Five scientists whose recent research demonstrates the breadth and depth of basic science at Baylor College of Medicine received the 2013 Michael E. DeBakey Excellence in Research Award, named in honor of the College’s first president, in ceremonies today.
The winners include Dr. Mauro Costa-Mattioli, assistant professor neuroscience; Dr. Martin Matzuk, professor of pathology & immunology; Dr. Jeffrey Noebels, professor of neurology; Dr. Matthew Rasband, professor of neuroscience, and Dr. Thomas "Trey" Westbrook, professor of biochemistry and molecular biology and molecular and human genetics. Each winner will present his work during the ceremonies.
The award is sponsored by the DeBakey Medical Foundation and consists of a commemorative medallion and funds to support further research.
Contributions to memory research
In nominating Dr. Costa-Mattioli, Dr. John Dani, a professor in the Department of Neuroscience at BCM, called his contribution to the scientific literature just "spectacular," spotlighting reports that appeared in the journals Cell, Nature Neuroscience and the Proceedings of the National Academy of Sciences (PNAS) in 2011 and 2013. The Cell paper focused on a virus-sensing kinase called PKR whose activity is altered in cognitive disorders. He and his colleagues found that PKR controls neuronal network rhythmicity and memory formation by regulating the synthesis of an immune protein called interferon gamma. This finding changed the way that scientists view the function of the immune system in the adult brain. His work shows that both PKR and interferon gamma are crucial for long-term memory formation. His PNAS paper explores the tenure of memory by examining change in the synapse, where information is transmitted between neurons. Newly formed memory remains "short-term" for only a few minutes before it is consolidated into long-term memory. This is thought to require induction of the expression of genes and the manufacture of new proteins. Costa-Mattioli found that control of translation (from messenger RNA into a protein) by the mammalian target of rapamycin complex 1 (mTORC1) plays a crucial role in memory processes, a finding that has implications for diseases such as Alzheimer’s, Autism spectrum disorder and also drug addiction. In his most recent paper in Nature Neuroscience, Costa-Mattioli and colleagues discovered that by regulating actin polymerization, the recently discovered mTORC2 complex links structural changes in the neuron that contribute long-term changes required for memory storage. This paper, the first in the memory field to combine mouse and fly genetics, show that mTORC2 decides whether a long-term memory will be stored in the brain. In addition, they have found a small molecule that promotes mTORC2 activity and acts as a "memory-enhancing drug.” Hence, mTORC2 could be a novel therapeutic target for the treatment of cognitive dysfunction.
Although Costa-Mattioli's memory enhancing pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be indeed very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory.
"To briefly indicate the level at which this work has penetrated the popular consciousness, it has become an answer on the long-running TV game show Jeopardy! for $1,200, 'M. Costa-Mattioli found a protein that controls memory formation, a possible help for this disease named for a German,'” wrote Dani.
Matzuk, also director of the new Center for Drug Discovery and vice chair of pathology & immunology, is an established investigator with an international reputation in reproductive medicine, wrote his nominator, Dr. Thomas M. Wheeler, chair of the Department of Pathology and Immunology at BCM. "As an investigator, Marty has been phenomenally successful; he has contributed more than 300 articles to the biomedical literature including 25 papers in Cell, Nature, and Science journals and has received multiple honors."
"Wheeler pointed specifically to a report in the journal Cell on which Matzuk was both first and co-communicating author. In the report, Matzuk and his colleagues identified a small molecular inhibitor JQ1 that targets a testis-specific protein called BRDT. The small molecule has a reversible, contraceptive effect on male mice. The finding evoked a firestorm of local, national and international media. He was interviewed by a variety of media, including BBC, Radio Australia and the local CBS affiliate. Stories about his work appeared in the Houston Chronicle, the Washington Post, Time, The Economist, U.S. News & World Report and The Atlantic, among others. The work was highlighted in Cell, Science, Nature and other scientific journals.
"In summary, Marty is exceptional even among exceptional people. He is one of the brightest, most creative, dedicated, and hard-working investigators that I have ever known," wrote Wheeler. This is the second DeBakey award for Matzuk, who was also a recipient in 1995.
Advances in epilepsy research
Noebels, also a professor in the departments of neuroscience and molecular and human genetics and director of director of the Blue Bird Circle Developmental Neurogenetics Laboratory, was nominated by Dr. Eli M. Mizrahi, chair of the Department of Neurology at BCM, who pointed to his ground-breaking research in epilepsy and his pioneering efforts to understand how a mutant ion channel gene can lead to an epileptic brain. He spotlighted three recent papers that highlight the depth of Noebels’ research. One in the journal Cell, found that mutation in known channel disease genes are common also in people without disease, the first time such an analysis has been done for genes now in common use for genetic diagnosis. He proposed a "rare variant pattern" hypothesis to disease causation, opening the door to computational modeling of biological systems in risk prediction.
A second article in the Journal of Physiology, demonstrated that opening a specific type of potassium channel (Kcnq) with a specific activating drug can compensate for the absence of a different potassium channel (Kv1), which is a cause of heart conduction abnormalities. It was the first published report of a K channel functional rescue using drugs and included the first microelectrode recordings of a single mouse vagal nerve.
The third article, in the Journal of Neuroscience, showed that deletion of the tau protein - usually associated with dementia in a form of Alzheimer’s disease - can prevent epilepsy and its sequelae in both mouse and fly models. The finding was part of a greater understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease. Noebels' work in this area has led to an understanding that epilepsy and Alzheimer’s disease may share defects in signaling within the brain’s memory circuits. Mizrahi also noted that Noebels is highly collaborative in his research and an outstanding mentor, having trained eight predoctoral students and 24 postdoctoral fellows in epilepsy research at Baylor as well as mentoring two junior faculty who have received federal training grants. In addition, he has received a three-year, $1 million planning grant from the National Institute of Neurological Diseases and Stroke to bring together five clinical and basic science academic centers to build a national "Center without Walls" for the study of sudden death in epilepsy, a disorder in which he is a leading researcher.
Rasband was nominated by Dr. Dora Angelaki, chair of the Department of Neuroscience at BCM, and Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and professor of molecular and human genetics at BCM, for "groundbreaking work on characterizing the molecular architecture of the axon initial segment and nodes of Ranvier...Nodes are essential for conduction of nerve impulses throughout the nervous system, and their disruption contributes to the pathophysiology of many disorders including multiple sclerosis, peripheral neuropathies, and other white matter diseases,” they wrote.
They cited three papers by Rasband as demonstration of his work. One, in PNAS, provides first evidence of a link between neuron-glia signaling and the cytoskeletal rearrangements that take place during myelination (the accumulation of a fatty layer called myelin around nerve fibers).
In a publication in the journal Cell, Rasband showed how the cytoskeletal and scaffolding protein ankyrin’ is recruited to and forms the axon initial segment, the "gatekeeper" of all neuronal output. In a recent publication in the journal Neuron, he and his colleagues described the components needed to make and assemble the nodes of Ranvier, the booster stations that enable electrical signals to travel from neuron to neuron.
"To say that Dr. Rasband is actively involved in graduate training is an understatement," wrote Angelaki and Zoghbi. "He is consistently one of the top-rated teachers in our Neuroscience program and was the inaugural recipient of the ‘Outstanding Educator’ award in 2011 at the Rush Record Neuroscience Retreat."
For his work, Rasband was also recently awarded a Jacob Javits Neuroscience Investigator Award by the National Institutes of Neurological Disorders and Stroke. This award provides seven years of funding for his research program.
New insights, breast cancer
Westbrook was nominated by two department chairs, Dr. Theodore G. Wensel of the Department of Biochemistry and Molecular Biology at BCM, and Dr. Arthur Beaudet, of the Department of Molecular and Human Genetics at BCM, and one center director, Dr. C. Kent Osborne of the NCI-designated Dan L Duncan Cancer Center at BCM. They based their nomination on three publications in high impact journals.
In the journal Cell, Westbrook and his colleagues described the tumor suppressor gene PTPN12 tyrosine phosphatase that is frequently mutated in a virulent form of breast cancer called triple negative because it lacks receptors of estrogen, progesterone and HER2. In its normal state, PTPN12 suppresses proliferation and malignant transformation by interacting with many tyrosine kinases that promote cancerous growth and change.
"These discoveries have tremendous potential for clinical impact because they point to a new strategy for rationally combining tyrosine kinase inhibitors that are ineffective individually but show significant synergistic effects against triple negative breast cancer," the nominators wrote. In fact, the new strategy is now being tested in the clinic by Dr. Mothaffar Rimawi, medical director of the Lester and Sue Smith Breast Center at BCM.
In the second article in the journal Science, Westbrook identified genes essential for the survival of cancer cells driven by the oncogene Myc and used a genetic screen to identify several novel signaling networks that are required for cells to tolerate Myc. This research and its offshoots provide a way to destabilize cell division in a way that may elicit a broader therapeutic window than similar drugs have now.
In the third article in PNAS, Westbrook described a new system called lentiviral pINDUCER that enables researchers to turn a gene on or off, partially solving a problem in mammalian research in development and disease.
"Collectively, these innovative tools have facilitated new genetic approaches and opened previously unexplored areas of research," the three nominators wrote.