That's why studying science the St. John's way was valuable, he adds: following the thinking of scientists throughout the ages—even when they were wrong—fosters resilience and creativity in problem solving.
"Ptolemy is wrong-elegantly, definitively, comprehensively wrong," says Holland. "I was like Ptolemy, but not as smart. The beauty is once you get to realize that you're wrong, then you still have space to go to find out what's right."
Holland and other researchers were successful in making important discoveries about the genetic cause of a devastating disease called Job's Syndrome—so named because the disease often causes painful boils, one of the many trials God inflicted on Job. "It's a fascinating disorder in which one gene is mutated, but it affects the function of everything, from brain to bone, to immune system to lung, to heart," says Holland. He led an NIH research team that discovered that Job's patients had an immune system that was doing part of its work too well, with white blood cells in overdrive, attacking systems of the body, but other parts incompetently.
A decade ago, Holland and his collaborators published the first comprehensive paper on Job's. For the past decade, he and other researchers hunted the gene that caused the disease, and just last year, they determined that mutations in the STAT3 gene were responsible. "We're still working on how to use those genetic observations to guide us to therapy," Holland explains. "Finding a mutation is exciting; understanding exactly what that mutation does is more complicated."
Not unlike the St. John's Program, research science calls for asking questions and making connections in unfamiliar territory. For the last four years, Holland has been working with a patient in her 30s, who furst sought medical attention for a movement disorder, but was referred to him because of the infections she also suffered. Her family history was intriguing: her grandfather, father, sister, and brother all died young of the disease, which also caused infections.
Holland had no answers until he delivered a paper at a conference and providentially decided to stay through the meeting, most of which was outside his research area. "Somebody presented a case that was exactly this woman," he says. Back in his laboratory, Holland looked up the gene responsible in that case and arranged to have his patient's DNA sequenced. He discovered a deficiency in the Thyroid Transcription Factor-1 (TTF7345;1) gene. "It controls the function of some of the cells in the brain that control movement, the formation of thyroid factors, some of the lining of the lungs, as well as some of the neurological function of the intestines. It also controls the production of some of the immunoglobulins, also called antibodies, which fight off infections in the body."
This woman's case allows Holland to explore compelling questions about genetics and infectious diseases. TTF-1 requires two copies, one each from the mother and the father; only one was passed along to his patient, and this haploinsufficiency is what has made her so ill. What turns this gene on? How could it be stimulated to do its work?
In early spring, the woman had already spent three months at the hospital, undergoing experimental treatments to boost proteins in the TTF-1 gene to stimulate it to function better. It's the first time anyone has tried any therapy for patients of this disease, Holland notes. "Now we're going in to give her a second set and see if we can't push her cells to finally make enough of this protein that she has not had all the years of her life," he says.
Perhaps he can make significant improvements in this patient's quality of life, and perhaps he can gain knowledge that can help her relatives. He admires her courage, and he's grateful for all his team has learned from her. "I'm a pretty hopeful guy," he says, "but I wouldn't do this if I didn't think there's a chance we can help her."
The day that started at 8 a.m. will extend to well after 6 p.m., when Holland will conclude an interview with a fellowship candidate. His wife, Dr. Maryland Pao, is a child psychiatrist who also has a demanding job as deputy clinical director for the National Institute of Mental Health. The couple have three daughters ranging from 19 to 9 years old. For fun, "we stay home," he says, although once a week he makes time to play ice hockey.
Holland draws interesting parallels between the college and his work at NIH. "St. John's is about trying to come up with new insights about the past in general. It's wonderful and I loved it. I wouldn't have gone any place else."
At NIH his work is about "trying to come up with new insights about the future. There's a greater opportunity for failure, but there are real opportunities for tangible success. When somebody gets better, that's fun. They get up and they do what they're supposed to do."
As for the answers he doesn't have yet, "I don't mind not knowing," says Holland. "I would mind if someone said you don't know and you can't know. That would be irritating. That's why I have a laboratory. The beauty of science is that there's a reward for both saying, I don't get it, and then saying, I want to figure it out. You don't get penalized for being ignorant—you get penalized for staying ignorant."
By Rosemary Harty
What regulates the body's internal clock?
Patricia Sollars: Neuroscientist
Patricia Sollars (A80) studies the biological clock that governs circadian rhythms in mammals;
her research may be helpful in remedies for jet lag and seasonal affective disorder
Located in the hypothalamus, the superchiasmatic nucleus is the primary regulator of circadian rhythms in mammals. It cues human beings to the sleep-wake cycle, and it tells creatures with seasonal breeding cycles that it's time to get going.
As a graduate student in neuroscience, Patricia Sollars (A80) first thought about the concept of an internal clock in a purely abstract, St. John's way: "I thought, ah, temporality—what is time?" she says, laughing at the memory. "Of course that's not even in the same ballpark."
Sollars was studying at Columbia University, rotating through laboratories that were studying various questions in neuroscience, when she first learned about the superchiasmatic nucleus (SCN). Although her initial concepts of the internal clock were "naïve," she says, the SCN captured her imagination in the same way in which she once pondered the nature of time along with Augustine. In one tiny area of the brain, she discovered a rich source of inquiry: Does the SCN alone regulate the internal clock? Is it part of a distributed network in the brain? When sight is taken away, how does the SCN continue to regulate circadian rhythms?
"Here was this one little nucleus that sits just on top of the optic chiasm in the brain," she says. "It was always there, but people knew so little about what it was doing. There were so many questions to ask, so many experiments to develop, on a molecular and a behavioral level. All biological creatures have the ability to regulate their activity to day/night cycles, and in mammals that is thanks to the SCN."
Sollars met her husband, Gary Pickard, then finishing up a post-doctorate fellowship in neuroanatomy, in the laboratory at Columbia. They have collaborated on research for most of the past 25 years, though Sollars is more interested in pursuing questions related to the brain function, and Pickard focuses more on anatomical research.
Sollars eventually completed her doctorate at the University of Oregon. She completed a fellowship at the University of Pennsylvania, where she served on the faculty, then joined her husband at Colorado State University. Until this year, she was a research scientist at the Department of Biomedical Sciences at Colorado State University; this fall she and her husband will move to the University of Nebraska, where they will teach and conduct research as part of the university's new veterinary program.
In Nebraska, Sollars will continue to research the SCN and its role in the circadian system. The term "circadian" comes from the Latin, Sollars notes, for "about a day." Most human beings have a circadian rhythm of about 24 hours—unless something knocks it out of balance, for example, shift work or flying across time zones. In her research, Sollars has deliberately altered the circadian rhythm of mice, hamsters, and rats to try to demonstrate that the SCN—relying on cues relayed through the optic nerves—autonomously regulates an important characteristic of circadian rhythms.
Sollars devised and carried out an experiment she believed would show definitively if the SCN was the master circadian oscillator. She based her experiment on the knowledge that each species, and even strains within species, have different endogenous circadian rhythms. "If you keep a mouse in constant darkness with no temporal cues, it will run [on an exercise wheel] with a period of 23.5 hours, and every day it gets up a half an hour earlier," she says. A golden hamster has an endogenous "free-running" rhythm of 24.06 hours, and a rat, 24.3 hours. Sollars' experiment involved a little meddling: what would a hamster do with the SCN from a mouse brain? If the clock was in the SCN, Sollars theorized, the hamster should have the mouse's circadian rhythm.
The first step was for her to test her transplant theory from hamster to hamster. "That worked like charm," she said. "When you lesion out a hamster's SCN and transplant one from another hamster, it restores rhythmicity at 24.06 hours."
Next, she knocked out a hamster SCN and implanted one from a mouse. When the hamster started running in his exercise wheel, Sollars didn't know what to expect. Amazingly, the hamster established a reliable rhythm of 23.5 hours—exactly that of a mouse.
"Then," she says with a sigh, "I made the mistake of taking it one step further." She implanted the SCN of a rat into the hamster, expecting a 24.3-hour cycle to emerge. "When the rhythm was restored, it was 23.5-the mouse again," she says. "I transplanted a rat SCN into a hamster, and the rhythm that comes back out is that of a mouse."
Far from being discouraged, Sollars has an entirely new line of inquiry: "One possibility is that this is species-specific. Perhaps the mouse and the hamster have autonomous clocks in the SCN and the rat could have a distributed clock network. Perhaps when you transplant the SCN from the rat into the hamster, you're leaving part of the clock behind." She published the findings of her experiment in the Journal of Neuroscience (March 1995).
Sollars had to put this question aside while she devoted more of her time to raising her children: Galen, 23, and Emilia, 17. She has continued to work with her husband on laboratory experiments at Colorado State that are more concerned with the anatomical underpinnings of the SCN, several of which may have beneficial medical applications.
Among their current projects is an investigation into the SCN's role in Seasonal Affective Disorder (SAD), a debilitating condition linked to the shorter days of winter. Evidence suggests that a serotonin defiit makes some people more vulnerable to the disorder. "With this particular deficit, you're not as responsive to the light input from the outside,"she explains. "You end up having an altered phase relationship, then that affects hormones, affects mood, and a lot of other secondary components."
Another clinical application of her work is the link between circadian rhythms and jet lag. Is there a way to enhance the way the internal clock works with other systems in the body to help individuals adapt to major shifts in time zones? "Your internal clock, it turns out, will rapidly shift to a new time-but all the other physiological phenomena in your body are out of phase," she says. Knowing more about the SCN's regulatory role may lead to the development of better remedies for jet lag.
It's in her nature, Sollars says, to demand to be intrigued, invigorated—even entertained—by her work. After two years of studying biology and chemistry at the University of Michigan, she started over again at St. John's. Here she discovered how a good question, paired with a sound method of inquiry, could lead to discoveries—or at least, new and more interesting questions.
"The best thing about St. John's was the chance to get to play with ideas," she says. "We'd have these long discussions, and you'd never know where they were leading because the process was most important."
"That's what I loved most about the Program and that's what I carried into the study of neuroscience. When you take on something as vast as the human brain, one of the most important things is the ability to ask questions from a variety of perspectives, to be open to all sorts of possibilities—to look for what you don't expect."
By Rosemary Harty
How do we create our internal cognitive world?
Leslie Kay: Neuroscientist
Rats can tell scientists a great deal about circuits in the brain involved in the sense of smell.
Shown are (L. to R.) Donald Frederick; Leslie Kay (SF83), with RG07 perched on her shoulder;
Cora Ames; and Daniel Rojas-Líbano.
Why do people who suffer from Parkinson's disease lose their sense of smell as the disease progresses? How does a whiff of Coppertone trigger memories of family beach vacations? And what exactly is happening in the network of our brains when we stop to smell the roses?
Leslie Kay (SF83) can't answer these questions yet, but she knows a lot more about how our olfactory system interacts with other circuits in the brain than when she began conducting research 17 years ago at the University of California at Berkeley.
As an Associate Professor of Psychology and Director of the Institute for Mind and Biology at the University of Chicago, Kay spends her time studying what happens in the brains of rats when they are faced with the task of distinguishing between two similar but distinct smells. Her research may someday contribute to a better understanding of devastating diseases such as Parkinson's and Alzheimer's.
Kay came to St. John's after dropping out of Stanford to take some time off. She went to Santa Fe with her then-husband, a hnnie, sat in on some classes, and soon enrolled as a January Freshman. The Program, she says, was a good choice for someone interested in too many disciplines to choose just one to study. "I was flipping back and forth between being a writer, a scientist or a mathematician. At Stanford, I switched my major four times," she explains. "The freshman year at St. John's hooked me. I love geometry, and studying Euclid, I was in heaven."
Between Kay's junior and senior years, St. John's tutor Gerald Meyers helped her secure an internship at Los Alamos National Laboratories with GenBank, an international repository of known genetic sequences from a variety of organisms. At that time, a clerked typed in the sequences, and Kay and the other students annotated coding regions and proteins. Still unsettled on her career path, she ended up working there for two and a half years after graduating from St. John's.
Kay went to grad school at UC Berkeley, dropped out, and worked as a programmer for several years before returning to the GenBank project, where she was a scientific reviewer and software designer. With programmers in great demand, Kay worked in the insurance industry for a brief time, but the attractive pay wasn't enough for her. In search of something fascinating, she returned to Berkeley, where she studied math, physics, and biology. Convinced that she had found her niche, she walked into researcher Walter Freeman's neuroscience laboratory and asked to do computational modeling of the brain. "He was a gruff guy, and said, 'we'll see.' He gave me data to analyze. I came up with an effect in the data, but not enough to prove it. I had to do experiments, and the experiments got me excited." Her "secret love" of statistics, combined with a desire to test theories for herself, propelled Kay into serious laboratory research.
For her doctoral thesis, Kay studied how different regions in the rat's brain talk to each other when the rats perform an olfactory task. At CalTech, where she did post-graduate research, she narrowed her focus to the activity found in single neurons. She tried to draw conclusions about objective odor responses from her research, "but it didn't work." She did discover, however, that even at the level of a single neuron, the activity of the first cells in the central olfactory pathway are strongly modulated both by the meaning of the odor (whether it suggests a sweet or bitter taste to the rat)) and the behavior the rat is trained to carry out in response.
After her post-doc, Kay had her choice between two positions: one in New York at Cold Spring Harbor Laboratories, and one in Chicago. "The University of Chicago was the only place I interviewed where they were excited by the fact that I went to St. John's," she notes.
While her laboratory focuses on the olfactory system and brains of rats, her findings may some day help scientists learn more about neurodegenerative diseases such as Parkinson's and Huntington's, because the sense of smell is affected early in the progression of these devastating diseases—sometimes many years before other symptoms appear.
"The interesting thing in the olfactory system is that you go directly from the nose to the olfactory bulb in the cortex," she explains. Then information is transmitted to the limbic system, including the hippocampus, amygdala and hypothalamus, which is important in emotional states and in memory formation. The signals are also carried to the basal ganglia, which is involved in disorders such as Parkinson's.
Kay and her students implant electrodes inside the brains of rats to record brain waves while they perform various odor discrimination tasks. When animals inhale, the olfactory bulb is stimulated, and theta waves—slow electrical pulses ranging from two to ten cycles per second—are observed. But when a mammal must distinguish between one smell and another, faster gamma waves of 40 to 100 cycles are observed in the olfactory bulb. However, in some circumstances when a rat has learned the association for a smell, a different pattern of 15- to 30-cycle beta waves emerges.
Gamma and beta waves are both evoked when rats smell the odors—but the results change dependent on the behavior involved in the experiment. This breakthrough came when Kay and her students observed differences in two experiments they were conducting. One researcher directed her rats to press the left lever for one odor, the right for another (a two-alternative choice task). The other student conducted a "go/no go" task, in which the rat would press a lever for one odor, and not press the lever for the other. In the latter experiment, the rats learned the task faster and displayed enhanced beta oscillations. In the former, they learned slowly and showed large gamma oscillations when the odors were difficult to discriminate.
It appears the go/no go task was much closer to what an animal does in its natural environment, she explains. "When an animal is foraging around and smells something, it's either something it eats, runs away from, or approaches," says Kay.
Disconnect the link from olfactory bulb to the higher brain—for example, by injecting lidocaine into the pathways—and the system only makes gamma oscillations, not beta. "Through many different studies, what we've seen is that beta waves are not isolated; they involve the entire olfactory system all the way into the hippocampus," she says. In this task the brain wave activity in the olfactory bulb correlates with what's happening in the higher brain, indicating that "the whole system is working together," says Kay.
It has been shown that part of the olfactory deficit in Parkinson's disease is due to diffiulty in sniffing, and Kay showed in a paper in 2005 that sniffing behavior couples the olfactory bulb with the hippocampus when rats learn odor associations. "We lose some of our olfactory sense as we age, but changes seen in Parkinson's and Alzheimer's are more pronounced, and the reason is unclear. We also know that if the olfactory bulb is taken out of rodents, they act depressed, their eating patterns change, they become more afraid of open spaces, and they give up more easily in tasks that are frustrating, and not because they can't smell, but because the olfactory bulb is missing," she says. "If they are treated for depression, they improve.
"The question I got started on, and the one thing that's held my attention all these years is: how do we create our internal cognitive world? The olfactory system offers a nice way to study that question because it is connected with all these other systems. And the circuitry is relatively simple—or it was. It's turned out we just didn't know as much as we thought we did."
A satisfying part of Kay's work is training graduate students to interpret data, to look for effects "that aren't visible to the naked eye." This analysis demands patience and skepticism—something philosophy teaches, too. Kay has never been willing to take anything for granted. "You think you know something and you go looking for the thing you know. It's like the hubris of the Sophists. We have a lot of prejudice about what the sensory systems might be telling the brain. I always go back to Hume and Descartes, and those guys—it's really about constructing our internal representation of the world."
"The thing about biology" Kay adds, "is that we can make hypotheses, and almost invariably [the answer] comes out somewhere in the middle. Then you have to do 10 more experiments to understand that result. We never quite prove anything. And I find that fascinating."
By Rosemary Harty