The 2013 HHMI Investigators: A-D

Peter Baumann, PhD
HHMI Early Career Scientist 
Stowers Institute for Medical Research

Peter Baumann’s research focuses on beginnings and endings: beginnings in the form of reproduction in unisexual lizards and endings in the form of the telomeres that protect chromosome tips.

Each time chromosomes are copied, telomeres—specialized stretches of DNA that extend from the ends of each chromosome—become progressively shorter. With each cell division, they erode further until cells are no longer capable of dividing and stop growing. An enzyme complex known as telomerase can lengthen telomeres by adding DNA using a dedicated RNA subunit as template. As a postdoctoral researcher, Baumann discovered a protein he named POT1 that binds to telomeres, protects them, and regulates telomerase activity. That regulation is critical, as shortening telomeres are associated with aging, but too much telomerase can lead to cancer. Today, Baumann continues to investigate the molecular and genetic mechanisms of telomere protection and lengthening. His work has identified the RNA component of telomerase in yeast and has helped explain how the enzyme is assembled from its components; his team is now expanding these studies to human telomerase.

Baumann also studies unisexual whiptail lizard species, in which the females can reproduce and thrive without a mate. He revealed how females can produce offspring without males and how they maintain a healthy genetic mix without the continuous reshuffling of genes from males and females. A goal of that research is to understand the molecular underpinnings of asexual reproduction, an endeavor that will inform agricultural research on how to harness desirable traits in unisexual lineages and expand our understanding of vertebrate evolution.

Michael S. Brainard, PhD 
University of California, San Francisco

Michael Brainard’s fascination with how the brain learns led him to the songs of birds. Songbirds and humans are rare experts at vocal learning, he explains, and birds offer an ideal model system for studying how this learning occurs. Brainard has been studying young male Bengalese finches, which learn their signature melody by trying to mimic the memorized song of their fathers, warbling the tune over and over until they get it right. In a series of creative experiments, Brainard showed that a group of structures deep in the brain, the basal ganglia, is crucial: It provides corrective feedback when birds hit wrong notes.

When Brainard blocked the signal coming from basal ganglia, however, he made a surprising discovery. Block the feedback signal and a bird doesn’t appear to learn, as expected. But unblock the signal and the bird immediately hits many more correct notes. The results show that the basal ganglia can “covertly” learn even when feedback is cut off.

Brainard is expanding his research to investigate what changes occur in the brain with aging that limit the adult bird’s ability to learn. And he’s planning genetic and inheritance studies to understand why some finches learn well while others learn poorly.

Jean-Laurent Casanova, MD, PhD
Rockefeller University

Jean-Laurent Casanova champions an unorthodox explanation for why some children fall ill with serious infections while their playmates remain healthy. Some apparently healthy children, he argues, were born with genetic mutations that sap the immune system’s ability to fend off a specific microbe.

Researchers had thought that these inherited immune impairments were rare and would undermine the body’s defenses against a variety of pathogens, as seen in patients with acquired immunodeficiencies, such as AIDS. But over the past 15 years, Casanova, a geneticist and trained pediatrician, and his collaborators worldwide have documented several examples of genetic glitches that leave some children vulnerable to particular pathogens. Their research has dissected the molecular malfunctions responsible. For example, herpes simplex virus-1 (HSV-1) usually causes nothing worse than cold sores in most children. But the same virus can spark a life-threatening brain illness (encephalitis) in others. Casanova’s team has shown that children with HSV-1 encephalitis carry gene mutations that hamper the production of virus-fighting molecules called interferons in the brain.

Casanova and his colleagues have made similar discoveries for tuberculosis, various fungal and bacterial diseases, and other infectious illnesses. Children are already benefitting from Casanova’s unconventional perspective. His work suggested a new way to treat infections—using recombinant molecules missing in the sick child resulting from a mutation—to boost the immune response to the invading microbe. He hopes that digging up novel vulnerabilities in our genes might help in devising ways to treat the pathogens that exploit them.

Adam E. Cohen, PhD 
Harvard University

Instead of prodding neurons with electrodes to measure their electrical activity, researchers can now watch as the cells fire off impulses, thanks to Adam Cohen. For a neuron to fire, inputs from neighboring cells must push the neuron’s membrane potential (a difference in voltage between the interior and exterior of the cell) above a certain threshold. Cohen and his colleagues rejiggered a light-sensitive protein from a microbe that inhabits the Dead Sea so that the protein flashes in response to changes in a cell's voltage. The researchers can genetically engineer cells to carry this protein and then use imaging to track cells that are firing.

Last year, the team put its genetically encoded fluorescent voltage indicator protein into rat brain neurons to observe individual action potentials, or nerve cell impulses. And Cohen's team is working to illuminate other kinds of cells that are electrically active. They are studying heart cells derived from patients who have potentially fatal genetic disorders that can lead to an erratic heartbeat. They hope that the pattern of flashes will reveal how heart cells fire abnormally. To learn how the heart gets in rhythm during embryonic development, the team has incorporated the protein into the heart cells of zebrafish.

Those applications might be just the beginning. After honing the technique, Cohen foresees using the voltage sensor protein to scrutinize networks of neurons as an animal learns, for instance, or to uncover how the developing brain gains the ability to transmit electrical signals.

Karl Deisseroth, MD, PhD 
HHMI Early Career Scientist 
Stanford University

As a practicing psychiatrist, Karl Deisseroth experienced firsthand the failure of drugs and other treatments to help many of his patients. So in his Stanford research lab, he founded a revolutionary new field of bioengineering and neuroscience, called optogenetics, for understanding and targeting specific pathways in the brain.

Deisseroth's first major innovation was slipping a gene that produces a light-sensitive protein from algae into neurons. Using a variety of proteins, Deisseroth's team has shown that it can stimulate or inhibit neurons with millisecond-precision flashes of light. By switching specific populations of neurons in the brain on or off to observe effects on behavior, they have obtained insights into the functions of neural circuits relevant to Parkinson's disease, anxiety, substance abuse, depression, narcolepsy, and autism. The approach, now being used in thousands of laboratories with which Deisseroth has shared his tools, offers tremendous promise for understanding normal circuitry, as well as aberrant brain circuits and treatment mechanisms in diseases such as depression, Parkinson's, and epilepsy.

And it's been made even more powerful by Deisseroth's latest achievement, CLARITY—a method of stripping the brain of its fat so that neural circuits can be seen and investigated with unprecedented clarity and completeness. Having built, applied, and distributed these revolutionary tools, Deisseroth is now setting his sights on new challenges, including developing methods to link circuit control with activity and structure of the same neural circuit. If successful, such an integrated approach will further deepen our understanding of neural systems and behavior in health and disease.

Michael A. Dyer, PhD 
HHMI Early Career Scientist 
St. Jude Children's Research Hospital

Few researchers can say they have made a discovery that overturned a long-held tenet of biological science. Yet early in his career, Michael Dyer has already done so twice.

His studies of the eye's retina have contested a century-old dogma: that mature, differentiated neurons can no longer divide and form new neurons. Witnessing a mature neuron divide while maintaining its synaptic connections was a transformative moment for Dyer—and a springboard for future investigations.

In another landmark finding, Dyer discovered that the early childhood eye tumor, retinoblastoma, is a striking counterexample to the textbook account of how cancers develop: that is, through years or decades of DNA-changing mutations that ultimately turn cells malignant. He showed that a single mutation in the Rb protein alters the turning off and on of numerous genes throughout the genome without altering DNA itself. This is called an epigenetic mechanism.