You are hereJanuary 31, 2011
An Interview with Sally Moody
This month our Feature Principal Investigator, Sally Moody, shares her academic journey with us and explains her motivation for pursuing a career in neural development and stem cell research. Sally is currently a Professor in Anatomy and Regenerative Biology at the George Washington University, Washington, DC.
‘I received a liberal arts education and took as many music courses as I did biology courses. This broad approach with a touch of serendipity has followed me throughout my scientific career. After college, I wanted to work for a few years to gain some financial independence. Because I had taken an histology course in college, I was hired as a laboratory technician for the Department of Anatomy at the University of Maryland School of Dentistry. I learned a wide range of histological, histochemical and electron microscopic techniques over the three years I worked there. The faculty encouraged me to enrol in their MS program, so while I worked full time, I also took the traditional anatomical courses (Gross Anatomy, Histology, Neuroanatomy and Embryology) and performed research. One person in the department, Richard Meszler, worked on the nervous system, and I was most fascinated by this topic. I did my MS research in his lab, identifying the specific motoneurons that innervate jaw closing and jaw opening muscles, and I described the different types of synapses that innervate the trigeminal motoneurons.
This experience made me realize that I wanted an academic career, and I wanted to learn everything I could about the nervous system. I enrolled in the University of Florida Department of Neuroscience to get a broad exposure to all aspects of the field. It just so happened that during my first semester in the Ph.D. program I took a Neuroembryology course that required me to complete a small research project in the professor’s laboratory. I chose to study how trigeminal motoneurons migrate during development because I was familiar with the adult system and had written about its development in my Master’s thesis. In the laboratory of Marieta Heaton, I learned how to perform microsurgery on chick embryos, cell birth dating techniques and a number of neurohistological stains to detect migrating neurons in the embryonic brain (a la Ramon y Cajal). What was to be a semester long project turned into my Ph.D. dissertation project.
At the time I was finishing my dissertation, there were no molecular approaches available in vertebrates to tease out the underlying mechanisms that direct immature neurons to migrate to the proper locations in the developing brain. Thus, I was at a bit of a loss what to study next, but knew I wanted to continue to ask questions about how the embryonic brain forms. While attending the Cold Spring Harbor Laboratory course on Developmental Neurobiology (in 1980, directed by Dale Purves and Paul Patterson), I became fascinated with the idea presented by Peter Lawrence in insects that lineage could influence the cell identity of embryonic cells. Therefore, I looked for a post-doctoral mentor who was asking questions about neuronal cell fate and lineage restrictions in vertebrates. In 1981 I moved to the University of Utah Department of Anatomy and Neurobiology to study with Marcus Jacobson. Marcus and G. Hirose were using a technique pioneered in the leech by Gunter Stent and David Weisblat of injecting horseradish peroxidase into embryonic cells as an inert lineage tracer. I used this technique to map the embryonic origins of motor and sensory neurons, and demonstrated that as motor axons exit the developing neural tube, they preferentially innervate somitic muscle fibers with the same embryonic ancestry. But, as I was preparing to go on the job market for an independent position as an Assistant Professor, I got distracted from the topic of axon guidance by fundamental questions in developmental biology regarding fate specification. Marcus was an enthusiast of the history of science, and every day in the lab we got not only a lecture on how to do our experiments, but also a lecture on the history of just about every aspect of developmental neurobiology. He loaned me a biography of Theodor Boveri while I was flying back to the east coast for job interviews, and I became very interested in the question of whether maternal molecules could determine the fates of the Xenopus blastomeres. Upon starting my faculty position at the University of Virginia, I set out to make a very complete fate map of the 2-cell through the 64-cell embryo so that we could then perform manipulations to test whether blastomere fates were determined by cell autonomous mechanisms or required cell-cell interactions. We published all the fate maps except the 64-cell stage; I had wearied of all the mapping, and realized that probably very few investigators would be manipulating these very small cells. But, I still have the slides and imagine that I will complete this map after my lab has run out of extramural support!
During my academic career, as an Assistant and then Associate Professor at the University of Virginia, and then as full Professor at the George Washington University, I have continued studies on numerous aspects of neural cell fate specification in the intact embryo. We have mainly utilized Xenopus for these studies because of their reproducible lineages, the ease of performing gene gain- and loss-of function in specific tissues, and the applicability of the information to other vertebrates. However, we collaborate with researchers using chick, fish, fly and mouse to best answer the question at hand. In one particular project, we are now moving into the mouse embryonic stem cells to determine whether what we have learned about the role of the FoxD4/5 transcription factor in the Xenopus embryo is applicable to mouse ESCs. In Xenopus, FoxD4/5 is required for the formation of the neural plate, and it regulates a number of early neural transcription factors that are expressed just after neural induction. In my view, these early neurally-induced cells are the embryo’s version of cells comprising a neurosphere. Therefore, we are turning to from the intact embryo to cultured ESCs to determine whether this gene has a role in mammalian neural fate specification and/or commitment.
In my current role as Professor, I teach lectures and labs to medical students and graduate students. I train undergraduate and graduate students in my lab and carry out research on the role of various transcription factors in determining the neural ectoderm and cranial placodes during early stages of development. I also serve on a number of graduate student dissertation committees, a variety of university committees and I chair the Institutional Biosafety Committee, which reviews research involving recombinant DNA and human pathogens. Other professional activities include being the Treasurer of the Society for Developmental Biology, serving as a reviewer for several granting agencies, and serving on editorial boards for journals such as Stem Cells.’ Professor Sally Moody.
An Interview with Sally A. Moody
By Carla Mellough
In your opinion, what has been your most exciting discovery, and why? What are the potential implications of this discovery?
Several years ago, we were searching for new genes that are involved in the earliest steps of neural development in the embryo. One of the genes we pulled out of a screen for vertebrate members of the Drosophila Forkhead family, FoxD4/5, is expressed maternally in the precursor blastomeres of the neural plate, and in the neural ectoderm right after neural induction. By knocking down the translation of this gene, we found that it is required for the neural plate to form, and for the expression of 11 other early neural transcription factors. By gain-of-function analyses, we showed that FoxD4/5 directly activates some of these genes, and down-regulates others. From a series of knock-down and rescue experiments we have been able to piece together a gene regulatory network for the earliest transcription factors expressed in the nascent neural ectoderm. This is exciting because the FoxD4/5 gene has not been studied in other vertebrates, so the information is novel. Also, because FoxD4/5 up-regulates neural transcription factors that act to maintain the neural ectoderm in an immature state and it down-regulates neural transcription factors that promote neural differentiation, we postulate that the role of FoxD4/5 is to maintain neurally induced cells in an immature, neural stem-like state. Thus, this gene could have a key role in maintaining a neural stem population in adult niches or in neurosphere cultures. Therefore, understanding the molecular mechanisms by which it acts and identifying its direct and indirect targets are important future studies. As mentioned above, for this reason we are now moving into the mouse ESC system to determine whether what we know about how this gene functions in the intact Xenopus embryo is applicable to mammalian stem cells. We hypothesize that understanding how this gene functions, learning to regulate its expression could potentially be used to prevent premature depletion of endogenous neural stem cells or promote neural differentiation.
How easy or difficult do you find it to keep abreast of the vast volume of new literature in the field?
The scientific literature has exploded, and it is very difficult to keep up-to-date not only in my own field, but also in related fields that are likely to impact my thinking about my own projects. I find that I frequently miss important papers in a field, even though I frequently perform PubMed searches as I write manuscripts and grant applications. I find that reviewing manuscripts for journals is another very useful way to keep up-to-date on a topic. I admit that I do not subscribe to any of the on-line services that alert one to recent publications. These probably work really well, but I find it difficult to deal with an email in-box that is already clogged with way too many messages. Outside my own specialty, I rely more and more on talks and posters at scientific meetings to get new information of more general biological interest.
How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?
The community of developmental biologists has traditionally been a very collaborative group, sharing reagents and techniques across labs and across the various model organisms. Our work over the past two decades would not have been possible without colleagues freely donating clones, antibodies and advice. As the field of neural development has entered the genomic and proteomic ages, however, everyone needs to become broader in their experimental repertoires and technical expertise. But, for someone with a small laboratory working at a university with very limited resources, this is a challenge. Therefore, collaborative projects, in which the actual experiments are performed in multiple labs, are becoming more and more important. We cannot afford the time or the finances to become adept at every experimental approach that is required to answer a question. Therefore, finding collaborators with complementary skills and expertise has become critical to our work.
It seems that the barrier is always being raised for the achievement of success in publishing manuscripts and obtaining funding. What effect do you think this has on the research that is being undertaken and the way in which it is conducted?
My answer to this question dovetails with the previous question. Because we are in a time where new approaches to answering cell and molecular biological questions are rapidly evolving, journals and study sections are expecting all researchers to apply multiple techniques to answering biological questions. This puts a significant strain, both on finances and personnel, on smaller labs. While large scale screens and high through-put approaches are being touted as the best way to have a broader, “systems” appreciation of a problem, it favours the very large laboratories found at research intensive universities. Although big science may result in more rapid progress, I think there are detrimental aspects to the “corporate science” approach. First, smaller labs are being squeezed out, and the domination of a field by a few factory labs can stifle advances. Second, many graduate students and postdoctoral scientists no longer believe they have a future as independent researchers. We are in danger of losing very talented, creative researchers and unique points of view.
How do you think the current funding situation will affect the progression of stem cell research in the short and/or long term?
I expect that stem cell research will continue to progress at a reasonable rate even though funding is likely to be flat for the foreseeable future. The reason is that this topic has caught the attention of the American public in hopes that stem cells will cure a number of diseases. Further, the push by the NIH to promote translational research fits very well with the stem cell field. However, I fear that the basic science research that has led to many of the advances in our understanding of stem cell biology will suffer. I was recently at a meeting making recommendations about “translational” research proposals and was dismayed to discover that many of the clinicians on the panel only considered a project translational if it included human subjects. This narrow view may make it very difficult for those moving from animal models to stem cells to capture the funding necessary to perform this intermediate important work. I am also concerned that in the long term, if cell replacement therapies are not developed, the public will become disillusioned by the promises that were made and turn a blind ear to the appeals from funding agencies for increased funding in this area.
A number of recent articles implicate that induced pluripotent stem cells (iPSC) may be more dissimilar to hESCs than was initially thought and thus cast some doubt over the applicability of iPSC for the treatment of human disease. In your opinion, how important do you think these differences are?
Unfortunately, the science of hESCs and iPSCs will always be in the shadow of the political and cultural ideologies of the public, the funding agencies and of the researchers themselves. This makes it very difficult to illuminate similarities and differences in an unbiased manner. Casting one cell type as superior to the other is not as productive as studying how each may be best manipulated for therapeutic use. We need unbiased assessments of the strengths and drawbacks of each cell type, and use that information judiciously.
What are your hopes for the future of stem cell research and clinical translation in your specialist area?
The development of transplantation therapies for congenital defects of the nervous system is the long-term goal of our research. For some of the genes that we are studying, homozygous mutants are embryonic lethal. However, congenital syndromes are observed in humans when the mutations are hypomorphic or interfere with binding to protein partners. In these cases, just increasing normal protein production, rather than complete gene replacement, could resolve the deficit. This may be achievable with transplantation of only a few stem cells over-expressing the normal protein at critical developmental windows. While there currently is tremendous interest in using stem cells to replace/repair damaged adult tissues, we are looking forward to improving the developmental outcomes of congenital deficiencies.
More information about the research team can be obtained from the lab website