Environmental Factor, October 2011, National Institute of Environmental Health Sciences
Council scientific talks showcase diverse research interests
By Ashley Godfrey
Like her colleagues on the NIEHS leadership team, Division of Extramural Research and Training Director Gwen Collman, Ph.D., foreground, followed Tishkoff's narrative with interest. Collman, who introduced Tishkoff's talk, sat with NIEHS/NTP Director Linda Birnbaum, Ph.D., Deputy Director Rick Woychik, Ph.D., and Miller, shown left to right. (Photo courtesy of Steve McCaw)
NIEHS Acting Scientific Director David Miller, Ph.D., right, introduced Jack Keene, Ph.D., to the council, as part of the report on the Division of Intramural Research (DIR). Keene is the chair of the NIEHS DIR Board of Scientific Counselors. After Keene gave his report, Miller introduced Yakel as the first scientific speaker at the meeting. (Photo courtesy of Steve McCaw)
Yakel, who has been at NIEHS since 1993, answered many engaging questions, both during and after his talk, from council members and NIEHS employees who came to hear him speak. (Photo courtesy of Steve McCaw)
Council member Palmer Taylor, Ph.D., suggested that Yakel has created a very good system to look at elements of schizophrenia. Palmer said that an animal model for schizophrenia could be very useful in terms of developing and testing therapeutic compounds for the disease. (Photo courtesy of Steve McCaw)
Tishkoff explained that one of her proudest accomplishments during her ten years of going to Africa to conduct research was communicating the findings of her genetic studies to the people who took part in them. “You would be amazed how few people actually return results,” she said, noting that receiving the results of her studies made the participants feel important, “like they matter too.” (Photo courtesy of Steve McCaw)
Two scientific presentations at the 134th meeting of the National Advisory Environmental Health Sciences Council Sept. 2 highlighted the vast range of the research interests supported by NIEHS. Jerrel Yakel, Ph.D., head of the Ion Channel Physiology Group(https://www.niehs.nih.gov/research/atniehs/labs/ln/pi/icp/index.cfm) in the NIEHS Laboratory of Neurobiology, and Sarah Tishkoff, Ph.D.(http://www.med.upenn.edu/tishkoff/Lab/Tishkoff/Tishkoff.html) , an NIEHS grantee(https://projectreporter.nih.gov/project_info_description.cfm?aid=8142824&icde=0) at the University of Pennsylvania, treated listeners to reports on cutting-edge research, ranging from the study of nicotinic acetylcholine receptors (nAChRs) in the mammalian brain to human evolutionary genetics in African populations.
Yakel - “Nicotinic Acetylcholine Receptor Function in the Brain: Role in Synaptic Excitability, Plasticity, and Disease”
In his talk, Yakel explained why understanding how nAChRs function in the brain is so important. These receptors are widespread throughout critical regions of the brain and deficits in nAChR signaling are associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
Through a combination of techniques, such as electrophysiology, measuring the electric current released by receptor activation, and Voltage Sensitive Dye (VSD) imaging, an optical method of measuring receptor activation, Yakel is able to map the location of these receptors in the mammalian brain more precisely and gather information about how activation of this type of receptor can affect the behavior of the entire circuit.
“Changes in synaptic plasticity could be one of the mechanisms involved in early learning and memory,” explained Yakel. He defined synaptic plasticity as involving long-term changes - from seconds to minutes and even days - in the synaptic currents generated by the activation of the receptors.
Previous studies by other researchers have shown that nicotine may have a pro-cognitive or neuroprotective effect in the brain of adults. By combining high frequency electrical stimulation with exogenously applied nicotine to nAChRs in the hippocampus, Yakel's lab is able to convert a short-term activation of the receptors into long-term activation, to enhance the plasticity of the whole circuit. Yakel believes that the long-term activation of the nAChRs could be a possible mechanism involved in the effects of nicotine on the adult brain.
Stimulating endogenous release of acetylcholine
Recently, Yakel has been interested in studying how the release of endogenously stimulated acetylcholine modulates hippocampal synaptic activity and plasticity. Using a combination of genetics and virology in mouse models, Yakel's lab has been able to specifically mark cholinergic neurons and then stimulate the release of acetylcholine by exposing these neurons to light. This input of acetylcholine induces various types of plasticity of the synapses in the hippocampus depending on the timing of the inputs.
“There is exquisite timing where acetylcholine release can dramatically alter the synaptic stream,” Yakel concluded.
Tishkoff - “African Integrative Genomics: Implications for Studies of Human Origins and Disease”
Tishkoff opened her talk by observing that her lab is focused on understanding human evolutionary genetics, to better understand the forces that shape and maintain genetic variation in contemporary populations. “I wear many hats,” Tishkoff said of her integrative systems and evolutionary biology approach to studying African populations.
Tishkoff pointed out that although Africa is the homeland of all modern humans, it is greatly underrepresented in genomic variability studies. She and her research team have made several trips to the continent over the past ten years, gathering an impressive amount of information about the genetic makeup of its different populations.
According to Tishkoff, understanding how genetic and environmental factors play a role in normal variable traits, such as height, can lead to a better understanding of the genetic architecture of complex traits, including disease susceptibility. She also believes that learning what forces shape genetic variability and plasticity can have a positive impact in the field of pharmacogenetics, the study of how the actions of, and reactions to, drugs vary among individuals.
Integrative genomics - looking at the whole picture
Instead of taking a traditional genomics approach, Tishkoff incorporates genomic, transcriptomic, epigenomic, proteomic, and metabolomic data obtained from genetically, ethnically, and geographically diverse Africans. Her goal is to identify the genetic and environmental factors that influence complex physiologic traits.
Recently, Tishkoff has undertaken what she describes as the largest study to date of high coverage whole genome variation in Africa. Her lab has sequenced the whole genome of 15 ethnically and geographically diverse Africans. Although the researchers are still in the early stages of analyzing this data, Tishkoff has already found 13 million variants sites that differ from the human reference genome in the sequences of the subjects.
About 5.5 million of these variants are novel, which is impressive considering that the current variant database, dbSNP, already contains about 30.4 million variants. The results of her preliminary study have convinced Tishkoff of the importance of more work of this kind.
(Ashley Godfrey, Ph.D., is a postdoctoral fellow in the Molecular and Genetic Epidemiology Group in the NIEHS Laboratory of Molecular Carcinogenesis.)
High impact of basic research in neurobiology at NIEHS
Yakel's most recent work was published in the journal Neuron, which is considered the highest impact journal in the neurobiology field. As Yakel said of his study, “We've demonstrated that when we stimulate the release of acetylcholine at just the right time in the hippocampus, we can induce a cellular change at synapses that use glutamate.”
In a preview article about Yakel's research, Darwin K Berg, Ph.D., of the University of California, San Diego wrote, “Gu and Yakel in this issue of Neuron report an elegant series of experiments in which they analyze the timing required for cholinergic modulation of synaptic plasticity... The authors point out that this timing dependence enables a single cholinergic input not only to determine the kind of plasticity a synapse undergoes but also to determine the synapses affected, thereby constraining the plasticity spatially to those synapses active within the requisite time window.”
Berg, DK.(https://www.ncbi.nlm.nih.gov/pubmed/21745634) 2011. Timing is everything, even for cholinergic control. Neuron 71(1):6-8.
Gu Z, Yakel JL.(https://www.ncbi.nlm.nih.gov/pubmed/21745645) 2011. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71(1):155-165. Story(https://factor.niehs.nih.gov/2011/august/science-investigators/index.cfm)
Impacting the scientific community as well as the local African community
One of Tishkoff's main goals is to ensure that her research is carried out in the most ethical manner possible. All of her studies must undergo institutional review board approval from the university, followed by an ethical review by each country where she is working, and then finally she obtains community and then individual consent from each of the participants in any of her studies. Tishkoff is also dedicated to training and capacity building in Africa in an effort to enable the native population to carry on future research on their own.
Along with fellow NIEHS grantee Leona Samson, Ph.D., Tishkoff is a recipient of the 2009 NIEHS Pioneer Award(https://commonfund.nih.gov/pioneer/Recipients09.aspx) . The Pioneer Award provides $500,000 in funding each year for five years, in support of investigators of exceptional creativity who propose bold and highly innovative new research approaches that have the potential to produce a major impact on broad, important problems in biomedical and behavioral research. One of Tishkoff's recent publications was the result of a ten-year collaboration with African, American, and European researchers.
Citation: Tishkoff SA, Reed FA, Friedlaender FR, Ehret C, Ranciaro A, Froment A, Hirbo JB, Awomoyi AA, Bodo JM, Doumbo O, Ibrahim M, Juma AT, Kotze MJ, Lema G, Moore JH, Mortensen H, Nyambo TB, Omar SA, Powell K, Pretorius GS, Smith MW, Thera MA, Wambebe C, Weber JL, Williams SM.(https://www.ncbi.nlm.nih.gov/pubmed/19407144) 2009. The genetic structure and history of Africans and African Americans. Science 324(5930):1035-1044.