Public Events: Dialogues of Discovery
Tim Harris, Director of Janelia's Applied Physics and Instrumentation Group, spoke to more than 400 members of the public about building microscopes and imaging science.
The series began in September 2007 with a lecture from internationally renowned physician-scientist and HHMI Investigator, Huda Y. Zoghbi, who shared her experiences with patients suffering from neurodegenerative diseases and her continuing efforts in the laboratory to develop therapeutic treatment options. Since then, we have hosted many public lectures. Lectures now occur four times each year.
For decades, scientists studying evolution have relied on fossil records and animal morphology to painstakingly piece together the puzzle of how animals evolved. Today, growing numbers of scientists are using DNA evidence collected from modern animals to look back hundreds of millions of years to a time when animals first began to evolve. One of those leading the charge is molecular biologist Sean Carroll.
Carroll, who became an HHMI investigator at the University of Wisconsin–Madison in 1990, is an internationally recognized evolutionary biologist. In April 2010, Carroll was named vice president for science education at HHMI, where he is responsible for directing the Institute’s portfolio of science education activities. HHMI’s science education programs are helping to inspire and train a new generation of students and scientists and to advance the public understanding of science.
A noted chronicler of Charles Darwin’s scientific legacy, Carroll has spent his career studying the genetic underpinnings of evolution and development, identifying the molecular mechanisms that lead to new traits and species. His “Dialogues of Discovery” lecture will detail the search for the origins of species and describe some of the great adventures that have occurred in that quest over the past 200 years. Carroll will chronicle the exploits of a group of explorers who walked where no one had walked, saw what no one had seen, and thought what no one else had thought. “Their achievements sparked a revolution that changed, profoundly and forever, our perception of the living world and our place within it,” Carroll says.
Carroll’s research focuses on identifying the ways new animal forms have evolved, and his studies of a wide variety of animal species have revealed how changes in the genes that control animal development shape the evolution of body parts and body patterns. Using the tools of genetics and molecular biology, he is looking back to the dawn of animal life some 600 to 700 million years ago. It is so long ago that there are virtually no fossils or other physical clues to indicate what Earth’s earliest animals were like.
“Evolution encompasses all of biology—it is our big picture,” Carroll explains. “When I was a student, we had a grand picture of animal evolution from the fossil record, but no knowledge whatsoever of how new animal forms arose. That is the mystery that I want to tackle.”
Carroll’s studies have uncovered evidence that an ancient common ancestor—a worm-like animal from which most of the world’s animals evolved—contained the set of “master” genes needed to grow appendages, such as legs, arms, claws, fins, and antennae. Moreover, Carroll says, these genes were operational at least 600 million years ago and are similar in all animals, from humans to vertebrates, insects, and fish. What is different, however, is the way these genes are expressed, leading some animals to develop wings, and others to grow claws or feet.
“We found the same mechanism in all the divisions of the animal kingdom,” Carroll notes. “The architecture varies tremendously, but the genetic instructions are the same and have been preserved for a very long period of time.”
Carroll is also studying the common fruit fly, Drosophila melanogaster, to reveal how genes control the development and evolution of animal form. His innovative approach to studying evolution has led scientists to a more detailed understanding of how animal patterns and diversity evolve. For example, by analyzing the genetic origin of the decorative spots on a fruit fly wing, Carroll has discovered a molecular mechanism that helps to explain how new patterns emerge.
The key appears to lie in specific segments of DNA, rather than genes themselves, that dictate when during development and where on an insect’s body proteins are produced to create spots or other patterns. The same molecular mechanism is likely at work in other animals, including humans, and helps explain the pattern of stripes on a zebra or the technicolor tail of the peacock.
Carroll and his colleagues chose to study the evolution of the wing spot on fruit flies because it is a simple trait with a well-understood evolutionary history. While ancient fruit fly species lack spots, some species have evolved spots under the pressure of sexual selection. The wing spots offer a survival advantage to males, who depend on the decorations to “impress” females to choose them in the mating process.
The discovery provides critical evidence of how animals evolve new features to improve their chances of reproductive success and survival. “We now have convincing proof that evolution occurs when accidental mutations create features such as spots or stripes that impart an advantage for attracting mates, hiding from or confusing predators, or gaining access to food,” Carroll explains. “These accidents are then preserved as small changes in the DNA.”
In addition to his scientific achievements, Carroll is recognized as an exemplary educator. In 2009, he received the Viktor Hamburger Outstanding Educator Prize from the Society for Developmental Biology. He is also a recipient of the Distinguished Service Award from the National Association of Biology Teachers. Along with David Kingsley, a fellow HHMI investigator, Carroll delivered the Institute’s 2005 Holiday Lectures on Science, “Evolution: Constant Change and Common Threads.”
He is also the author of several books, including Remarkable Creatures: Epic Adventures in the Search for the Origins of Species, a finalist for the 2009 National Book Award in nonfiction. He writes a monthly column (also called “Remarkable Creatures”) for the science section of The New York Times and has served as a consulting producer for the public television program NOVA. In March 2010, Carroll received the Stephen Jay Gould Prize, in recognition of his efforts to advance public understanding of evolutionary science.
Growing up in Iowa City, Iowa, a young Tom Cech found rocks more interesting than RNA.
By junior high, he was so enamored with crystals and fossils and meteor showers that he would knock on the doors of geology professors at the nearby University of Iowa and quiz them about the structure of minerals and how they arose.
This obsession with the physical sciences may seem strange for someone who eventually became famous for his groundbreaking studies of biologic molecules. But that interest in structure and function started Cech down a path that eventually led to the Nobel Prize in Chemistry in 1989. He and fellow Nobel laureate Sidney Altman of Yale University independently discovered that RNA is not just a passive information carrier; it can stimulate chemical reactions in living cells, a shocking finding at the time.
“I found that being able to apply the principles of chemistry to understanding something that was alive was particularly exciting to me personally,” Cech says.
Cech’s parents were the first to stir this interest in science, especially his father, a physician and amateur physicist. It was “impossible in my family to ever take a family walk without him asking why the trees were turning color or something about the hydrodynamics of the water flow in the river running through town, always stimulating an inquiry of nature,” he remembers.
That interest in physics and chemistry continued through elementary and high school, spurred by inspiring teachers and encounters with scientists. At Grinnell College in Iowa, Cech loved studying Homer’s Odyssey, Dante’s Inferno, and constitutional history—but he avoided biology. Cech majored in chemistry at Grinnell, and then chose to go to graduate school in chemistry at the University of California, Berkeley.
But by the time he left college, Cech had discovered that traditional physical chemistry research wasn’t for him. “The pace of the work just didn’t suit my own personality, which is quite impatient,” he explains. “Of course, that is the very definition of graduate work, doing the research, so being a physical chemistry grad student represented a bit of a conundrum.” Luckily, Cech came upon John E. Hearst, a professor of chemistry at Berkeley who was using his own physical chemistry background to study chromosomes. Cech knew nothing about chromosomes, but Hearst “was bouncing off the walls with excitement about it,” Cech says. “I thought I would give it a try. And I just loved it.”
Cech received quick feedback from his experiments with chromosomes—sometimes even the same day—and he found that he loved constantly revising his thinking. “There was this constant interplay between ideas and experiments, which would then generate the next set of ideas. That much better fit my personality.”
After receiving his Ph.D. at Berkeley, Cech expanded his knowledge of biology with a postdoctoral fellowship in the lab of Mary Lou Pardue at the Massachusetts Institute of Technology. In 1978, Cech and his wife Carol, a fellow Grinnell graduate and biochemist, both joined the faculty of the University of Colorado at Boulder. There, he settled into the work that would eventually overturn conventional wisdom about RNA.
Prior to Cech’s research, most scientists believed that proteins were the only catalysts in living cells. In 1982, his research group showed that an RNA molecule from Tetrahymena, a single-celled pond organism, cut and rejoined chemical bonds in the complete absence of proteins. This discovery of self-splicing RNA provided the first exception to the long-held belief that biological reactions are always catalyzed by proteins.
In 1989, Cech was awarded the Nobel Prize in Chemistry. As the Nobel committee wrote, “This discovery, which came as a complete surprise to scientists, concerns fundamental aspects of the molecular basis of life. Many chapters in our textbooks have to be revised.”
Cech, who was named an HHMI invesitgator investigator in 1988, later branched into an entirely different area of research—studying the structure and replication of telomeres, the ends of chromosomes. Research by different teams had shown that aging of human cells is linked to a cell’s failure to maintain the length of its telomeres. The enzyme responsible for elongating telomeres, telomerase, has been the subject of intense scrutiny because it may be a useful target for cancer therapeutics or diagnostics. Cech’s team cloned and sequenced the gene for the catalytic subunit of human telomerase and, later, the gene for the protein that caps off the telomeric ends of human chromosomes. They continue to study telomere function with the long-term goal of better understanding the mechanism of telomere replication.
In January 2000, Cech was named president of HHMI, the nation’s largest science philanthropy. His tenure as president has been marked by innovation and significant programmatic expansion. Under his leadership, HHMI opened its first freestanding research facility—the Janelia Farm Research Campus—as a new model for conducting interdisciplinary research. Cech also introduced focused competitions to identify exceptional physician-scientists engaged in patient-oriented research, broadened the HHMI investigator competitions to embrace more interdisciplinary research, and initiated the institute’s first-ever competition for early career scientists.
Throughout his tenure as president, he has maintained his lab in Boulder, visiting once a month to keep his research going and his mind engaged in science. In April 2008, Cech announced that he plans to step down as head of HHMI to return to his lab on a full-time basis. There, he hopes to continue making the occasional discovery—and return to the classroom to engage the next generation of potential scientists.
According to Roian Egnor, her research into the neural basis of natural animal behaviors, a field called neuroethology, involves too many different scientific disciplines for one person to master in a lifetime. But in many institutions, finding good collaborators and getting them together is difficult. So when she learned about Janelia Farm’s highly collaborative approach to neuroscience, she thought, “Wow. This is exactly what we need.”
Science has long been a part of Egnor’s life. She spent her early childhood in Tunisia, where her father taught science at a middle school for the children of American families living abroad. “We would go camping in the Sahara, and I can remember crawling out of my tent in the early morning and seeing desert foxes,” she says. “I’ve always been interested in watching animals. If you stop and watch for a while, you realize there is a lot going on there.”
She received a degree in biology with a focus on integrative neuroscience at Bryn Mawr College, where she was introduced to the work of Masakazu “Mark” Konishi, a pioneering neuroethologist at the California Institute of Technology.
Two years after graduating from Bryn Mawr—a period that encompassed working in Parisian AIDS clinics, training dolphins to recognize specific frequencies of sound, and tracking monk seals in Hawaii—Egnor joined Konishi’s lab, where she contributed to an ongoing study of barn owl hearing. Few animals can track sounds better than barn owls. They are so adept at it that they can catch a mouse at night just by tracking the rustling of leaves as the rodent scurries about. This acuity stems from the parabolic sound collectors built into the owls’ heart-shaped faces and the “massively” developed auditory pathways that analyze those sounds in their brains. The pathway is ideal for study, says Egnor.
“We know that barn owls, like humans, use differences in the intensity and arrival time of sounds at the two ears to figure out where a sound is coming from,” she says. “In the owl, intensity and time are processed in two separate neural circuits, and converge in the midbrain to form a map of auditory space.”
“We knew from previous work,” says Egnor, “that these neurons need both time and intensity information to form their map.” She then interfered with their ability to analyze time differences by playing unrelated sounds through
custom-made headphones.
According to Egnor, that should have prevented the owls from being able to track noises, but it didn’t. The owls still oriented to sounds, but their reactions were slower and less accurate. Similar results from lesion experiments implicate forebrain circuitry. This distinction—between a precise, fast, but demanding midbrain circuit, and a sloppier, slower, but more forgiving, forebrain circuit—may be a general feature of neural circuit design, says Egnor.
From Caltech, Egnor moved to Mark Hauser’s lab at Harvard, where she began working with the complex social vocalizations of a small New World monkey, called the cotton-top tamarin.
Egnor’s work with owls, dolphins, and monkeys has focused on individual animals in controlled conditions that remove much of the complexity of real world social interactions. Part of the reason, she says, is technological; the tools don’t exist to study animals in natural, uncontrolled situations.
“As neurobiologists, we’re always studying the behaviors we can study,” she says. “But that’s not how behavior works. Behavior is complicated and messy and there are lots of animals involved and they are never doing just one thing at a time.” Egnor says the draw of Janelia is the freedom to take the leap and try to develop the tools to make those more complex studies possible.
Her experiments at Janelia will attempt to record and characterize the vocalizations of 40 or more mice in the same enclosure, going about their daily uncontrolled lives. “Problem number one is just keeping track of all the mice,” she says. “Then, you have to keep track of what they’re paying attention to as they vocalize: Are they thinking about what they smell or are they thinking about what they see or are they thinking about both? They are right next to this female, but are they thinking about the female across the cage?”
Some people are lean, others more Rubenesque. Ron Evans has discovered that, to some degree, the difference between a couch potato and a marathon runner lies in the activity of a family of genes that controls the storage and burning of fat.
By exploring the function of these key regulatory genes, Evans hopes to deepen our understanding of the molecular basis of obesity-related diseases such as diabetes and syndrome X, a disorder characterized by high blood pressure, heart disease, and insulin resistance. Ultimately his studies could lead to the development of drugs that might help people slim down and improve their overall health.
“Follow the energy—that’s my story,” says Evans, an HHMI investigator at the Salk Institute in San Diego. “It’s all about the energy.”
The focus on energy applies equally well to both Evans’s science and his personal philosophy. In the lab, Evans explores the regulation of metabolism: how cells balance their energy input and expenditure. But his investigations are powered by his enthusiasm, curiosity, and irrepressible energy. “I was a real lab rat,” says Evans of his early days at the bench. “Fifteen- or 16-hour days were pretty normal. It was work, work, work—and I loved it.”
That degree of dedication is not unusual, says Evans. “When you’re engaged in a scientific adventure, it really gets your juices flowing.” And science has been working its charms on Evans since he was in high school. “I was good at it,” he says, “and I think I had a good feel for it.”
Evans signed on as a graduate student to work with UCLA researcher Marcel Baluda. The lab was studying tumor-causing viruses that use RNA as their genetic material. What Baluda—and his competitors—were trying to figure out was how these viruses convert their RNA to DNA, a feat that they perform after infecting a host cell but that runs counter to the way all other organisms operate.
Baluda and his lab got scooped. Two other biologists—Howard Temin and David Baltimore—discovered the enzyme that transforms RNA into DNA, work that eventually earned them a Nobel Prize. Evans plowed ahead. “My goal—and it wasn’t necessarily the most lofty goal—was to get a Ph.D. fast.” Evans’s efforts paid off. He published half a dozen papers in under four years and was well positioned to secure a good postdoctoral fellowship.
His first choice was the lab of “the arch nemesis, David Baltimore,” says Evans. But when Evans went for a visit, he discovered that Baltimore was preparing to go on sabbatical to Rockefeller University to work with molecular biologist James Darnell. Evans decided to go there as well.
“That was an exciting time and an ideal choice,” he says of his stay in Darnell’s lab. He began studying a problem that would hold his interest throughout the rest of his career: how cells control the activity of their genes, a process central to life. Although Evans started out studying viruses, which were easy to work with, he really wanted to work with mammalian genes. In particular, he wanted to determine how the growth hormone gene is regulated by steroid and thyroid hormones. Researchers believed that receptor proteins that bind to these hormones could function as a genetic switch to control gene activity. To find the switch, Evans first needed to isolate the growth hormone gene. The only problem was that scientists had imposed a moratorium on manipulating cellular genes until they could sort out the relevant ethical and safety issues.
While they debated, Evans prepared the proper facilities for handling mammalian DNA and got all his reagents ready. Finally the moratorium was lifted. “At midnight on the day you could start cloning,” he says, “we made the first library”—a collection of fragments that represents all the genes in an organism. Within days, they’d found the growth hormone gene, which Evans packed up and took with him to the Salk Institute, where he started his own lab.
With the gene in hand, Evans next focused his attention on identifying the genetic switch that turns it on. “It was extremely difficult,” he says, “because nobody really knew how to do it.” In addition to his effort, several labs around the country were taking different approaches to find the molecules that would help unlock the secrets of gene control. This time, Evans got there first. He and his colleagues were able to isolate the gene for the glucocorticoid receptor, the first of a series of related switches that allow hormones to control genes.
In short order, Evans found two more receptors capable of regulating the gene for the growth hormone, and more soon followed. Each works in a similar way. It binds to some sort of activating molecule—a hormone or vitamin—and then heads for the nucleus, where it finds the proper chromosomes and tweaks gene activity. The first dozen receptors form what Evans calls a “nuclear receptor superfamily.” And these were just the beginning.
Evans knew that when he searched the genome for genes that were similar to those that encode these nuclear receptors, he could see “faint signals” indicating their presence. “We knew there were more receptors out there.” He and his team decided to chase them.
To date Evans has turned up nearly 50 receptors that are part of this nuclear receptor superfamily. Two of these receptors, PPAR-gamma and PPAR-delta, play key roles in regulating the storage and burning of fat. PPAR-gamma snatches fat from the blood and squirrels it away inside fat cells. Its sister protein, PPAR-delta, regulates how muscles burn fat. When kept on a high-fat diet, mice that lack PPAR-delta become obese. Mice that are engineered to produce an overactive version of the receptor in their muscle tissue remain sleek and lean. PPAR-delta revs up cellular fat-burning pathways and beefs up the animals’ slow-twitch muscle mass. And the engineered animals put this muscle to good use. When placed on a rodent-sized treadmill, these “marathon mice” will run twice as far as their normal relatives.
Timothy Harris has always measured things. “It’s just one of those traits that some of us were handicapped with or blessed with in this world,” he says, recalling that his childhood self counted the seconds it took to jump off a 50-foot bridge into a reservoir.
So it’s no surprise that he has spent his adult life inventing better ways to make scientific measurements or that his former research team at Helicos BioSciences achieved a goal set by scientists 20 years ago: to simultaneously sequence millions of different pieces of DNA. “The scale of what we did was completely outside current practice,” Harris says, adding that single-molecule sequencing is a key step to personalized medicine, which will allow doctors to choose the best treatment for each patient.
As the first member of his family to graduate from college, Harris opted for secure employment as a researcher at Bell Labs rather than an academic position. During his 18 years at Bell, he developed new optical methods for studying semiconductors, even though his degrees were in chemistry rather than physics. “If I needed to know something about a field that I knew nothing about, there was almost always someone in the building who had invented that field or pioneered important parts of it,” he explains.
He applied this philosophy to studies of microscopic semiconductors called quantum dots, which are included in optical switches, solar cells, and anti-counterfeiting ink. They initially were difficult to study, because their properties are determined by size, which varies widely, rather than by composition. Therefore, Harris wanted to look at individual quantum dots, even though they are only a few atoms in diameter.
In early 1990, Harris discovered that Eric Betzig (now a scientist at HHMI’s Janelia Farm Research Campus) had arrived at Bell. Betzig was the inventor of near-field scanning microscopy, and he wanted to build a video-rate near-field microscope. Harris, however, was more interested in a microscope with sufficient sensitivity to allow single-quantum dot fluorescence. “So Eric and my talented postdoc [Jay Trautman] improved the microscope’s sensitivity 10,000 times in one step,” he says.
Quantum dots were puzzling because they emit only half the light they receive. Using the new near-field microscope, Harris, with Lou Brus of Bell Labs and scientists from MIT, discovered the unlikely fact that quantum dots blink. “I like that project,” he says, “because it showed that you could find out something fundamentally different about quantum dots that you couldn’t possibly know unless you looked at them one at a time.” Scientists later learned to minimize quantum dots’ blinking, making them more useful for commercial applications.
Upon leaving Bell Labs in 1996, Harris became interested in biological measurements that generate huge amounts of data. At SEQ (now Amersham), his team invented an automated imager that allows drug developers to see the effects on cells of thousands of compounds in one fell swoop. At the rate of 40,000 tests per day, it can screen a million compounds in a few weeks instead of years. The IN Cell Analyzer 3000 has been purchased by drug companies around the world, and it has been used to discover a compound that slows the spread of cancer cells.
The Single Molecule Sequencing technique is one of the most recent breakthroughs. Scientists had sequenced the human genome by the time Harris moved to Helicos in 2004, but not on a grand scale. “If you don’t look at a lot of individuals, you won’t see the differences,” says Harris, whose team invented a way to sequence up to one billion different DNA molecules on a solid surface viewed with a microscope. Because DNA does not have to be copied before it is sequenced, the method is cheaper and avoids a major source of errors.
Single-molecule DNA sequencing could improve the diagnosis and treatment of cancer, Harris predicts, because conventional methods find only the most common mutations in tumor samples. “If you could study [the DNA of] 50 individual tumor cells, you could find a dangerous mutation even if it were present in only 5 of those cells,” he explains.
Although sequencing one person’s genome currently costs about $50,000, the price could plummet to $1,000 (a goal set by the National Institutes of Health) with increased efficiencies and decreased reagent use. At that point, people could have their DNA sequenced to determine their disease susceptibility and whether a particular drug would likely help or harm them. It should also be possible to compare thousands of human genomes.
When Harris joined Janelia Farm in 2008, he set two priorities. One was to get his boat into the Potomac, since he is an avid sculler. The other—which continues to engage his attention—is to find better ways to study the brain. “Brains are really complicated, and if you can’t figure out how to make a lot of measurements, you’re never going to understand them,” he says.
As director of the Applied Physics and Instrumentation Group at Janelia Farm, one of Harris’ goals is to assemble “a world-class team of measurement experts.” Harris and his small team work with colleagues to develop and deploy new technologies to the Janelia Farm research community. The group addresses technological problems that are not easily addressed with commercially available tools, and creates solutions that are accessible to biologists. Where practical, new tools are brought into users’ labs and disseminated broadly. The group’s current projects include an apparatus for evaluating the properties of fluorescent labeling molecules that make cells or their components visible under a microscope, and electrical probes that can simultaneously detect the activity of more than 100 neurons.
Ironically, many of the tools Harris is developing are designed to be used by neuroscientists—although Harris himself has never studied neurobiology. “But you can learn any new field as long as you have experts to teach you,” he adds. “And Janelia is full of wonderfully talented people.”
As a group leader at Janelia Farm, Anthony Leonardo studies salamanders and dragonflies, efficient killers that are far more likely to be found roaming Janelia’s bucolic landscape than inside the laboratory itself. But the salamander and dragonfly are Leonardo’s chosen subjects in research that is building a bridge between the macroscopic world of behavior and the microscopic world of neural circuits.
Leonardo is one of the top young investigators in neuroethology, the study of the neural basis of animal behavior. He earned his Ph.D. in computation and neural systems from the California Institute of Technology in 2002 and has long been fascinated by the brain and how animals behave as they do. His undergraduate training in artificial intelligence and computer science at Carnegie Mellon University included experience modeling human cognition. But it was as a graduate student at Caltech, under the guidance of Masakazu Konishi, that Leonardo began to look inside living brains to understand the complexities of neural circuit dynamics.
That creative early research, probing the mechanisms that underlie song generation in the zebra finch, produced some surprising findings. Leonardo tested the prevailing theory that once zebra finches have learned their songs through mimicking a bird serving as a tutor, those songs then become hardwired in the bird’s brain. He developed a computer-controlled system to perturb the feedback heard by singing adult finches. By replaying their recorded songs slightly out-of-sync, Leonardo found that the finches’ songs deteriorated markedly. After Leonardo withdrew the distorted feedback, the zebra finches gradually recovered their original songs. “We revealed that the songs were stable not because they had become hardwired but because they are maintained dynamically,” he says.
Leonardo did the second portion of his doctoral work at Bell Labs, where he collaborated with Michale Fee to help develop a miniature, motorized microdrive—a tiny device implanted onto the bird’s head—that could monitor the activity of several individual neurons while the bird sang.
The results of experiments done with the microdrive were surprising. “We had assumed that when the bird produced two similar sounds at different times in his song, the same patterns of neurons would fire in the same sequence. Instead, we found that the bird uses entirely different sets of neurons to encode the same sound,” Leonardo says.
In essence, the bird has played a clever trick—because it sings only a single song, it represents each moment in the song with a different set of neurons. “We hypothesize that this makes learning much faster and more robust because correcting errors in one portion of the song does not affect sounds produced at later times,” Leonardo explains. Elegant theoretical work in the laboratory of HHMI investigator Sebastian Seung at MIT has tested this idea and shown that the structure of neuronal firing patterns can indeed arise from song-learning rules that minimize learning time.
What relevance can lessons from a bird brain have for understanding the human mind? Leonardo’s hope is that, just as single neurons in different species operate according to the same physical principles, the same logic applies to networks of neurons. “We often have the sense that beneath the complexity of the countless connections linking neurons into a circuit, there lies some relatively simple computation,” Leonardo says. “My goal is to develop an understanding of those computations.
Model systems like the songbird are useful because they have a complex yet stereotyped behavior that is generated by a small number of brain areas. These types of systems present well-defined and tractable problems. We should be able to solve them in their entirety, from the earliest stages of sensory processing to the final moments of motor control.”
Enter the salamander, an amphibian that excels at snagging flying insects with its “ballistically launched” tongue. While a postdoctoral fellow in the lab of Markus Meister at Harvard, Leonardo studied how salamanders capture their rapidly moving prey. He investigated a circuit in the retina that might allow the salamander to predict the motion of its prey a few moments into the future. Without such a circuit, the salamander’s tongue would hit where its prey was moments ago, rather than its real position. Leonardo showed that the circuit that produces this computation does so only for a small range of target sizes and speeds that are matched to the prey captured by the salamander. So signatures of the salamanders’ specialized prey preferences may actually begin in the retina.
At Janelia Farm, Leonardo and postdoctoral researcher Bart Borghuis have demonstrated that the behavior of the salamander is broadly consistent with the underlying retinal position prediction. Just as the retina computes the future position of the target, the salamander launches its tongue toward the position the prey will attain in a few hundred milliseconds. This time compensates for neural delays in the salamander’s brain as well as the time it takes to align its head to the prey’s position.
Leonardo and Borghuis are now working to determine whether the computations in the salamander’s retina actually cause its behavior. “To do this,” he says, “we need to show that as the accuracy of position estimation in the retina begins to fail, the way in which the computation breaks down is mirrored exactly in the behavior. If we can do that, then we will begin to believe we have the seeds of a mechanistic description of how salamander prey capture works.”
In addition to salamanders, he has begun a second line of research to study the neural circuitry underlying prey capture in the dragonfly. One project will attempt to implant miniature electrodes into dragonfly target tracking neurons and record from them wirelessly while the dragonflies fly and catch prey. “Of tremendous importance to our work,” he says, “is looking at neural circuits in different brain areas and different animals. What we would really like to know is: are there fundamental principles that govern how neurons solve behavioral problems?”
Three of biology’s great ideas are the gene theory, the theory of evolution by natural selection and the proposal that the cell is the fundamental unit of all life. When considering the question of ‘what is life?’ these ideas come together, because the special way cells reproduce provides the conditions by which natural selection takes place allowing living organisms to evolve. A fourth idea is that the organization of chemistry within the cell provides explanations for life’s phenomena. A new idea is the nature of biological self-organization on which living cells and organisms process information and acquire specific forms. Nurse will discuss how these great ideas have influenced and changed the way we think of science today.
A Nobel laureate and HHMI Trustee, Nurse was elected president of the Royal Society in 2010. The Society is a self-governing fellowship of many of the world’s most distinguished scientists drawn from all areas of science, engineering, and medicine. Its fundamental purpose, as it has been since its foundation in 1660, is to recognize, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity. Prior to leading the Royal Society, Nurse served as president of The Rockefeller University. He was also chief executive of Cancer Research UK, the world's largest cancer research organization outside the U.S.
Nurse is a distinguished scientist who shared the 2001 Nobel Prize in Physiology or Medicine with Leland Hartwell and R. Timothy Hunt for fundamental discoveries concerning control of the cell cycle. A geneticist who uses fission yeast as a model system, he continues an active research program that focuses on the cell cycle and how the cell organizes its internal structures to prepare for cell division.
A native of England, Nurse graduated from the University of Birmingham in 1970 and received his Ph.D. from the University of East Anglia in 1973. Nurse headed laboratories at the University of Sussex, the Imperial Cancer Research Fund (ICRF), and Oxford University before rejoining the ICRF in 1996 as its Director General. He presided over its merger with the Cancer Research Council.
Nurse's research has been recognized around the world. He is a Fellow of the Royal Society and, in 1995, became a foreign associate of the National Academy of Sciences. He has received the Gairdner Foundation International Award (1992), the Alfred P. Sloan Jr. Prize from the General Motors Cancer Research Foundation (1997), and the Albert Lasker Award for Basic Medical Research (1998).
Dr. Perlmutter is the former Executive Vice President for Research and Development at Amgen, Inc., the world’s largest biotechnology company. A graduate of Reed College (Portland, Oregon), Dr. Perlmutter received his M.D. and Ph.D. degrees from Washington University (St. Louis) in 1979. Thereafter he pursued clinical training in internal medicine at the Massachusetts General Hospital and at the University of California at San Francisco. From 1981 to 1984 he was a Lecturer in the Division of Biology at the California Institute of Technology. He joined the Departments of Medicine and Biochemistry and the Howard Hughes Medical Institute at the University of Washington (Seattle) in 1984, and in 1989 became Professor and Chairman of the Department of Immunology there.
During this period, Dr. Perlmutter focused his scientific efforts on the elucidation of signaling pathways governing lymphocyte development and activation. In 1997 he left the University of Washington to join Merck and Co., where, as Executive Vice President, Worldwide Basic and Preclinical Research, he helped to craft strategies that led to the introduction of new therapies for serious infections and for diabetes, as well as vaccines to prevent cervical cancer and shingles. He left Merck in 2001 to lead the worldwide research and development efforts at Amgen, Inc.
Under his direction, Amgen successfully re-focused its discovery efforts on the amelioration of grievous illness, increasing its product portfolio by five-fold. Dr. Perlmutter is also a director of Stem Cells, Inc., Chairman of the Board of Trustees of Reed College, and was recently the Chairman of the Board of Directors of the Institute for Systems Biology, a not-for-profit research institute based in Seattle, Washington. He was previously President of the American Association of Immunologists, and is a Fellow of the American Academy of Arts and Sciences.
For more than three decades, Gerald M. Rubin has thrived as an experimental geneticist, research director, teacher, mentor, and biotech-company cofounder. A vice president of Howard Hughes Medical Institute (HHMI) since 2000, Rubin was named in 2003 the first director of HHMI’s Janelia Farm Research Campus.
At Janelia, Rubin directs scientific programs that are speeding the development and application of new tools for transforming the study of biology and medicine.
A native Bostonian, Rubin gravitated to math and science in high school at Boston Latin, and obtained his first paying job at the age of 14 washing glassware in a cancer research laboratory at Massachusetts General Hospital. Planning to major in chemistry, he entered the Massachusetts Institute of Technology (MIT), where he took his first formal biology courses. Rubin was deeply impressed by the humility of one professor, biologist Salvador E. Luria, who came to work the morning he learned he won the Nobel Prize and immediately erased a big “congratulations” message the students had written on the board. “He told us that just because he had won the Nobel Prize, it didn’t mean his work was superior to that of his peers,” says Rubin.
It had been 15 years since the discovery of the DNA double helix, and Rubin recognized that biology had entered a new era and that he wanted to be a part of it. He also discovered, at MIT and in the two summers he spent at the Cold Spring Harbor Laboratory, that he had a strong affinity for experimental science.
After receiving his B.S. in 1971, Rubin won scholarships to study at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge, England, where scientists such as Francis Crick, Sydney Brenner (now a senior fellow at Janelia Farm), Fred Sanger, and Max Perutz, were making great discoveries in biology. “All these heroes I had read about in my courses were there, walking around and doing experiments in the lab,” says Rubin.
For his Ph.D., which he received in 1974, Rubin sequenced a yeast RNA made up of 158 bases. Nowadays, he points out, automated machines can read out 1,000 such sequences a second. “What took two years of my life now can be done in a millisecond!”
From England, Rubin went to Stanford University for postdoctoral studies in the biochemistry laboratory of David S. Hogness, who has been called the founder of modern genomic analysis. Hogness was using the common fruit fly, Drosophila melanogaster, a longtime workhorse of genetics research, in expanding the techniques of gene cloning. Hogness had begun cloning Drosophila sequences in bacterial plasmids, and Rubin’s initial postdoctoral project was to compile the first library large enough to represent the entire fly’s genome.
After his postdoctoral fellowship, Rubin returned to Boston and a position at Harvard-affiliated Dana-Farber Cancer Institute, continuing work on Drosophila genetics. But his scientific style was at odds with Harvard’s highly political and competitive academic culture, and in 1980 he accepted a position in Baltimore at the Carnegie Institution of Washington, in the embryology department headed by Donald D. Brown.
Rubin fluorished at Carnegie. He and developmental biologist Allan C. Spradling, now an HHMI investigator, achieved a breakthrough by inserting, for the first time, foreign genes into the embryos of multicellular organisms—Drosophila—and showed that the genes were expressed in the cells of the adult. The key was harnessing a certain type of naturally occurring transposable DNA sequence, called the “P element,” that can insert itself into a cell’s DNA. In their much-cited 1982 paper published in Science, Spradling and Rubin reported that they had used P elements carrying a wild-type gene for red eye color to correct a white-eye mutation in fruit flies.
Rubin’s growing scientific stature soon caught the interest of Daniel E. Koshland, a biochemist at the University of California, Berkeley, who had taken on a controversial revamping of that institution’s biological sciences program. Rubin came aboard in 1983 as the John D. MacArthur Professor of Genetics and later became head of the genetics division. In 1987, a banner year, he was chosen to be an HHMI investigator and elected to the National Academy of Sciences—at the unusually young age of 37.
While in California, Rubin and two colleagues founded a biotech company, Exelixis, located in South San Francisco, for the purpose of translating discoveries about genetic pathways in the fruit fly to problems of human medicine.
Rubin’s highest public profile emerged from his partnership with the maverick scientist-entrepreneur J. Craig Venter to sequence the Drosophila genome as a warm-up to the contentious race to sequence the human genome. While the National Institutes of Health (NIH)-funded effort took a more cautious path to the enormous task, Venter and his company, Celera Genomics, gambled on a faster and less expensive—but potentially riskier—“whole-genome shotgun” method.
In 1998, Venter approached Rubin, then head of the Berkeley Drosophila Genome Project, and proposed that they collaborate to perform the fruit fly genome sequencing at no cost to the public. In March of 2000, Venter and Rubin announced the nearly complete sequence of the 120 million units of DNA contained in the fruit fly’s five chromosome arms.
With the raw sequence in hand, Rubin and about 60 Drosophila researchers, computer scientists, and staff gathered at Celera headquarters for a frenzied, two-week-long “annotation jamboree.” Using algorithms being refined in all-night sessions, the scientists analyzed the sequence and discovered a total of 13,600 genes on the chromosomes. Rubin calls it “the most intellectually stimulating time of my career.”
In 2000, Rubin was named vice president for biomedical research at HHMI, a job that would bring him back to the East Coast and, three years later, make him director of planning for Janelia Farm. His fantasy for success at Janelia, Rubin says, is that people will say, “‘Nothing extraordinary came out of Janelia Farm for a while, but then, truly unanticipated discoveries started coming out after five or ten years. (Those discoveries) clearly only happened because they patiently supported very bright people to work on difficult problems. They had the right people and a synergy developed between those people—those discoveries might never have been made in another setting.’”
The Howard Hughes Medical Institute and the Janelia Farm Research Campus invite the public to attend the next Dialogues of Discovery lecture. Karel Svoboda, a group leader at the Janelia Farm Research Campus, will deliver a public lecture titled “Shining Light on How the Brain Works” at HHMI’s Janelia Farm Research Campus in Ashburn, VA.
Svoboda, a neuroscientist, wants to understand how neurons, the cells of the brain, work together in huge circuits to produce our perception of the world. To investigate how the brain controls behavior, his lab studies the neural circuits that animals use to locate objects based on sensory cues. Using light-based tools, he can spy on these circuits in their habitat, namely the brain, and also manipulate circuits with tremendous precision.
The last 10 years have yielded revolutionary light-activated molecular tools, based on genes discovered in bacteria, algae, and marine organisms. Scientists use these tools to observe and manipulate neurons in the brain. Svoboda's presentation will provide a historical overview of these developments and highlight their importance for basic science and the treatment of brain disorders.
Svoboda has a long-standing interest in the development of optical and molecular methods for neuroscience. He has devised techniques so precise that he can detect the opening of single calcium channels in tiny synapses in the intact brain. As part of an interdisciplinary team at Janelia Farm, he is also developing better gene-based sensors of neural activity.
Prior to moving to Janelia Farm when the campus opened in 2006, Svoboda was an HHMI investigator at Cold Spring Harbor Laboratory. He received a Ph.D. in biophysics from Harvard University and did his postdoctoral research at Bell Labs.
For some people, the steroid androstenone, a component of male sweat, has a sweet or even pleasant floral scent. Other people can’t smell it at all. But when Leslie Vosshall sniffs it, she recoils in disgust, likening it to the smell of a sweaty armpit.
Vosshall has discovered that a person’s genetic makeup strongly influences the olfactory response to this chemical. In 2007, her lab and that of her Duke University collaborator Hiroaki Matsunami published a report, which revealed that people who hate the smell of androstenone are more likely to carry two good copies of a gene for OR7D4, an olfactory receptor in the nose. Individuals who do not find the smell offensive tend to lack one or both good copies of the gene.
Vosshall, who is on the faculty at The Rockefeller University, believes this research may describe the first known genetic variation underlying individual differences in odor perception. The idea for the experiment was born of the same probing curiosity that has fueled Vosshall’s research on other aspects of smell—the fascinating but least understood of the senses.
However, the majority of her research involves not humans but insects like the vinegar fly, the fruit fly Drosophila melanogaster, and the mosquito. They serve as relatively simple models for probing how the brain and nervous system transform olfactory cues into specific behaviors. Moreover, some of the insects she studies are pests that devour crops or spread infectious diseases, which can have devastating economic and health consequences. The discoveries Vosshall is making about how these insects detect odors and how odors influence their behavior may help researchers identify new ways to fend off the insects.
In the 1990s, as a postdoctoral fellow in the lab of Nobel laureate Richard Axel, an HHMI investigator at Columbia University, Vosshall was excited by the series of landmark discoveries Axel’s group was making about the way the olfactory system detects, encodes, and perceives odors. Working with Axel, she identified a large family of genes in Drosophila that function as odor receptors.
As an independent scientist at Rockefeller, she created a nearly complete map of the fly’s olfactory system and identified odorant receptors in Drosophila larvae. To the surprise and consternation of many in the field, Vosshall found that insects have evolved a set of smell receptors unlike those in humans and other animals. Instead of attaching to G protein-coupled receptors (a large family of transmembrane receptors that sense molecules outside the cell and activate signaling pathways and other cellular responses inside the cell), odorant molecules are detected in insects by transmembrane receptors that seem to function as ion channels.
It has long been known that mosquitoes are attracted to the carbon dioxide that humans exhale; in 2007, Vosshall identified two membrane proteins in fruit flies and mosquitoes that detect this gas. Still, she does not believe carbon dioxide is the only thing that attracts mosquitoes to humans. After all, she says, mosquitoes seem to go after some individuals voraciously while others are rarely bitten—yet everyone emits carbon dioxide. “If it were just carbon dioxide, mosquitoes would be falling into your beer,” she says.
For the past five years, Vosshall’s team has studied how insect repellents containing the chemical DEET ward off mosquitoes and other bugs. Her lab recently showed that DEET confuses insects by jamming their odor receptors. Understanding how the chemical works may help researchers develop compounds that are equally effective but longer lasting or more convenient to use.
As an HHMI investigator, Vosshall would like to make the mosquito a viable model organism for answering scientific questions. She acknowledges that the proposal is a significant departure from her current research, but she believes the time is right for such a giant step. She sees a tremendous opportunity to apply the advanced transgenic technology routinely used in other insect models to aid in understanding the female mosquito’s life cycle and what drives it to bite humans. Likewise, she notes, the wealth of information in the mosquito genome sequence data may help researchers develop, among other things, more targeted, less toxic insect repellents.
One point of attack might be the protein Orco, which Vosshall found is expressed in nearly all olfactory neurons of the fly and acts as a generic coreceptor in tandem with specific odorant receptors. “If you make flies without the orco gene they can’t smell,” she says. “And if you put the gene back into this fly, you cure its smell problem.”
That revelation led to Vosshall’s publication of a research article in early 2008 that showed for the first time how the commonly used insect repellent DEET works. The United States Army discovered it in 1957, and although DEET is highly effective and widely used worldwide, researchers did not know how it worked. Vosshall’s experiments showed that DEET acts on pairs of olfactory receptors that include Orco.
Thus, the Orco gene/protein is a “cornerstone” of insect olfaction, Vosshall adds, suggesting that blocking Orco might be a selective and “clean” strategy for repelling harmful insects. “A medfly, for example, wouldn’t be able to smell citrus crops,” she says. Or in areas of endemic malaria, mosquito netting might be impregnated with a compound that inhibits this vital olfactory protein, effectively “blinding” mosquitoes to the scent of their human targets.
With so many infectious diseases transmitted by insect vectors, Vosshall hopes her research will help lessen the burden of illness in the developing world.
In the nervous system, even small genetic blunders can have huge biological consequences. Mistakes in key genes can cripple our ability to move, speak, and interact with the world. Using some of the most advanced techniques in genetics and cell biology, Huda Zoghbi and her collaborators have unraveled the genetic underpinnings of a number of devastating neurological disorders, including Rett syndrome and spinocerebellar ataxia type 1. Their discoveries could lead to better methods for treating such diseases and provide new ways of thinking about more common neurological disorders, including autism, mental retardation, and Parkinson’s disease.
In 1975, Zoghbi enrolled in medical school at American University in western Beirut. Then war erupted in Lebanon. “Bombs were falling everywhere,” she says. “It soon became dangerous to leave the campus.” When her first year was completed, Zoghbi went home, fully intending to return to school in the fall. But when she got there, she learned that her younger brother had been hit by shrapnel. He wasn’t badly injured, but Zoghbi’s parents decided to send her and her brothers to stay with relatives in the United States. She was accepted at Meharry Medical College in Nashville, Tennessee, where she finished her medical training.
Zoghbi soon found herself drawn to disorders that affect the activity of the brain. “Neurology grabbed me because of how logical it is,” she says. “You observe the patient, analyze her symptoms, and work backward to figure out exactly which part of the brain is responsible for the problem. It’s like a puzzle.” In her second year of residency, Zoghbi encountered a very puzzling patient indeed. The girl had been a perfectly healthy child, playing and singing and otherwise acting like a typical toddler. Around the age of two, she stopped making eye contact, shied away from social interactions, ceased to communicate, and started obsessively wringing her hands. “She made a huge impression on me,” says Zoghbi, who set out to determine what could have caused this sudden neurological deterioration.
Sixteen years after she saw that first patient, Zoghbi and her collaborators identified MECP2, the gene responsible for Rett syndrome. Children afflicted with this rare neurodevelopmental disorder develop normally for about 6 to 18 months and then start to regress, losing the ability to speak, walk, and use their hands to hold, lift, or even point at things. MECP2, it turns out, encodes a protein whose activity is critical for the normal functioning of mature neurons in the brain; it is produced when nerve cells are forming connections as a child interacts with the world. The disease occurs primarily in females, because boys who inherit an inactive form of MECP2—which lies on the X chromosome—usually die shortly after birth. Girls survive because, with two X chromosomes, they stand a good chance of inheriting a healthy copy of the gene.
Zoghbi and her colleagues have also identified the mutation responsible for spinocerebellar ataxia type 1 (SCA1), a neuro-degenerative disorder that renders its victims unable to walk or talk clearly, or eventually to even swallow or breathe. The culprit is a sort of genetic stutter that increases the size of the SCA1 gene. The normal gene harbors a stretch of nucleotides in which the sequence CAG is repeated about 30 times. In individuals with the disease, the tract expands to include 40 to 100 iterations. As a result, the product of the mutant gene—a protein called ataxin-1—grows large and sticky, forming clumps throughout the cell. These ataxin-1 aggregates overwhelm the molecular machinery that cells use to recycle damaged proteins and eventually disable the neurons involved in controlling movement. Using mice and flies that produce the mutant protein, Zoghbi is searching for compounds that enhance the clearance of ataxin-1 tangles. Such drugs could slow the progression of the disease or prevent it altogether.
Ask Charles Zuker how he got into researching how we taste, and he’ll tell you it was driven by his desire to decipher how the brain represents our sensory experiences. Zuker wants to do more than understand why sugar is sweet. He wants to know how the brain can turn reception into perception. How do the physical and chemical stimuli that we take in all the time—through sight, hearing, taste, touch, and smell—turn into signals that neurons transmit to the brain? How does light hitting your eye change into a chemical signal that makes you squint? How do sound waves hitting the eardrum transform into words that you “hear” in your head? Why does a drop of lemon juice on the tongue make you wrinkle your nose?
Zuker and his laboratory have made advances in the understanding of sight and hearing. They’ve also discovered taste receptors for four of the five tastes: sweet, sour, bitter, and “umami” (savory). Salt is the fifth, and it’s only a matter of time before Zuker tracks it down. Perhaps more important than just discovering the receptors is Zuker’s research showing that each taste cell is hardwired for one taste. Scientists used to think that every taste bud could pick up on all five tastes, and that a different signal would be sent to the brain for each one. Zuker’s lab did experiments with mice that proved that taste cells are simpler than that. Each taste cell has only receptors for one taste modality. And each cell sends a specific signal to the brain. This signal doesn’t change, even if you swap out one receptor for another. For example, you can remove the receptor from a “sweet” cell and replace it with a receptor that’s normally activated by a bitter chemical, and now “bitter” tastes sweet.
This research has obvious commercial implications—for example, what if we could find ways to reduce our “dependence” on sugar and salt, two key food ingredients that have a significant impact on our well-being? In 1999, Zuker started Senomyx, a company that looks to identify novel flavors and taste enhancers for the food and beverage industry. “It’s interesting to work on something that could ultimately [improve] human health, and perhaps help enhance our human sensory experience so we can get more joy out of life.”
But not work on just anything. In Zuker’s mind, scientists should not only do good science, but also solve tangible questions. “We could just do fun experiments, but those might not lead to answers that help us move forward,” he says. Zuker’s grandparents moved to Chile from Poland and Russia to escape the Holocaust. As a child in Chile, Zuker loved microscopes the way some boys love Legos. “I played with a microscope from the time I had coordinated movements,” he says. “For my bar mitzvah, when I was 13, I got a binocular microscope. For the first time, I could look at minute things with both eyes. That opened up a whole new world.”
Zuker went to college at 16. At 20, he started graduate school at MIT. By 26, Zuker had his Ph.D. and was a postdoc in Gerald Rubin’s lab at the University of California, Berkeley. (An HHMI investigator since 1987, Rubin is now director of HHMI’s Janelia Farm Research Campus.) He then took a position at the University of California, San Diego, where he has been since 1986.
His lab is a mix of think tank and traditional. About half the lab focuses on a specific problem; the other half consists of what Zuker calls “rogue scientists”—people working on their own questions.
“These people come here with a visceral need to solve something they want to solve, rather than coming here so I can tell them what I want them to solve,” he says. This has led to a diversity of work, including a paper on the evolution of fly eyes (Nature 12 October 2006) that showed that one protein, called spacemaker, is a key element in the evolution from ancestral insect eyes (and those of modern bees) to the more complex modern eyes of fruit flies and house flies. Without the protein, an eye is more primitive; add the protein, and help it transform into a modern eye. “It’s very exciting,” Zuker says of the results.
Letting people do their own thing comes easy to Zuker. He has always followed his bliss. “Research is not a career for me,” he says. “It flows in my veins. It is not by choice; it is who I am.”