Opening Remarks, with Dr. Stratakis
By Shana R. Spindler, PhD
“You know that I’m Greek, and I always try to give some Greek wisdom when I present,” said Dr. Constantine Stratakis as he opened the Ninth Annual NICHD Fellows Retreat. Dr. Stratakis, scientific director of the NICHD Division of Intramural Research, went on to recount the story of Mentor, a trusted companion of Odysseus in Greek mythology, who was tasked with advising and protecting Odysseus’ son, Telemachus, when Odysseus left for war. Dr. Stratakis likened the retreat to an event about mentorship and leadership. “You lead from the first time you go into a lab,” said Dr. Stratakis. A mentor is not just an advisor, but also someone who is trusted, he said.
Large round tables filled the room at the Smithsonian National Museum of the American Indian, and a scenic landscape painted the wall of glass windows to the right. Postdocs, graduate students, and support staff sat silently, waiting to hear more words of wisdom, listening for that special recipe to obtain success even during difficult times; for it is no secret that budgets have tightened. Perhaps Dr. Stratakis could sense the anticipation. “Don’t view yourself as a victim of the times…as the weaker side of the equation” said Dr. Stratakis, “Seize the opportunity to lead!”
Attend retreats, talk to colleagues, participate in Office of Education activities, and network, network, network, he said. Submit abstracts, give talks, apply for outside funding, and—maybe most importantly—embrace learning, said Dr. Stratakis. “The secret to success is to find happiness in what you do.”
Science, the Arts, & the World, with Dr. John Bohannon
By Erin Fincher
Dr. John Bohannon is a scientist and an academic, just like many of us. He completed his doctoral degree in molecular biology, worked as a Fulbright scholar, and served as a Harvard visiting scholar. However, he hasn’t allowed his scholarly pursuits to get in the way of having a really good time. In his keynote talk, Bohannon introduced us to the concept that science can—and should be—fun.
Dr. Bohannon presented ways to have fun with science, and regaled us with tales from his exciting career in science journalism. Bohannon encourages scientists to get out of the lab every now and then, to collaborate with others, and to find ways to combine science with other interests. He prompted us to apply our scientific knowledge and skill set to everyday questions that interest us (like whether we can distinguish pâté from dog food).
Dr. Bohannon emphasizes creativity as a way to convey science, pointing to his “Dance Your Ph.D.” competition as an example. Having fun is about engaging with the world, and Dr. Bohannon advocates going out and interacting with people. As proof that he follows his own advice: he collaborated on the award-winning “Green Porno” video series with Isabella Rossellini, an actress and artist he greatly admires.
Perhaps most importantly, he gives permission to be bizarre, to do something unexpected with our science. Not only is it fun, but it can make us stand out from the crowd. In today’s competitive economic climate, being unique and memorable can be the key to getting that coveted position or funding.
Fun, Dr. Bohannon claims, is an undervalued commodity in science. Doing something interesting and exciting with your work can be a rewarding experience in itself, but can also have greater positive consequences for your growth as a scientist and ultimately, as a person. Dr. Bohannon’s keynote speech was thought-provoking, inspiring, and, in keeping with his theme, an all around good time.
For more information, visit http://www.johnbohannon.org/
Breaking Brains and Monkey Wars: Fellow Presentations 1 & 2
By Libby Barksdale, PhD
For the morning session of fellow presentations, we heard from two University of Washington alums: Dr. Megan Wyeth from the McBain lab, and Dr. Amanda Dettmer from the Suomi lab. Megan presented first with the monumental task of explaining how the auxiliary proteins Neto1 and Neto2 alter glutamate receptor expression at hippocampal synapses. But let’s take a step back: when receptors (protein complexes embedded in the neuron’s membrane responsible for receiving chemical signals from other neurons) don’t function properly, the result is an imbalance of excitatory and inhibitory signals in the brain, which can lead to neuropathological conditions such as epilepsy.
Research over the past decade has shown the importance of auxiliary proteins for normal synaptic function, and thus the maintenance of the excitation/inhibition balance. Using electron microscopy to examine two subsets of glutamate receptors (known as kainate and NMDA receptors) in wild type mice and mice lacking the Neto1 and Neto2 auxiliary proteins, Dr. Wyeth found that the number of glutamate receptors she examined were altered in the absence of Neto1 and Neto2; kainate receptors decreased, while NMDA receptors increased. Using electrophysiology, Dr. Wyeth showed that eliminating Neto1 and Neto2 proteins resulted in reduced signal size in kainate receptors, and slower speeds of signaling in the NMDA type. Therefore, Neto proteins are necessary for proper synaptic, and ultimately brain, function.
Dr. Dettmer followed with some monkey tales, describing how she uses population studies of rhesus monkeys to investigate predictors of infant mortality rates (IMR). Rhesus monkeys are a good model system for these studies, she explained, because the amounts of maternal and familial care necessary for an infant’s survival are comparable to that needed for human infants. In 2009, an uprising at the NIH Animal Center in Poolesville, MD, resulted in the deposition of the historically dominant Family #1 and the promotion of Family #2 to top-dog (or top-monkey) status. This afforded Dr. Dettmer the opportunity to test the relationship between IMR and the stressful situations accompanying “warfare,” with infant mortality defined as spontaneous abortions, still births, and infants that were culled within the first month after birth.
Looking at three possible predictors (population density, chronic stress, and intra-group conflict), Dr. Dettmer identified a positive correlation between all three conditions and IMR. As population density increased—the tribe numbered over 100 monkeys for the first time ever in 2008—so did chronic stress, as measured via hair cortisol levels and the number of fight wounds. Since then, the population has been capped at 65-70 monkeys, and both stress levels and reported fight wounds have decreased—and importantly so has IMR. The take-home message: population-level events can, and do, affect individual mothers.
NICHD Scientific Update, with Dr. “Denny” Porter
By Kevin Francis, PhD
While speakers earlier in the retreat agenda emphasized finding happiness or contentment in your career, the theme for the internal update by Dr. Denny Porter was finding fulfillment in your work. Denny is a board-certified pediatrician and clinical geneticist, senior investigator, and program head of NICHD's Program in Developmental Endocrinology and Genetics, as well as the NICHD clinical director. Dr. Porter shared his lab's recent basic science and translational clinical work on Niemann Pick, Type C1 (NPC) patients.
NPC is a rare disease characterized by mutations in the genes NPC1 or NPC2, resulting in sphingolipid accumulation within patient cells and organs, causing toxicity and severe organ dysfunction. Using animal models and 2D gel electrophoresis, Dr. Porter's group identified a number of novel NPC biomarkers to provide readouts of therapeutic successes or failures. He followed up with a discussion of a potential therapy for NPC, (2-hydroxypropyl)-beta-cyclodextrin (simply known as cyclodextrin), which showed strong efficacy in animal models and subsequently moved to phase I clinical trials in the NIH Clinical Center.
Many issues arise when researchers move from the bench to bedside that must be planned for (or avoided). Dr. Porter concluded his presentation by discussing how we as scientists must balance risk versus efficacy when translating findings to patients. The time required for drug development and FDA approval, drug delivery mechanisms, and patient sample size were all problems that Dr. Porter and his group had to circumvent or overcome to move cyclodextrin toward the bedside. Dr. Porter's presentation provided excellent perspective both for basic and for clinical researchers on the successes and tribulations associated with translational science.
Flying Blind in NAPPA: Fellow Presentations 3 & 4
By Celine Cluzeau, PhD
The afternoon fellow presentations included two fascinating topics: the neural substrates of color vision and high-throughput approaches to mapping host-pathogen protein interactions, presented by Dr. Krishna Melnattur and Dr. Kimberly Decker, respectively. Dr. Melnattur aims to explore the genetic basis of behavioral neural circuits. While in Dr. Chi-Hon Lee’s lab at the NICHD, Dr. Melnattur has investigated the representation of color vision in the brain using the small fruitfly Drosophila as his model system.
Dr. Melnattur developed a novel aversive-conditioning behavioral assay to assess color discrimination in flies: an octagonal arena of blue and green LED panels with an infrared laser used as heat punishment to train the flies to avoid blue or green colors. Using this assay, he demonstrated that two specific photoreceptors, called R8 and R7 in Drosophila, are required for color vision. Furthermore, abolishing the synaptic input of two types of neurons, labelled Tm5a,b,c and Tm20, abolished the flies’ color preference, implying that these specific neurons are required for perception of colors.
Next, Dr. Kimberly Decker shared her interests in identifying the mechanisms of virulence gene regulation by pathogenic bacteria. Her postdoctoral work in Dr. Matthias Machner’s lab focuses on the interactions of Legionella pneumophila, the bacterium that causes Legionnaire’s disease, and its host, the human macrophage. During the infection process, L. pneumophila injects about 300 effector proteins into macrophages, which appear to modify various cellular processes. However, only a few of these effector proteins have been characterized in detail.
Dr. Decker used Nucleic Acid Programmable Protein Array (NAPPA) technology, a process that immobilizes DNA templates on an array surface to generate proteins in situ just before experimentation, to screen host-pathogen, protein-protein interactions. She began her experiments with the well-studied LidA protein as proof-of-principle for this novel technique. In addition to some known targets of this bacterial protein, she identified an interesting novel target involved in negatively regulating mammalian cell growth.
NICHD Scientific Update, with Dr. Todd Macfarlan
By Nazanin Ashourian, PhD
About 46 percent of the human genome is composed of transposable elements (TEs), segments of DNA that can independently replicate and change their positions in the genome, and their remnants. The debate on whether TEs have a symbiotic or a parasitic relation with our genome has been ongoing ever since their discovery by Barbara McClintock in the early 1950s, winning her the 1983 Nobel prize. While some of the initial models in the 1980s described TEs as selfish DNA, there has been growing evidence for their neo-functionalization and beneficial features in our genome.
Work by Dr. Todd Macfarlan has provided additional support for a synergetic relation between TEs and mammalian genomes. As an example of this positive relationship, Dr. Macfarlan and colleagues have shown that some of the cell fate genes essential for early mammalian embryonic development are later repressed using the regulatory sequences of retroviruses—a type of TE.
Some of Dr. Macfarlan’s work centers on endogenous retroviruses (ERVs), retroviruses that have integrated their DNA into the host genome to be passed to the next generation. Macfarlan and his team found that ERVs seem to utilize preferential silencing mechanisms: i.e., the cellular mechanisms used to silence one class of retroviruses do not necessarily work on another.
To explain this observation, Dr. Macfarlan proposes a model in which universal repressor complexes target distinct ERV elements via direct interactions with zinc finger proteins (DNA binding proteins whose structures are maintained by zinc ions) that are specific for each ERV. The idea is that zinc finger proteins bind to specific (or a set of specific) sequences unique to each class of ERV elements and subsequently recruit universal repressor complexes.
Dr. Macfarlan’s work is a view into the secretive world of transposable elements. Once thought to be the ultimate genomic parasites, we are learning that these DNA sequences may now be an integral part of normal development.
Key Note Address, with Dr. Shirley Tilghman
By Erin Fincher
Dr. Shirley Tilghman, president of Princeton University, was our second keynote speaker of the day. Dr. Tilghman gave a fascinating talk entitled “Educating a Biomedical Workforce in the 21st Century.” She began by telling us about her time as a postdoctoral fellow at NIH.
When she first came to NIH in the late 1970s, the climate of postdoctoral training was very different than it is today. In 1980, it took on average of 9-12 months for investigators to secure their first NIH grant. Today, that number has skyrocketed to almost five years. The average age at which an investigator secures his or her first RO1 grant is 42, and the average age of primary investigators is close to 50. In 1980, these numbers were much lower. All of this, Dr. Tilghman claims, is indicative of a deeply dysfunctional system of postdoctoral education and training. There is a clog in the educational pipeline, so to speak, but how do we fix it?
Dr. Tilghman offered a number of recommendations for changing the state of postdoctoral education in the biomedical sciences. She advocates changing the way graduate students are utilized and funded. Dr. Tilghman recommends that graduate students be treated as students, rather than cheap labor; education needs to be of primary importance during graduate training. And the training postdocs obtain needs to adequately prepare them for their next career moves.
Dr. Tilghman also advocates changing the way we fund fellowships, offering more training grants rather than research grants, capping the number of years that graduate students can be funded by NIH grants, increasing stipends for postdocs, and providing full benefits. Ultimately, Dr. Tilghman tells us, in order to unclog the educational pipeline, we need to change the culture of education in biomedicine. It may seem a monumental task, but Dr. Tilghman has provided us with some concrete steps in the right direction.