Top Baylor Discoveries:
|Discoveries concerning the peptide hormone production of the brain.Towards the end of the 1950′s, Roger Guillemin and Andrew Schally (co-winner of the Nobel Prize that year) developed extracts that in one case made the pituitary release ACTH, another TSH (Thyroid Stimulating Hormone), a third one LH (luteinizing hormone) and FSH (follicle-stimulating hormone, the gonadotrophic hormones) etc. They termed these substances “releasing factors or hormones,” RF or RH. The one inducing the release of TSH, thus was called TSH-RF or TRF. In 1969,the nature of these hypothalamic factors was established when they made TRF in a pure form that released TSH from the hypophysis. They then determined the structure of TRF. Within the same year the Guillemin group synthesized TRF. Approximately two years after, LH-RH was isolated, sequenced and synthesized, first by Schally and then by Guillemin. Guillemin’s and Schally’s discoveries laid the foundations of modern hypothalamic research. The experiences from animal research were rapidly transferred to humans and brought into clinical work. Several new peptides were isolated from the hypothalamus, the foremost somatostatin, which decreases the production of pituitary growth hormone.|
|Development of the Dacron graft to repair damaged blood vessels, which made possible the surgical repair of damage to blood vessels, including aneurysms, and opened the door to the field of cardiovascular surgery.
In 1954, Michael E. DeBakey had been in Houston about five years when he visited a local department looking for material for a graft he was developing. One of the clerks showed him Dacron, a new “miracle” fiber and he thought it might work. He sewed the first one himself on his wife’s sewing machine. Later, the grafts were woven without seams to insure that they would not leak. The grafts opened the door to repairing damaged blood vessels, a procedure not possible before. Out of this came the field of cardiovascular surgery.
|Elucidation of the mechanisms by which the cell regulates division. Loss of the cell’s ability to regulate its division is a critical step in the development of cancer. Synergistically merging the tools of genetics and biochemistry, Drs. Harper and Elledge isolated the characterized human gene, CIP1 that encodes a critical negative regulator of the cell cycle. CIP1 binds and inhibits a class of protein kinases (cyclin-dependent kinases [Cdks]) that are required for the G1/S transition, the rate-limiting step in cell proliferation. CIP1 is transcriptionally regulated by the tumor suppressor p53. Mutations in p53 are the most commonly found lesion in human tumors, being present in more than 50% of all carcinomas. The discovery by Drs. Harper and Elledge that p53 regulates an inhibitor of Cdks provided for the first time a mechanistic explanation of how this tumor suppressor protein negatively regulates the cell cycle. The fact that mutations in p53 are the most common lesion in human carcinomas indicates that loss of the CIP1 pathway is a critical determinant in tumorigenesis. November 1993, two papers – one by Drs. Harper and Elledge and one by Dr. Vogelstein and his group – were published simultaneously in Cell. The significance of these two papers is borne out by the publication of reviews announcing the discovery in Cell, Nature and Science. The discovery was heralded as “the most dramatic discovery of the year” by the editors of Science and significantly contributed to the selection of p53 as the 1993 Molecule of the Year by the journal. The Journal of NIH Research included this discovery as “one of the five most important developments in the field of cell cycle research in the last five years.” Subsequent research has further delved into how these activities take place. Overall, this body of work by Drs. Elledge and Harper has been the key discovery to our understanding of the mechanisms that underlie the control of cell proliferation and has forged a critical link between two large important fields of study – cancer research and cell cycle research.|
|Discovery of the role of acetyl CoA carboxylase II in fat accumulation. The work in Wakil’s laboratory centers around an enzyme called acetyl-CoA carboxylase (ACC) that exists in two forms – ACC1 and ACC2. When mice are genetically engineered so that they do not produce ACC2, the reaction sounds like something out of a snake-oil weight reduction advertisement. The mice can eat more and weigh less. In fact, they can eat more of a high-fat, high-carbohydrate diet than mice that do produce the enzyme, and yet they do not gain as much weight nor do they develop type 2 diabetes.|
|Discovery of how virus causes infantile diarrhea and development of viral protein for vaccination.In the past, it was believed that rotavirus caused disease only by killing absorptive cells in the intestines. Dr. Estes discovered that the viruses such as rotavirus also make a protein that functions as an enterotoxin, a toxin that causes vomiting and diarrhea. Enterotoxins have been described for bacteria, but this is the first time one has been described for a virus. This new concept could explain how other viruses cause diarrheal diseases. She is now trying to prove that new treatments can be developed based on the fact that the rotavirus protein causes diarrheal disease.|
|Among the most dramatic was the discovery by David L. Nelson, PhD and C. Thomas Caskey, MD of the FMR1 gene responsible for fragile X syndrome. This is the first of a family of unstable DNA sequences called triplet repeats (CGG trinucleotide repeat in the FMR1 gene, in this case). The description of the triplet repeats opened the door for the discovery of a host of neurodegenerative disorders associated with these mutations.|
|Defining the mechanism for steroid hormone action, showing that steroid hormones acted by inducing specific mRNAs, and that co repressor-coactivator exchange at the receptor C-terminal tail was the mechanism. Developing the best early animal model for studying the mechanism of steroid hormone action, the O’Malley lab demonstrated ‘de novo’ synthesis of the oviduct specific proteins ovalbumin and avidin in response to estrogen and progesterone. He showed that steroid hormones changed the transcriptional program of newly synthesized RNA, and went on to demonstrate that steroids induced the specific mRNAs for ovalbumin and avidin proteins. He correctly predicted that the primary hormonal response was at the level of transcription- thus indicating that steroid receptors were transcription factors. With these experiments, the overall pathway of steroid-receptor-DNA-mRNA-protein-function was established. It focused the entire field on the nucleus. He then discovered an important pathway for activating steroid receptors- the ligand independent pathway, which plays a crucial role in breast/prostate cancers and represents the now accepted mechanism by which most orphan receptors are activated in vivo. He showed that steroid receptors activated transcription of a target gene by recruiting/stabilizing general transcription factors at the promoter (TATA). He used protease and antibody epitope mapping to discover the correct inactive and activated structures of the C-terminal tail of the receptor. O’Malley then completed the molecular action pathway by the biochemical discovery of a nuclear receptor corepressor, predicting it exchanged with a coactivator in the presence of hormone. He then cloned the first authentic ‘steroid receptor coactivator’ (SRC-1), and showed coactivators to be functional in cells and animals and to have diverse actions in cellular signaling. These conceptual advances substantiated Molecular Endocrinology as a new field of biological science, which has grown enormously in size and importance to physiology, pharmacology and medicine.|
|Preimplantation diagnosis.This controversial technique married genetic diagnosis with the manipulation of ova in vitro to enable physicians to diagnose diseases resulting from single-gene mutations in embryos developing in the lab. Embryos that lack the gene mutation can then be implanted in the uterus. The first clinical use of the technique took place in London and resulted in the birth of a healthy baby.|
|Discovery of the Cytoplasmic Microtubule Complex in eukaryotic cells. (CMTC) In the mid-1970s, Dr. Brinkley made the first antibodies against a protein he purified from cow brains known as tubulin. Using these antibodies as probes, he was the first to demonstrate, by indirect immunofluorescence microscopy, the presence of an elaborate fibrous skeleton in the cytoplasm of eukaryotic cells that he termed the cytoplasmic microtubule complex (CMTC). Prior to his discovery, microtubules had only been detected by electron microscopy and were only seen as fibers attached to the mitotic spindles of dividing cells and within processes known as cilia and flagella. When Brinkley first examined human cells by immunofluorescence microscopy, he found that microtubules were also plentiful in the cytoplasm of non-dividing cells where they radiated out from a single interior focus, know as the centrosome, and attached to the plasma membrane, forming an elaborate skeleton. Every cell displayed a CMTC that was found to function in maintaining cell shape and as needed for cell movement. Later, it was discovered that individual microtubules of the complex served as tracks on which large protein complexes moved as they entered and exited the cells. He also discovered that the CMTC was a dynamic complex that that could be completely disassembled as cells rounded up and entered mitosis. Brinkley found that as the cytoplasmic microtubule subunits were disassembled when cells entered mitosis, they were recycled to form microtubules of the mitotic spindle as needed for chromosome movement, and partitioning the genome into new daughter cells. When mitosis was completed, the microtubules of the spindle were, again, disassembled and again recycled to form the new CMTC needed as each daughter cells flattened and made contact with neighboring cells. Brinkley’s discovery coincided with the discovery of two other fibrous components in human cells, the actin filaments and intermediate filaments that have collectively become known as cell’s cytoskeleton. The cytoskeleton, especially the CMTC, is a universal components of all eukaryotic cells and involved in many aspects of cell development and division and implicated in many diseases including cancer, neuronal disorders and many others.|
|First successful gene therapy for diabetes in mice.Using a factor called NeuroD that was specific to cells that produce insulin and other hormones, Chan and his colleagues were successful in curing diabetes with gene therapy– at least in mice. Their report, published in the journal Nature Medicine, described how the combination of NeuroD and betacellulin, a growth factor, induced a cure in the mice for at least four months after a single shot. “It makes all the other hormones as well,” said Chan, chief of the division of diabetes, endocrinology metabolism and a professor of medicine and molecular and cellular biology. The other hormones included glucagon, somatostatin and pancreatic polypeptide, which may play a role in controlling insulin production and release. At the same time, it did not produce cells that made digestive enzymes. “Until now, it has not been possible to induce the formation of islets by any gene therapy approach,” he said. “It’s a proof of principle. The exciting part of it is that mice with diabetes are ‘cured.|
|The discovery of electromotility in sensory hair cells of the mammalian hearing organ. In 1983, Dr. Brownell led a research team in discovering an electrically driven form of cellular movement (electromotility) in outer hair cells from the mammalian cochlea. While all hair cells generate voltage changes (receptor potentials) in response to sound-evoked movements of their hair bundles, outer hair cells alone produce movements of the cell body in response to such voltage changes. Thus, outer hair cells perform mechanoelectrical and electromechanical transduction simultaneously, in a biological analogue of piezoelectric behavior. Furthermore, relative to other known cellular movements, the movements of the outer hair cells are unique in being voltage-driven and independent of ATP and calcium. The discovery of electromotility instigated an explosion of both basic and clinical research efforts, some incorporating the findings into models and tests of hearing, others investigating the underlying membrane-based motor mechanism. On the clinical side, outer hair cell electromotility explains why otoacoustic emissions correlate with hearing health and has facilitated the rapid expansion of otoacoustic emissions measurement as a hearing test. Efforts to uncover the underlying mechanism were rewarded by the recent molecular genetic demonstration that electromotility and cochlear sensitivity both depend upon the presence of a specific membrane protein; this result also confirmed the importance of electromotility for cochlear sensitivity. Remarkably, the protein produces a rudimentary electromotility when inserted into other cell types|
|The discovery of the active properties of dendrites.Dr. Johnston’s laboratory discovered active electrical processes in dendrites, which were previously thought only to respond passively to the ongoing electrical activity at synapses and elsewhere in the neuron. They went on to show that the active processes they discovered have direct and profound consequences upon the synaptic plasticity that underlies such phenomena as learning and memory and information processing. As part of these pursuits they confirmed a longstanding hypothesis, Hebb’s theory, that has been one of the theoretical cornerstrones of contemporary neuroscience. The work provides key insights into the mechanisms by which action potentials back‑propagate into dendrites and the role they play in synaptic integration and synaptic plasticity. His research has important implications for the fields of neurobiology and learning and memory and suggests new models for neuronal computations.|
|Development of “knockout” mice, allowing the study of specific gene mutations and the diseases they cause.Leading the way in this field was Dr. Allan Bradley who developed the technique of gene knock-out by homologous recombinant and facilitating its application to the study of development and oncogenesis. Dr. Bradley’s laboratory is internationally recognized for pioneering many aspects of embryonic stem (ES) cell technology and homologous recombination. This technology has become the focus of an enormous amount of research in many different laboratories where it is used to generate mutant mouse lines which are invaluable research tools used to address a diverse array of important biological questions. For example, the normal development roles of proto-oncogenes such as wnt-1(int-1) and c-src and c-myc have been established by his laboratory.|
|Baylor College of Medicine was one of three sites named by the National Human Genome Research Institute to complete the sequencing of the human genome. It also led the sequencing of the rat genome and participated in the sequencing of many more so-called model organisms. It is currently involved in sequencing the bovine genome.|