Meet the 2013 HHMI Investigators
Marc R. Freeman, PhD
Neurons hog the attention, but our brains couldn’t operate without the unassuming neural cells called glia. Marc Freeman is working to bring these overlooked cells—which represent about 60 percent of brain cells—their share of credit.
Freeman has been dissecting the role of glia in brain development, function, and healing after injury, when glia hurry to the damaged area and devour cellular debris to allow for brain recovery. Working on fruit flies, Freeman and colleagues pieced together a complex circuit involving a damage-stimulated protein called Draper and more than 20 molecules that mobilize glia.
Freeman’s team is learning that the appetite of glial cells may prove crucial in building brain circuitry—from wiring neurons in the brain to establishing synapses, the junctions between nerve cells. They discovered that glia slip into synapses under construction and remove cellular junk, which is necessary for the growth of healthy synapses. They have also homed in on a subtype of glial cells in the fly, called astrocytes, and found that these cells help orchestrate the formation and function of synapses.
Freeman’s interest in the brain’s response to injury led to the identification of a suicide mechanism in axons, the projections from neurons that transmit messages to other cells. His lab found that injured axons activate a program that drives their own destruction. Mutations in one gene in this pathway result in severed axons surviving about 50 times as long after injury. Freeman intends to probe this axon degeneration pathway more deeply in hopes of identifying factors that help neurons survive or fend off damage, with the ultimate goal of blocking this pathway to stop neurodegenerative disease.
Chuan He, PhD
By bringing a chemist's perspective to biological problems, Chuan He has made some surprising discoveries. His work has shed light on the roles of metals in biological systems, identified bacterial regulators of virulence and antibiotic resistance, illuminated mechanisms of DNA repair, and revealed new modes of genetic regulation.
He now wants to understand how the addition and removal of methyl groups on genetic material reversibly alter gene activity. Such modifications to DNA are well known to influence how the genetic code is read, and in 2011, He's group showed that reversible modifications to RNA can have similar effects. He found that the most prevalent internal methylation on human messenger RNA, methylation of the nucleoside adenosine, is reversible and could affect protein levels in cells. His lab went on to demonstrate that two functionally significant human proteins, FTO and ALKBH5, remove methyl groups from RNA. He now plans to continue exploring the scope, mechanism, and effects of reversible RNA methylation in biological regulation.
He's laboratory is also known for developing chemical technologies to label and sequence a recently discovered chemical modification in DNA—5-hydroxymethylcytosine, or 5hmC—that is particularly abundant in the brain. Current research suggests that 5hmC is an intermediary molecule produced when DNA is demethylated and it may directly impact gene activity in various cells. He's tools made it possible to detect and survey the exact locations of 5hmC as well as its further oxidized derivatives, such as 5-formylcytosine, or 5fC, in the mammalian genome. He will continue to explore their functional roles as well as the mechanism of demethylation.
Hopi Hoekstra, PhD
Hopi Hoekstra doesn’t stay within the lines, at least not when it comes to scientific disciplines. In her quest to understand the genetics of adaptive evolution, she is doing research that spans cell and molecular biology, ecology, behavior, genomics, evolutionary theory, and computational biology.
Hoekstra has taken deer mice—the most abundant mammal in North America and one of the most well-studied ecologically—out of their natural setting and into the lab. Using wild deer mice as a model system, she’s studying the molecular basis of how adaptation to novel selective pressures generates and maintains diversity in nature. She wants to understand every step of the process, from DNA sequence changes to phenotypes to the ecological and evolutionary significance of those phenotypes.
Her early work, in which she helped identify the molecular basis of melanism (dark coloring) in lava-dwelling populations of rock pocket mice, was one of the first examples of a specific gene influencing evolution by natural selection. Then Hoekstra combined field and lab-based approaches to show how individual and cumulative genetic changes in deer mice could cause fast, dramatic variation in the animals’ morphology and reproduction, which improved their ability to survive and reproduce in the wild. Some of her latest research delves into the genetics and evolution of behavior: Hoekstra identified specific regions of deer mouse DNA that are involved in how long the mice’s burrows are and whether they contain an escape route. She is now extending this approach to study exploratory and parental behaviors. Such research sets the stage for future work, which she hopes will lead her to a general understanding of the adaptive process—from the molecular to the neurobiological to the organismal level.
Neil Hunter, PhD
Neil Hunter’s research is changing the way scientists think about how chromosomes swap segments to shuffle their genes and repair DNA damage. The process, known as homologous recombination, is critical for reproduction and fuels evolution. When it fails, birth defects, miscarriage, and cancer can result.
Homologous recombination occurs when a broken chromosome uses a second, intact chromosome as the template for its repair. This process is critical for repairing both intentional and accidental breaks in DNA. While homologous recombination is essential for maintaining the integrity of the genome, it can also introduce genetic diversity, which creates an opportunity for new traits to evolve.
Hunter focuses on how homologous recombination proceeds and is regulated during meiosis, the cell division process that produces sperm and eggs. During meiosis, the chromosome complement is halved so that the normal chromosome number is maintained after fertilization occurs, with each parent contributing one full set of chromosomes. Homologous recombination creates connections, called crossovers, between paternal–maternal chromosome pairs that are essential for their distribution to sperm and egg cells. Defective recombination results in sperm and eggs with the wrong number of chromosomes, a situation that can cause pregnancy miscarriage and diseases such as Down syndrome.
Hunter has developed innovative techniques to monitor the molecular steps of recombination in budding yeast cells, and he has used them to identify unexpected aspects of the process not revealed by conventional techniques. His future studies will integrate yeast and mouse molecular genetics, high-resolution imaging of chromosomes, biochemistry, and mathematical modeling to continue to investigate the details of homologous recombination during meiosis.
Akiko Iwasaki, PhD
"Good" bacteria in the gut do more than help digest food. They can also boost the immune system in its fight against flu infections in the lungs. That's one of the many surprising findings made by Akiko Iwasaki, whose research straddles the fields of immunology, microbiology, and virology.
Iwasaki was the first to show the crucial role of dendritic cells in recognizing certain DNA and RNA viruses. Dendritic cells are the watchdogs of the immune system, patrolling skin and mucosal surfaces for foreign invaders. She was the first to identify receptors that spot the virus, and she revealed the importance of autophagy (a process in which cells destroy unwanted material inside them) in responding to viral pathogens. She's even created a new vaccination approach against viruses that attack through the lining of the lungs, vagina, and other mucosal surfaces. By priming the immune system with a standard vaccine and then pulling activated immune system cells to the genital tract with cell-attracting chemicals, she's been able to prevent development of herpes in mice. Iwasaki now is testing this prime-and-pull vaccination strategy against HIV and exploring how harmless viruses that live within the body affect the immune system.
Nicole King, PhD
Nicole King fearlessly staked her postdoctoral research on a daring hypothesis and a poorly understood organism. She set out to prove that choanoflagellates, single-celled organisms that can also exist as multicellular colonies, are the closest living relatives to animals and may illuminate animal origins. While a possible relationship between choanoflagellates and animals was first proposed in the 1840s, choanoflagellates were ignored during the molecular era. King chose to investigate animal origins using DNA sequencing and comparative genomics to look for molecules and pathways that choanoflagellates share with multicellular animals.
Her gamble paid off. Her research, continued in her laboratory at the University of California, Berkeley, has revealed that choanoflagellates are equipped with many genes required for animal multicellularity, including molecules cells use to communicate with and adhere to one another—indicating they evolved long before the origin of animals. King says the single-celled ancestor of animals probably looked a lot like a choanoflagellate.
Her most exciting recent finding came about when she solved a seemingly mundane problem. Although some choanoflagellates readily form colonies in the wild, they stubbornly refused to do so in the lab. The dilemma was resolved when she discovered that prey bacteria from the natural environment of the choanoflagellates produce a lipid that triggers colony development, raising the possibility that a similar interaction may have contributed to the evolution of animal multicellularity. Today, King is using the tools she developed to investigate how single-celled choanoflagellates differentiate and organize themselves into colonies.