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The 2013 HHMI Investigators: L-P

Summary

Meet the 2013 HHMI Investigators

Christopher D. Lima, PhD
Memorial Sloan-Kettering Cancer Center 

Christopher Lima doesn’t pick easy problems. A structural biologist, he is investigating how cells attach small proteins—like ubiquitin and the related molecule SUMO—to other proteins to modify their function or fate. Alongside those studies, he is exploring the molecular mechanisms that underlie RNA processing and degradation—modifications to an RNA copy of a gene that influence its stability and ability to be used as a template for protein production. These fundamental cellular processes present challenges, because the cellular machines that carry them out are complex, often made up of many proteins or parts. Further, they involve reactions in which many of the structures Lima is trying to study exist only temporarily, changing quickly as the reactions proceed.

Lima is known for using ingenious methods and sheer persistence to determine the structures of the proteins and complexes involved in RNA processing and protein modification and following up with genetic and biochemical experiments that clarify how they function in cells. His work is revealing how an RNA-degrading complex called the exosome recognizes damaged or unneeded RNAs; how the small protein SUMO, which helps direct proteins to certain parts of the cell and influences their interactions with other molecules, gets attached to its targets; and how these processes are regulated.

Harmit Malik

Harmit S. Malik, PhD
HHMI Early Career Scientist 
Fred Hutchinson Cancer Research Center 

Tales of battles, ancient and modern, are written in our genes—and Harmit Malik is their Homer. A geneticist, virologist, and evolutionary biologist, Malik chronicles an endless genetic arms race not just between organisms and pathogens but also within an individual species’ genome.

Malik sees the human genome as a tapestry documenting past evolutionary conflicts. Delving deeper into genes that help fend off viral invaders, Malik and his colleagues have shown that adaptations in those genes offer a record of virus evolution. That insight created a whole new field, indirect paleovirology, in which scientists try to identify ancient viruses by virtue of the imprints they left on the evolution of host genes. The structure of our genome reflects a “negotiated truce,” he says, and the best way to understand that truce is to reconstruct the events that produced it. This approach has profound implications for medicine as well as science, because it uncovers new antiviral strategies, new mechanisms of immunity, and new clues about autoimmune diseases like lupus.

Malik’s lab is also investigating evolutionary competition between components that are involved in the essential process that ensures that chromosomes divide and segregate equally during cell division. He has pioneered the idea that chromosomal competition for evolutionary dominance can drive the unexpectedly rapid evolution of these essential components. These findings have direct implications for how chromosomal imbalances can occur in cancer and for how two recently diverged species can become reproductively isolated from each other.

Tirin Moore

Tirin Moore, PhD 
HHMI Early Career Scientist 
Stanford University 

Tirin Moore wants to understand how the brain’s sensory and motor networks work together to produce higher cognitive functions. His studies of the neural circuits and processes that control visual attention are advancing scientists’ understanding of how the human brain extracts information from the environment to guide behavior.

Moore identified the neural circuitry that enables us to focus our visual attention on something of interest while ignoring irrelevant information in the visual field. His research showed that neurons in the brain’s prefrontal cortex that were previously known to control eye movement also help focus attention, even in the absence of movements. When an animal plans a gaze shift to a visual target, the prefrontal neurons fire more strongly. This action modulates signals within the visual cortex, where visual information is processed, which in turn enhances sensory signals related to the target, and thus attention.

Moore believes that defects in this function are the root cause of attention deficit hyperactivity disorder (ADHD) and that his research could lead to improved treatments for this and other conditions that impair attention. For example, people with ADHD have abnormal dopamine transmission in the prefrontal cortex. He showed that altering dopamine levels within the prefrontal cortex in the brains of macaque monkeys increased the fidelity of sensory signals within the visual cortex, just as voluntarily directed attention does.

Moore’s comprehensive studies of visual attention continue, and as he develops new tools to address fundamental problems in systems-level neurobiology, he intends to expand his research to other perceptual and cognitive functions.

Vamsi Mootha

Vamsi K. Mootha, MD 
Massachusetts General Hospital 

Vamsi Mootha has a passion for mitochondria. These ancient cellular organelles, which house the cell's power generators, can cause a host of diseases when they malfunction. Mootha first learned of these conditions as a medical student, and began both doing basic research on the organelle and seeing his first patients with mitochondrial disease. These experiences led him to dedicate his research training and professional lab to the biology of this organelle.

Mootha aims to bridge the divide between molecular studies and the physiology of complex systems. Mitochondria contain small amounts of their own DNA, and Mootha was struck by how much research on mitochondrial diseases focused its search there—even though most mitochondrial proteins are actually encoded by DNA in the cell's nucleus. Using his background in math and computational biology, he set out to create a more complete picture of mitochondrial biology and its contribution to disease.

He has since resolutely pushed the field forward. On the physiology side, his lab characterized the molecular identity of the mitochondria's calcium uniporter, a key channel of communication between the organelle and its cell. And on the disease side, he used cutting-edge and innovative approaches to define the 1,100 proteins in mammalian mitochondria, developed computational tools to predict protein function, and linked mitochondrial gene mutations to human disease.

In less than a decade, Mootha's work in basic biology has led to genetic diagnostics, prenatal screens, and a more complete understanding of an organelle that can be involved in a multitude of common diseases, including neurodegeneration, type 2 diabetes, and cancer. He sees hundreds of mitochondrial components still waiting to be characterized, a multitude of genetic and cellular pathways to describe, and the potential to find cures for some devastating disorders.

Dyche Mullins Dyche Mullins, PhD 
University of California, San Francisco 

Dyche Mullins says the most interesting questions in his lab often boil down to this: How does a mindless mob of macromolecules actually become a living cell? To achieve the sort of spatial organization associated with even the simplest cells, tiny molecules must transmit and integrate information across long distances—hundreds to hundreds of thousands of times their own length.

One way to establish such long-range order is to assemble the individual molecules into larger, ordered structures: membranes, cell walls, and cytoskeletal polymers. The actin cytoskeleton, made up of actin filaments and other molecules, is one such complex assembly. It enables cells to change shape, to move, to transport cargo, and to establish polarity (making one end of the cell different from the other). Scientists in the Mullins laboratory focus on learning how cytoskeletal polymer networks are assembled, how they function, and what roles they play in prokaryotic and eukaryotic cells.

Mullins has discovered some of the key molecules and mechanisms that choreograph assembly of the actin cytoskeleton. In particular, he showed that a protein complex, called the Arp2/3 complex, creates branching networks of filaments that push forward the leading edge of crawling cells. His laboratory also identified mechanisms of actin assembly carried out by proteins such as Spire and JMY, both of which are required for normal embryonic development. In addition to identifying regulators and understanding how they work, the Mullins laboratory is investigating how cytoskeletal systems contribute to health problems such as drug-resistant infections, metastatic cancers, and developmental defects.

Evgeny Nudler

Evgeny Nudler, PhD 
New York University 

Taking risks and venturing into new areas of research have been common threads in Evgeny Nudler’s career. He has made major discoveries in topics as diverse as the mechanics of RNA synthesis, cellular adaptations to stress, and bacterial resistance to antibiotics.

Nudler illuminated a fundamental principle of RNA synthesis, showing that RNA polymerase works like a ratchet, powering forward and then backtracking as it makes RNA. He then showed that this herky-jerky motion, which he called “backtracking,” helps cells manage RNA growth and allows for gene regulation and proofreading.

Nudler’s lab and another group discovered independently that messenger RNA molecules called “riboswitches” sense cellular levels of metabolites—such as vitamins, amino acids, ions, and other small molecules—and adjust gene activity accordingly. Nudler’s group also identified an RNA molecule in mammalian cells that, in combination with another factor, plays an important role in sensing heat and other protein-damaging conditions.

Another discovery by Nudler’s team revealed a previously unknown defense mechanism that bacteria use to fend off antibiotics. Humans use nitric oxide and hydrogen sulfide to control physiological functions ranging from blood pressure to neurotransmission. Nudler’s team has shown that bacteria produce and use these gases for a different purpose—to protect themselves from antibiotics, oxidative stress, and the immune system of their host.

Nudler next wants to learn how the bacteria that dwell harmlessly inside other organisms, including humans, influence the aging of their hosts. To tackle this question, he and his colleagues are now designing probiotic strains of bacteria that significantly extend the lifespan of the roundworm Caenorhabditis elegans.

Ardem Patapoutian, PhD 
Scripps Research Institute 

Touch provides us with crucial information about our environment, yet it remains poorly understood at the molecular level. Touch-sensitive cells can warn of danger from hot, cold, and toxic substances. These cells can also tell us when we experience a gentle touch or when a hammer accidentally hits our finger. The sensing of mechanical forces and their translation into chemical signals influence a variety of biological processes. Hearing depends on mechanosenstion, and the sensory modality also controls the function of the heart, blood vessels, lungs, and kidney.

Ardem Patapoutian has advanced the understanding of thermosensation with the discovery of ion channels in touch-sensitive cells that respond to changes in temperature. He calls them the body's molecular thermometers. For example, one of them preferentially responds to cool temperatures and the cooling compound menthol. Another, which also responds to cold, is a general sensor of noxious chemicals, including ingredients in garlic and wasabi. Its activation causes pain and inflammation.

How cells sense mechanical forces, like pressure and stretching, is one of the last big unsolved questions in vertebrate sensory research, Patapoutian says. It has proven difficult to pinpoint the molecules underlying cells' sensitivity to mechanical forces, but here Patapoutian has broken new ground, identifying two novel ion channels, Piezo1 and Piezo2, that are responsible for that sensitivity. These channels are present in a wide variety of tissues, and Patapoutian plans to investigate how they function to regulate various biological processes, as well as how they may contribute to disease. At the same time, he will continue to search for other sensory ion channels.