Interview With a Scientist: Namandjé Bumpus, Drug Metabolism Maven

Medications are designed to treat diseases and make us healthier. But our bodies don’t know that. To them, medications are merely foreign molecules that need to be removed.

Before our bodies can get rid of these drug molecules, enzymes in the liver do the chemical work of preparing the molecules for removal. There are hundreds of different versions of these drug-processing enzymes. Some versions work quickly, others work slowly. In some cases, the versions you have determine how well a medication works for you, and whether you experience side effects from it.

Namandjé Bumpus Exit icon, a researcher at Johns Hopkins University School of Medicine, is interested in how human bodies respond to HIV medications. She studies the enzymes that process these drugs. Her research team discovered that a genetic variant of a liver enzyme impacts the way some people handle a particular HIV drug. This variant is found in around 80 percent of people of European descent. She describes her work in this video.

Bumpus recently presented her research to a more scientifically advanced audience at an Early Career Investigator Lecture at the National Institutes of Health. Watch her talk titled Drug Metabolism, Pharmacogenetics and the Quest to Personalize HIV Treatment and Prevention.

Dr. Bumpus’ work is supported in part by NIGMS grant R01GM103853.

New Streamlined Technique for Processing Biological Samples

Illustration of Slug flow microextraction.
Researchers have discovered a faster, easier and more affordable technique for processing biological samples. Credit: Weldon School of Biomedical Engineering, Purdue University.

It’s not unusual for the standard dose of a drug to work well for one person but be less effective for another. One reason for such differences is that individuals can break down drugs at different rates, leading to different concentrations of drugs and of their breakdown products (metabolites) in the bloodstream. A promising new process Exit icon called slug-flow microextraction could make it faster, easier and more affordable to regularly monitor drug metabolites so that medication dosages could be tailored to each patient’s needs, an approach known as personalized medicine. This technique could also allow researchers to better monitor people’s responses to new drug treatments during clinical trials. Continue reading

Understanding Complex Diseases Through Computation

Scientists developed a computational method that could help identify various subtypes of complex diseases. Credit: Stock image

Complex diseases such as diabetes, cancer and asthma are caused by the intricate interplay of genetic, environmental and lifestyle factors that vary among affected individuals. As a result, the same medications may not work for every patient. Now, scientists have shown that a computational method capable of analyzing more than 100 clinical variables for a large group of people can identify various subtypes of asthma, which could ultimately lead to more targeted and personalized treatments. The research team, led by Wei Wu Exit icon of Carnegie Mellon University and Sally Wenzel of the University of Pittsburgh, used a computational approach developed by Wu to identify several patient clusters consistent with known subtypes of asthma, as well as a possible new subtype of severe asthma that does not respond well to conventional drug treatment. If supported by further studies, the researchers’ proposed approach could help improve the understanding, diagnosis and treatment not just of asthma but of other complex diseases.

This work also was funded by NIH’s National Heart, Lung, and Blood Institute.

Learn more:
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Meet Shanta Dhar

Shanta Dhar
Shanta Dhar
Fields: Chemistry and cancer immunotherapy
Works at: University of Georgia, Athens
Born and raised in: Northern India
Studied at: Indian Institute of Science, Bangalore; Johns Hopkins University, Baltimore, Md.; and Massachusetts Institute of Technology, Cambridge, Mass.
To unwind: She hits the gym
Credit: Frankie Wylie, Stylized Portraiture

The human body is, at its most basic level, a giant collection of chemicals. Finding ways to direct the actions of those chemicals can lead to new treatments for human diseases.

Shanta Dhar, an assistant professor of chemistry at the University of Georgia, Athens (UGA), saw this potential when she was exposed to the field of cancer immunotherapy as a postdoctoral researcher at the Massachusetts Institute of Technology. (Broadly, cancer immunotherapy aims to direct the body’s natural immune response to kill cancer cells.) Dhar was fascinated by the idea and has pursued research in this area ever since. “I always wanted to use my chemistry for something that could be useful [in the clinic] down the line,” she said.

A major challenge in the field has been training the body’s immune system—specifically the T cells—to recognize and attack cancer cells. The process of training T cells to go after cancer is rather like training a rescue dog to find a lost person: First, you present the scent, then you command pursuit.

The type of immune cell chiefly responsible for training T cells to search for and destroy cancer is a called a dendritic cell. First, dendritic cells present T cells with the “scent” of cancer (proteins from a cancer cell). Then they activate the T cells using signaling molecules.

Dhar’s Findings

Dhar’s work focuses on creating the perfect trigger for cancer immunotherapy—one that would provide both the scent of cancer for T cells to recognize and a burst of immune signaling to activate the cells.

Using cells grown in the lab, Dhar’s team recently showed that they could kill most breast cancer cells using a new nanotechnology technique, then train T cells to eradicate the remaining cancer cells.

For the initial attack, the researchers used light-activated nanoparticles that target mitochondria in cancer cells. Mitochondria are the organelles that provide cellular energy. Their destruction sets off a signaling cascade that triggers dendritic cells to produce one of the proteins needed to activate T cells.

Because the strategy worked in laboratory cells, Dhar and her colleague Donald Harn of the UGA infectious diseases department are now testing it in a mouse model of breast cancer to see if it is similarly effective in a living organism.

For some reason, the approach works against breast cancer cells but not against cervical cancer cells. So the team is examining the nanoparticle technique to see if they can make it broadly applicable against other cancer types.

Someday, Dhar hopes to translate this work into a personalized cancer vaccine. To create such a vaccine, scientists would remove cancer cells from a patient’s body during surgery. Next, in a laboratory dish, they would train immune cells from the patient to kill the cancer cells, then inject the trained immune cells back into the patient’s body. If the strategy worked, the trained cells would alert and activate T cells to eliminate the cancer.

Genetic Discovery Could Enable More Precise Prescriptions

Prescription pad with DNA illustration on it. Credit: Jane Ades, NIH’s National Human Genome Research Institute.
New insight into the genes that affect drug responses may help doctors prescribe the medications and doses best suited for each individual. Credit: Jane Ades, NIH’s National Human Genome Research Institute.

Scientists know that variations in certain genes can affect the way a person responds to medications. New research by Wolfgang Sadee Exit icon at Ohio State University shows that drug responses also depend on previously overlooked parts of DNA—sections that regulate genes, but are not considered genes themselves. This study focused on an important enzyme abbreviated CYP2D6 that processes about one-fourth of all prescription drugs. Differences in the enzyme’s performance, which range from zilch to ultra-rapid, can dramatically alter the effectiveness and safety of certain medications. Researchers discovered two new genetic variants that impact CYP2D6 performance. One of these, located in a non-gene, regulatory region of DNA, doubles or even quadruples enzyme activity. Coupling these findings with genetic tests could help doctors better identify each patient’s CYP2D6 activity level, enabling more precise prescriptions. The findings also open up a whole new area of investigation into genetic factors that impact drug response.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Learn more:

Ohio State University News Release (no longer available)
Using Genes to Guide Prescriptions Article from Inside Life Science Series

New Approach Subtypes Cancers by Shared Genetic Effects

Cancer

Cancer tumors are like snowflakes—no two ever share the same genetic mutations. Their unique characteristics make them difficult to categorize and treat. A new approach proposed by Trey Ideker and his team at the University of California, San Diego, might offer a solution. Their approach, called network-based stratification (NBS), identifies cancer subtypes by how different mutations in different cancer patients affect the same biological networks, such as genetic pathways. As proof of principle, they applied the method to ovarian, uterine and lung cancer data to obtain biological and clinical information about mutation profiles. Such cancer subtyping shows promise in helping to develop more effective, personalized treatments.

Learn more:

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