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Dennis Ko, MD, PhD[/caption]
[dropcap]W[/dropcap]hat makes one person more likely than another to get an infectious disease? That’s a question Dennis Ko, MD, PhD, would like to answer in his new role at Duke, where he is studying the genetic basis for differences in susceptibility to infection and inflammatory disorders.
Dr. Ko, who started at Duke in September, is a faculty recruit through the School of Medicine’s Partnership Hires Recruiting Initiative, a program that encourages strategic interdisciplinary recruitment of the very highest caliber faculty members. Ko is an assistant professor in the Division of Infectious Diseases, the Duke Center for Human Genome Variation and the Department of Molecular Genetics and Microbiology.
“Over the last two years, we’ve had four exciting partnership hires – with the Department of Molecular Genetics and Microbiology, the Sarah W. Stedman Nutrition & Metabolism Center, and the Institute of Genome Sciences and Policy – where we’ve gotten together to find the very best talent,” said Mary E. Klotman, MD, chair of the Department of Medicine. “I think this initiative is providing the Department of Medicine with faculty who have diverse backgrounds and skill sets to share with our trainees and presents exciting opportunities for our faculty to start putting together large multi-investigator projects.”
Ko is well positioned for collaboration, a fact that drew him to Duke. His laboratory, located in the Carl building, uses a cellular screening approach called high-throughput human in vitro susceptibility testing (Hi-HOST) that Ko developed as a post-doctoral scholar at the University of Washington in Seattle, where he worked for six years.
Using cell lines from hundreds of different people, Ko infects the cells with the same strain of bacteria at exactly the same amounts and then identifies variation in cellular traits.
“There is less environmental variation going on there,” Ko said. “If someone was doing a genome-wide association study of infectious disease susceptibility in people, you’d worry, ‘Is this strain actually the same as that strain? Are people here in this part of the city getting exposed the same as this other part?’”
Dennis Ko, right, and research scholar Raul Salinas, PhD, look at spleens from mice infected with Salmonella that have been stained for cell death.[/caption]
Dennis Ko, MD, PhD[/caption]
[dropcap]W[/dropcap]hat makes one person more likely than another to get an infectious disease? That’s a question Dennis Ko, MD, PhD, would like to answer in his new role at Duke, where he is studying the genetic basis for differences in susceptibility to infection and inflammatory disorders.
Dr. Ko, who started at Duke in September, is a faculty recruit through the School of Medicine’s Partnership Hires Recruiting Initiative, a program that encourages strategic interdisciplinary recruitment of the very highest caliber faculty members. Ko is an assistant professor in the Division of Infectious Diseases, the Duke Center for Human Genome Variation and the Department of Molecular Genetics and Microbiology.
“Over the last two years, we’ve had four exciting partnership hires – with the Department of Molecular Genetics and Microbiology, the Sarah W. Stedman Nutrition & Metabolism Center, and the Institute of Genome Sciences and Policy – where we’ve gotten together to find the very best talent,” said Mary E. Klotman, MD, chair of the Department of Medicine. “I think this initiative is providing the Department of Medicine with faculty who have diverse backgrounds and skill sets to share with our trainees and presents exciting opportunities for our faculty to start putting together large multi-investigator projects.”
Ko is well positioned for collaboration, a fact that drew him to Duke. His laboratory, located in the Carl building, uses a cellular screening approach called high-throughput human in vitro susceptibility testing (Hi-HOST) that Ko developed as a post-doctoral scholar at the University of Washington in Seattle, where he worked for six years.
Using cell lines from hundreds of different people, Ko infects the cells with the same strain of bacteria at exactly the same amounts and then identifies variation in cellular traits.
“There is less environmental variation going on there,” Ko said. “If someone was doing a genome-wide association study of infectious disease susceptibility in people, you’d worry, ‘Is this strain actually the same as that strain? Are people here in this part of the city getting exposed the same as this other part?’”
From cells to patients
With the Hi-HOST model, Ko can measure and study naturally occurring variation in cellular traits and then conduct experiments to determine if the identified genetic variants are actually affecting critical functions in the cell. Working primarily with Salmonella, Ko infects cells with Salmonella to induce a proinflamatory form of cell death called pyrotosis, a pathway that is also implicated in many autoimmune diseases. “The idea is that we can study this in the controlled laboratory setting, identify this important genetic variation and then take it a step further,” he said. “We do lots of experiments to show whether the effects of each genetic variant are actually real and not just a correlation - can we alter the expression experimentally and get the same sort of effects? Can we figure out the mechanism of action?” Ko then looks for collaborators who have relevant patient populations to relate data to. For example, a researcher in Vietnam collected DNA samples from healthy controls and patients with Salmonella typhi infection, or Typhoid fever, and Ko gave her a list of genetic variants that are now being genotyped in the patient samples. “She’s now genotyping in the patients and controls to see whether, for example, a variant that makes cells less likely to be invaded by Salmonella actually has an effect in people,” Ko said. “Our hypothesis is that in people with that same variant, the bacteria may be less likely to invade the cells in their gut to cause Typhoid fever.” Applying his work to other pathogens has led Ko to collaborations with researchers at Duke. Ko is working with Raphael Valdivia, PhD, associate professor of molecular genetics and microbiology, and his post-doctoral scholar Jeffery Barker, who are interested in responses to Chlamydia trachomatis. “The ultimate goal would be that we will identify human genetic variants that affect Chlamydia infection in these cells in vitro and that will be informative in terms of what affects Chlamydia susceptibility in people,” Ko said. Ko says he is excited to form these collaborations and to find other pathogens – viruses, bacteria, fungi – that he can apply to the same system. “Each of those things will be interesting in and of itself, but then combining that whole metadata set of all these different pathogens, I think, is going to reveal shared biology between these different pathogens that we didn’t know before,” he said.Cellular clues to disease
There are two questions Ko asks of potential collaborators. To basic science researchers: “Are there particular cellular phenotypes that you think are important for disease, for example, if you have a cellular phenotype that you think is somehow correlated with disease x and it’s easily scaled up, we can do this same sort of screening approach,” he said. To clinicians: “What do you think are the most pressing needs in the diseases you study, and are their cellular markers of that disease that would be useful if we understood the underlying genetic variation?” Ko has received additional institutional support with a Whitehead Scholar Award, a fund established at Duke by the Whitehead Charitable Foundation and Edwin C. Whitehead to support new assistant professors who show exceptional potential in basic biomedical research. “Dennis’ accomplishments demonstrate that he a young investigator who brings distinction to the receipt of the Whitehead,” said Joseph Heitman, MD, PhD, James B. Duke professor and chair of the Department of Molecular Genetics and Microbiology. “He is committed to research and making discoveries that advance human health and our ability to contravene disease and is someone who recognizes new developments and their impact on the direction of research, adjusting his focus to capitalize upon these opportunities.”Biology and medicine
Ko credits his interest in finding links between cell biology and medicine to his training. He earned a bachelor’s degree in biochemistry at Cornell and completed a MD and PhD at Stanford in 2005. “I’m always thinking of the medical relevancy of what I’m doing. I do basic science studies to figure out how these genetic variants affect infection. To me a big part of that is asking does this actually matter for patients out there who might be infected with the same bug?” But Ko’s interest in his research developed much earlier in his career. He credits a moment in his high school biology class for inspiring his career in research. “One of the things that got me really excited was when I first learned in my high school biology class that people with the Sickle cell allele had protection against malaria,” he said. “I thought that was the coolest thing. So basically what I’m trying to do is identify more genes and genetic variants that are like that. I feel really blessed that somehow I am able to work on what I’ve always wanted to work on even though back in high school I had no idea how I’d do it.” Ko, a native of Fremont, Calif., moved to Durham from Washington with his wife Emily Ray Ko, MD, PhD, who works at Durham Regional Hospital, and their 3-year-old daughter, Olivia. For more information about Ko’s research and publications, visit http://mgm.duke.edu/faculty/ko/index.htm. [caption id="attachment_9529" align="aligncenter" width="1024"]
Dennis Ko, right, and research scholar Raul Salinas, PhD, look at spleens from mice infected with Salmonella that have been stained for cell death.[/caption]