Sanford-Burnham’s founders, William and Lillian Fishman, appreciated the important impact that postdoctoral fellows have on medical research and created a tradition of fostering the development of young scientists. The Fishman Fund Award was established in 2001 by Mary Bradley and Reena Horowitz to honor that tradition. Each year, five individual awards of $6,000 each are given to select postdocs for career development. This year’s award was presented on September 8. Read about each of the winners, their research, and their career goals below.
L to R: Armi Williams (accepting on behalf of Roberto Tinoco), Gregory Aubért, Martina Pröll, Aman Mann, and Malene Hansen (accepting on behalf of Caroline Kumsta)
Germline-less C. elegans nematodes with an autophagy marker shown in green. (Image courtesy of the Hansen lab)
Aging is generally accepted as a universal fact of life, but how do humans and other organisms age at the molecular level?
At Sanford-Burnham, a team led by Dr. Malene Hansen uses a type of worm called Caenorhabditis elegans to work out the molecular underpinnings of the aging process. Recently, they found that two cellular processes—lipid metabolism and autophagy—work together to influence worms’ lifespan. Autophagy, a major mechanism cells use to digest and recycle their own contents, has become the subject of intense scientific scrutiny over the past few years, particularly since the process (or its malfunction) has been implicated in many human diseases, including cancer and Alzheimer’s disease. (See Autophagy 101.)
The Hansen group’s latest study, published online September 8 in Current Biology, provides a more detailed understanding of the roles autophagy and lipid metabolism play in aging.
“The particular worm model we used in this study is known to live longer than normal worms, but we didn’t completely understand why,” said Dr. Hansen, assistant professor in Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study. “Our results suggest that increased autophagy has an anti-aging effect, possibly by promoting the activity of a fat-digesting enzyme. In other words, it seems that recycling fat is a good thing—at least for worms.”
heart muscle in a fruit fly (image courtesy of the Bodmer lab)
Heart disease is the leading cause of death in the United States, accounting for more than 25 percent of all deaths each year. While many factors work together to contribute to heart disease—including environment, lifestyle, and genetics—we only have control over the first two. To address the third factor (genetics), researchers at Sanford-Burnham recently turned to fruit flies.
Fly and human genes are so closely related that the sequences of newly discovered human genes, including many that contribute to disease, can often be matched up with fly counterparts. Since fruit flies are relatively easy to work with (they’re small, breed quickly, and don’t require a lot of maintenance), they often give scientists clues to the functions of human genes and helps them develop drugs that target them.
As Dr. Rolf Bodmer, director of Sanford-Burnham’s Development and Aging Program, explains in the Journal of Cell Biology, “We use fruit flies to learn about the fundamental genetic mechanisms that are important for the development and function of the heart.”
Dr. Bodmer himself discovered early in his career that flies lacking Tinman, a protein that regulates the expression of other genes, fail to develop heart tissue during embryonic development. If Tinman is removed later during fly development, the flies’ hearts don’t function properly.
Now researchers in Dr. Bodmer’s lab, led by postdoctoral researcher Dr. Li Qian, uncovered a genetic network that controls heart development and function in fruit flies and mice, with additional clues that it might also play a role in human heart health.
NeuroMap was founded by (left to right): Daniel Norton, Dr. Alexey Terskikh, Dr. Dmitry Sivtsov and Dr. Andrew Rabinovich. (Photo by Sean M. Haffey, courtesy of San Diego Union-Tribune)
By Peijean Tsai
When a person is diagnosed with depression, pinpointing the right treatment is typically a trial-and-error process that frustrates both doctors and patients. Chronic symptoms interrupt everyday life while the patient seeks an effective remedy.
To address this challenge, NeuroMap, an early-stage company, is developing assays using induced pluripotent stem cells (iPSCs) to accurately predict how individuals with major depressive disorder (MDD) will respond on a personal level to medications, such as selective serotonin re-uptake inhibitors (SSRIs), the most commonly prescribed antidepressants.
“Some will have to go for months or years to find the right drug, and that’s what we’re trying to eliminate,” says Sanford-Burnham’s Dr. Alexey Terskikh, who founded NeuroMap with Dr. Dmitriy Sivtsov, a psychiatrist at the University of California, San Diego (UCSD) School of Medicine, computer scientist Dr. Andrew Rabinovich and Daniel Norton of UCSD’s Rady School of Management.
This novel concept – personalized depression therapeutics based on Sanford-Burnham technology – is what catapulted NeuroMap to win first prize earlier this month at the 5th Annual UCSD Entrepreneur Challenge’s Business Plan Competition, one of three contests the organization holds each year. The competition was judged by professionals from San Diego’s technology and entrepreneurial communities and presented before a public audience. The honor also awarded the startup company $57,000 in cash and entrepreneurial services, which Dr. Terskikh says will help move the company forward with its efforts to secure funding from government and private sources.
Dr. Pamela Itkin-Ansariis an expert on diabetes – especially type 1 diabetes, the kind that mostly affects children. Type 1 diabetes is caused by a person’s own immune system, as they attack the insulin-producing beta-cells in the pancreas.
But, as it happened, observations made while researching one area of biology can inform another. That’s how Dr. Itkin-Ansari and her team found themselves studying pancreatic cancer.
“During the course of our diabetes studies, we noted that a particular growth stimulus we were investigating pushed pancreatic duct cells into the cell cycle – essentially converting them from quiet, complacent cells to cells that divide and proliferate,” explains Dr. Itkin-Ansari, adjunct assistant professor in Sanford-Burnham’s Development and Aging Program. “And since duct cells are the precursors of pancreatic cancer, we knew immediately that this could have important implications for pancreatic cancer.”
During embryonic development, only neural crest stem cells expressing the SOX2 gene go on to become neurons in the brain. (Cartoon by Valeriya Yanushevskaya)
Early in embryonic development, the neural crest – a transient group of stem cells – gives rise to parts of the nervous system and several other tissues. But what determines which cells become neurons and which become other cell types? It turns out a gene called SOX2acts as a stem cell gatekeeper – only cells expressing it have the potential to become neurons.The SOX2 gene encodes a transcription factor, a type of protein that switches other genes on or off. SOX2 is one of two key genes researchers use to generate induced pluripotent stem cells (iPSCs), which are capable of differentiating into all cell types for research and potential therapeutic applications.
In a paper published May 5 in the journal Cell Stem Cell, Drs. Alexey Terskikh, Flavio Cimadamore and colleagues show that SOX2 maintains the potential for neural crest stem cells to become neurons in the peripheral nervous system, where they interface with muscles and other organs. These results could help better inform therapies aimed at neurocristopathies, diseases caused by defects in the neural crest, which include microphthalmia and CHARGE syndrome.
According to Dr. Cimadamore, post-doctoral researcher and first author of the study, “Neural crest cells are notoriously difficult to study in humans because of their very early and transient nature – a woman is usually not even yet aware of her pregnancy when they start to migrate and differentiate. So here we took advantage of an embryonic stem cell-based model of human neural crest previously developed in our lab to get a better understanding of the molecular pathways that control the differentiation potential of such cells in humans.”
Drs. Gregg Duester and Christina Chatzi
Researchers in Dr. Gregg Duester’s lab study retinoic acid, an active form of vitamin A. They want to know how retinoic acid tells the right body parts to form in the right places at the right time in a developing embryo. To figure out retinoic acid’s role, they compare mice with and without the ability to convert vitamin A to retinoic acid. Over the years, the Duester lab has mostly focused on the developing limb buds (precursors of arms and legs) and somites (precursors of vertebrae and skeletal muscle), though they also recently looked at retinoic acid in the heart and reproductive organs. Now we can add another organ to the Duester list: the brain. “I’d avoided the brain for a long time because it isn’t my area of expertise,” says Dr. Duester. “But when a new postdoc joined my lab who had studied the brain and stem cells in mice during graduate school, we decided it was time.”
This new postdoctoral researcher, Dr. Christina Chatzi, started with mice lacking Raldh3, one of several enzymes that produce retinoic acid. She then took a look at what’s happening in that model’s basal ganglia, the part of the brain that sits right below the cerebral cortex. The cortex contains excitatory neurons that drive learning and memory, while inhibitory neurons in the basal ganglia keep those cortical functions in check. As Drs. Duester and Chatzi show in a paper published online April 12 by the journal PLoS Biology, one region of the basal ganglia – the primitive part that fish have, too – requires retinoic acid to make inhibitory neurons. Another part, the more advanced section that came about later in evolution, doesn’t.
That’s a pretty cool finding because neurobiologists are beginning to appreciate that proper brain function relies on a careful balance of inhibitory and excitatory neurons. An imbalance has been implicated in some neurological disorders.
Dr. Alexey Terskikh, photo by Nadia Borowski Scott
The neural crest is a versatile population of stem cells found in a developing embryo. In humans, neural crest arises during the third to fourth weeks of pregnancy, and then the cells specialize into a diverse set of cells, including certain types of nerves, skin, bone and muscle. Scientists have long appreciated this crucial event in development – when it goes wrong, a number of skeletal and nervous system disorders can result. But they haven’t really been able to study it properly in the laboratory. That’s because of the transient nature of the neural crest – it typically only exists for about two weeks in humans (with few exceptions). After that, the cells have migrated away and differentiated into other tissue types. Dr. Alexey Terskikh (along with Dr. Marianne Bronner-Fraser at the California Institute of Technology, Sanford-Burnham’s Dr. Evan Y. Snyder, postdoctoral researchers Dr. Carol Curchoe and Dr. Jochen Maurer and others) recently discovered a way to overcome this problem. In a study published recently in the journal PLoS ONE, they developed a new protocol for generating early migratory neural crest cells from human stem cells.
“This new system allows us to dissect what happens during human development – something that is not accessible in any other way,” says Dr. Terskikh, associate professor in Sanford-Burnham’s Development and Aging Program.
In the process known as meiosis, a single cell divides into two cells. But instead of receiving two copies of each chromosome (that’s mitosis), each daughter cell receives only one copy, giving it half the number of chromosomes found in a normal adult cell. Those cells go on to become sperm or eggs – which together might produce an offspring that inherits half its chromosomes from each parent. Even though they aren’t needed until sexual maturity, females begin meiosis to make eggs in utero, while males don’t begin meiosis and sperm-making until after birth. The reason for this gender discrepancy? Nobody really knows.
“I’m a developmental biologist, not a reproductive expert,” says Dr. Gregg Duester, professor in Sanford-Burnham’s Development and Aging Program, “but it seems to me that by better understanding meiosis and sperm and egg production, we might better understand infertility – a problem that is estimated to affect about nine percent of couples.”
In 2006, an Australian group published a landmark paper in the journal Science, in which they identified an enzyme that is found in developing testes, but not ovaries. Without this enzyme, called Cyp26b1, mice prematurely initiate meiosis in the testes. Based on these results, the group concluded that Cyp26b1 must be what determines the timing of meiosis in females vs. males. They also went on to claim that it must be because Cyp26b1 degrades retinoic acid, a derivative of vitamin A. In the five years since, something like 25 papers have built on this paradigm – retinoic acid in the ovaries triggers meiosis, while Cyp26b1 in the testes keeps retinoic acid at bay and prevents meiosis from occurring at that time.
Just one problem – the paradigm is wrong.