Stavros Lomvardas, a young investigator at the University of California San Francisco, has just been awarded funding from RSRT for an innovative project which has the potential to not only help to clarify the function of the MeCP2 protein but also discover drugs to reverse the deficits incurred when the protein is mutated. Below are excerpts from a recent conversation with Dr. Stavros.
MC: I am always fascinated by how scientists end up in their chosen career. Was it a relatively late decision for you or did you know as a boy that you were destined for science?
SL: I guess in my heart I always knew. Even when I was a very little kid I was always designing little experiments. I grew up in Athens, Greece. My father was dentist who had a deep interest in biology. I found his love for biology very inspiring. He would always bring me books and talk to me about experiments and help me to design my own. So from a very young age I knew I wanted to be a scientist.
MC: It’s my impression that most scientists go into this field for the love of basic science and not with the goal of understanding or treating disease. Would that be a fair statement with regards to you?
SL: Yes, it would be fair. To be quite frank until 5 years ago I was completely dedicated to basic science and did not have any real interest in applying my knowledge to treat disease. I thought it was utopic to expect that basic science could be used, at least in the near future, to treat diseases. But the last 5 years have changed me dramatically. Maybe it has to do with having my own children. Or maybe dealing with health issues that have cropped up in my extended family and realizing that there are people out there who are really suffering. I realize now that scientists cannot sit at our lab benches preoccupied only with the joy of doing pure science. We have an obligation to also help people. The idea of doing experiments that might actually have medical applications is very appealing to me right now. Maybe I’ve just matured but I find the concept very fulfilling.
MC: For a young investigator you have a very impressive training and publication record. In fact, you have worked with not one but two Nobel Laureates.
SL: I came to the U.S. as a graduate student in 1998 and trained in the lab of Dimitri Thanos at Columbia University. The Thanos lab and the lab of Nobel Laureate, Eric Kandel, also of Columbia had an extensive collaboration that lasted a number of years. It was a very interesting experience for me personally. After I received my PhD in 2002 I transferred to the lab of Richard Axel for my post-doc training.
Dr. Axel, together with Linda Buck, shared the Nobel Prize in 2004 during my second year in the lab for solving the question of how we recognize and remember thousands of different smells. They discovered a large gene family comprised of about 1500 different genes that correlate to an equal number of olfactory receptors, each of which detect a small number of smells. These receptors are located on the olfactory receptor cells which in turn are located in the upper part of the nasal epithelium.
Interestingly, each olfactory receptor cell has only one type of odorant receptor, and each receptor can detect a limited number of odorant substances.
MC: Did the Nobel Prize make working in the Axel lab any different?
SL: Dr. Axel was an extremely admired scientist among his peers. I don’t think receiving the Nobel Prize changed how his peers viewed him. While the prize brought lots of attention from the outside community it did not change his already existing celebrity status in the scientific world. What did change is the demands on his time – for a number of years, and to some extent still now, he was insanely busy.
I will always remember the call I received from him while he was in Sweden receiving his Nobel. He was eager to know how an important experiment that I was undertaking was proceeding. The call is an example of Dr. Axel’s philosophy – science first. For me the experience was quite surreal.
Overall I was very fortunate to have trained in labs where the bar of what is considered good science and ground-breaking research was set very high.
MC: How did your research come to include MeCP2?
SL: Toward the end of my post-doc I had started working on DNA methylation and other epigenetic modifications of olfactory receptors. I was a fellow of the Helen Hay Whitney Foundation and at a Foundation meeting I saw a friend, Joe Zhou, who worked on MeCP2 in Michael Greenberg’s lab at Harvard. I had certainly heard of MeCP2 and knew of its involvement in Rett Syndrome but had never considered working on this protein myself. Joe gave an interesting talk which enticed me to do some preliminary experiments. I asked Joe for some antibodies against MeCP2 and I quickly noticed a peculiar expression pattern in the olfactory epithelium. Also the Ronnet lab in John’s Hopkins had published some very interesting results regarding MeCP2 function in the development of the olfactory epithelium, so I got really interested. We then ordered the knockout mice and started working seriously. So my entry into the Rett field was, like many things in science, quite serendipitous.
MC: Please give our readers some insight into your RSRT funded experiment.
SL: My experiment leverages the discovery that MeCP2 deficient olfactory receptor neurons (ORN) have a very robust readout. They co-express molecules that are never expressed in the same neuron in wild type mice. Part of our experiment will capitalize on this finding to screen for drugs that can reverse the deficit – in other words find drugs, using high throughput screens (HTS) that can turn off one of ectopically expressed molecular markers.
MC: The reviewers of your proposal as well as our advisors had a common observation. They commented that the leap to the HTS was exceptionally clever and unconventional.
SL: The idea to undertake a HTS came to me last December during at a scientific meeting organized by RSRT. As you know RSRT brought together about two dozen scientists, including the top minds in epigenetics and Rett Syndrome, to brainstorm about MeCP2 function. During the stimulating discussions it hit me that as far as I could tell there were no existing straightforward assays for MeCP2 deficiency. It occurred to me that our finding could be leveraged to develop an assay for drug screening. At first it seemed like a crazy idea. But the more I spoke to people the more they liked the idea. I am quite hopeful that we can find some molecules that can turn off one of the two markers and be effective also in vivo.
MC: This is a prime example of translational research – in other words a logical next step of taking a basic science discovery and designing an experiment with clinical applications – that most individuals outside the science arena believes happens naturally – but actually needs to be pushed, facilitated and funded – often by research organizations such as RSRT.
SL: Yes, absolutely. For me the first key turning point was reading Adrian Bird’s reversal paper. It was a beautiful paper; the experiments were so elegant and the results so dramatic. The second key turning point was attending the RSRT meeting which led to the idea of the HTS.
MC: You’ve been studying MeCP2 for about 3 years now. Has anything surprised you?
SL: Before I started working on MeCP2 I could not understand why people were struggling so much to understand the function of this protein. After all, there is a knockout, with a severe set of symptoms. So why don’t we have a clear list of target genes that are regulated by MeCP2. Now that my lab is focused on this protein I am realizing that we are not dealing with a traditional molecule. MeCP2 is not a traditional repressor or activator in that when you remove it you do not see huge effects on other genes. It’s a very intriguing molecule indeed. My personal hypothesis is that MeCP2 is a modulator involved in the fine tuning of nuclear processes. This is where my lab as an edge in choosing the olfactory epithelium because we can work on a very pure population of neurons.
MC: Parents reading this who have children with Rett Syndrome are probably wondering if their child has problems with smell.
SL: I don’t know. We are doing experiments now to delete the protein in the olfactory epithelium and will test whether there are olfaction deficits in the mice. I would expect that there may be subtle problems of discriminating between smells.
MC: This is a pretty difficult time economically for young scientists. Are you also feeling the impact?
SL: Yes I am certainly feeling the impact, especially being in CA. My first two years of having my own lab have been very rough. I had serious problems attracting funding from anywhere. It was a very painful experience because I was establishing a lab, recruiting and training people and trying to get enough funds to stay afloat. Fortunately my department and the UCSF supported me during this very difficult phase. Things have improved slightly but the situation remains challenging. Funding from RSRT is greatly appreciated.
MC: Over the past decade I have administered peer review for almost 1000 Rett grants. I have seldom seen the kind of unanimous enthusiasm that your application generated. I wish you success and look forward to updating our readers about your progress.