Meet the 2009 Early Career Scientists.
Credit: ©2009 Paul Fetters
Kevin Eggan believes that understanding the true causes of human disease is one of the most difficult scientific challenges of our time. To meet it, the Harvard University researcher is working with two different types of stem cells—lines derived from human embryonic stem cells and induced pluripotent stem (iPS) cells that have been derived from the skin cells of individuals with different genetic diseases. Both cell types can be used to study disease initiation and progression. Eggan has focused, in particular, on amyotrophic lateral sclerosis (ALS). He has successfully derived motor neurons from human embryonic stem cells and used them to observe how neurons are destroyed in ALS. His studies resolved a long-standing question, showing that motor neurons do not commit suicide, but are killed by another component of the nervous system, the glial cells. Eggan has also used adult skin cells from ALS patients to produce patient-specific stem cell lines. With the ability to make ready quantities of disease-specific cells, researchers will be able to study the roots of the disease process and speed drug discovery.
Joaquin M. Espinosa
University of Colorado at Boulder
Credit: ©2009 Glenn Asakawa
Joaquin Espinosa, a biologist at the University of Colorado at Boulder, plans to be the first scientist to map all the effects of the tumor suppressor protein p53. Over the past three decades, researchers have published some 40,000 articles about p53, which prevents cancer by driving cells to commit suicide in response to stressful stimuli. Still, much remains to be learned about p53 and why cancer arises when it stops functioning properly. Espinosa plans an ambitious project to catalog all of p53's actions and how those actions vary in different cell types and under different conditions. He hopes these studies will expose new targets for the next generation of anticancer drugs. He also plans to investigate how perturbing p53's network of influence affects cancer development and response to treatment in animal models and in human tissue samples.
Marc R. Freeman
University of Massachusetts Medical School
Credit: ©2009 Robert Carlin
Researchers shopping for a model in which to study glial cells—which support, feed, and protect neurons—didn't find much, until Marc Freeman focused his attention on the fruit fly. Freeman identified 100 fruit fly genes that are turned on in glial cells to facilitate nerve development, migration, and communication. In his lab at the University of Massachusetts Medical School, he is using the fruit fly to study how glial cells contribute to a characteristic behavior of injured neurons: the withering away of the long projections, called axons, after they are separated from the cell's nucleus. Although glial cells sense injury and step in to manage the trauma, researchers poring over that axonal decay have largely ignored their role. Freeman wants to know exactly which glial genes are involved—an important consideration in designing potential therapies for spinal and nerve injury and neurodegenerative disease.
Mark A. Frye
University of California, Los Angeles
Credit: ©2009 Leslie R. Lee
Mark Frye wants to unravel the neuron-by-neuron code for sight, smell, and motor control. That's why he glues flies to sticks before placing them in tiny flight arenas he's constructed in his University of California, Los Angeles lab. He then turns on a light show, pumps in some appetizing smells, and watches the insects' tiny brains process the information. Frye has already discovered that scent and sight combine to push flies toward rewards much more aggressively than either sense alone. And he's found that groups of startled flies on a tiny treadmill stampede in unison in response to visual cues, suggesting that the insects possess some basic social communication. He's now delving deeper, dissecting the genes that control these behaviors.
University of Washington
Credit: ©2009 Paul Fetters
There are things so small that biologists restrain their hopes of seeing them up close. That was the outlook for aquaporin, a tiny channel that allows water molecules to pass one at a time through the cell membrane. Then in 2005, Tamir Gonen used cryo-electron microscopy to produce an extraordinarily detailed image of an aquaporin. Gonen's picture revealed that the aquaporin molecule is coated in a thin double layer of lipids like those that make up a cell's membrane, and it provided clues into how lipids and proteins have coevolved to form biological membranes. In his lab at the University of Washington, Gonen is now focusing on a class of channels that passively transport glucose through the cell membrane. Though these proteins are of considerable interest to diabetes researchers, no one has ever seen one in action. Scientists have high hopes that Gonen will present them with a revealing portrait soon.
Eric C. Greene
Credit: ©2009 Alan Orling
Eric Greene is a “visual biologist,” a new breed of scientist who invents tools that help him spy on individual protein molecules or protein complexes as they interact with single molecules of DNA. He hopes to reveal information about how cells repair, maintain, package, and decode their genetic information. For example, the cellular machinery that replicates our chromosomes is not perfect, and permanent mutations can be introduced into the genome if replication errors are not corrected quickly. One way cells correct these errors is by employing mismatch repair proteins to excise the error and replace it with the correct DNA. In his Columbia University lab, Greene uses his unique imaging technology to gather new information about how mismatch repair proteins move along a DNA strand during the course of a repair reaction—leading some researchers to rethink their ideas about DNA repair. He believes single-molecule biophysics is ripe for further advances that will continue to reveal astonishing new details about how molecules “behave.”
Massachusetts General Hospital
Credit: ©2009 MGH Photography
Konrad Hochedlinger at Massachusetts General Hospital is developing safer and more efficient methods of genetically reprogramming cells. Within the last three years, scientists have found ways to coax mature adult cells to regress to a state from which they can develop into nearly any kind of cell in the human body. These induced pluripotent stem (iPS) cells are valuable tools for studying disease processes and learning how to repair damaged tissues. However, scientists have used retroviruses to deliver the genes needed to force cells into that more youthful state—a potentially risky strategy because the viral genes can integrate with the host genome and set the stage for the development of cancer. Hochedlinger’s elegant solution was to replace the retrovirus with a harmless adenovirus, which disappears after its job is done. Through detailed examinations of the mechanisms that enable genetic reprogramming, Hochedlinger intends to further improve stem cell models for studying development and disease.
University of California, Davis
Credit: ©2009 Paul Fetters
University of California, Davis geneticist Neil Hunter is elucidating the molecular machinery that shuffles the genetic deck by swapping strands of DNA segments. The process, known as homologous recombination, is central to evolution, reproduction, and prevention of cancer. Without it, the production of sperm and eggs would fail and genetic diversity would be constrained. Dividing cells would fail to properly repair breaks in their DNA, causing cancer. In yeast, Hunter has identified several previously unknown steps of homologous recombination. Now he’s moving his research into mice, where the process more faithfully mimics that seen in people. His future findings might have broad implications for fixing infertility and preventing cancer.
Susan M. Kaech
Credit: ©2009 Michael Marsland/Yale University
When the immune system generates protective T cells to fight an infection, it retains a memory of the pathogen in the form of a reservoir of memory T cells that offer long-term protection should the pathogen reappear months or years later. These cells share important features with stem cells: longevity, self-renewal, and a high potential to proliferate. Yale University's Susan Kaech is studying the genetic programs that control the formation of memory T cells and bestow these stem cell-like characteristics on T cells during infection. She is studying whether it is possible to boost immune memory—work that may help improve the design of vaccines.
Jeffrey S. Kieft
University of Colorado School of Medicine
Credit: ©2009 Jim Spencer
When a virus infects a cell, it hijacks the cell's protein-making machinery and uses this as part of how it churns out copies of itself. Some viruses, such as hepatitis C and HIV, deploy a clever shortcut that bypasses several steps in the protein-making process and relies on a specific part of the viral RNA to do so. Jeffrey Kieft, a structural biologist at the University of Colorado School of Medicine, provided the first detailed and complete three-dimensional view of one of these viral RNAs—called an internal ribosomal entry site, or IRES. He is using this structure to understand how the RNA works. Now, he is broadening his research program to explore the structure and evolution of additional RNAs that other viruses use to manipulate their hosts in a myriad of ways. His goal is to find new targets for drugs that could help wipe out the diseases these viruses cause.
University of Colorado at Boulder
Credit: ©2009 University of Colorado
The 100 trillion microbial cells that live in and on each of us may outnumber our human body's cells by a factor of 10. Many are beneficial strangers, digesting food we couldn't touch on our own or warding off pathogens; others influence how the immune system develops or how drugs are metabolized. Yet until Rob Knight created new computational methods to compare the vast amount of genetic information contained in these microbial communities, scientists had little idea how much these communities differ among individuals or even between different parts of a single person's body. By comparing millions of DNA sequences from thousands of microbial communities, Knight has revealed that microbe populations can vary more between two different habitats within the body—the mouth versus the gut, for example—than they do in distant environmental habitats, such as hot springs and ice caps. His lab at the University of Colorado at Boulder is investigating the causes of this astonishing diversity to unravel how microbes contribute to human health and disease—in particular, obesity, inflammatory bowel disease, and malnutrition.