It’s His Metabolism
Jamey Young, assistant professor of chemical and biomolecular engineering, likes to build bridges. But rather than physical structures, Young focuses on spanning the divide between biology and engineering, diabetes and cancer, and plants and animals.
Cell metabolism—especially its rate, known as flux—is the thread that connects his various research interests.
“Can we inhibit the metabolic pathways that cancer cells depend on for fuel and kill them, or at least slow them down?”
“I like to have my hands in different things at the same time,” Young says. “That’s one of the things that keeps work exciting to me, taking ideas from one field and applying them to another. If it’s alive, it depends on metabolism.
“As an engineer, I have certain tools that your typical biologist doesn’t have. That gives me the opportunity to contribute something new with the approaches that we’ve been developing,” he says. “By applying a technique called metabolic flux analysis, we are able to map the rates of many different metabolic pathways inside of cells at the same time. It’s like generating a traffic report on the cell’s metabolism.”
His research was given a boost in 2010 when he received a prestigious five-year National Science Foundation Early Career Development (CAREER) award to explore toxicity caused by excess lipids. This particular area of research could bring potential discoveries for patients with diabetes.
With a focus on identifying disease therapies that target metabolic differences between normal and diseased cells, Young’s work has expanded in several directions that could play a major role in cancer treatments, pharmaceutical production and food supplies. But that’s getting ahead of things a bit.
“We’re working to find new drug targets and treatment strategies, not necessarily the drugs themselves. It takes a lot of work to go from identifying basic disease mechanisms to creating a drug that will target those mechanisms and then testing whether it will be safe to use in people,” he says. “The things we’re studying will contribute fundamental understanding to guide this process.”
Potential to Impact Diseases
While a graduate student in the chemical engineering program at Purdue University, Young focused primarily on bacterial cell metabolism. When he began to pursue postdoctoral studies, he made a conscious decision to expand into biomedical applications.
“Really, when you look at diseases that involve metabolism, diabetes and obesity are the key ones. I knew that my expertise in metabolism could be directly applied to those diseases. But there are plenty of other diseases out there that directly or indirectly involve altered cell metabolism,” he says.
The ability to work closely with leading medical researchers, particularly in the areas of diabetes and cancer, made Vanderbilt appealing when Young sought a faculty position in 2008.
“Vanderbilt has one of the most well-known and well-resourced diabetes centers in the country. The cancer center is also one of the leading centers in the country. I can do things here that I couldn’t do at other places because of the collaborators,” Young notes.
Diabetes and cancer may seem worlds apart, but they involve dysregulation in many of the same metabolic pathways. In diabetes, Young is exploring whether proteins can be inhibited or activated to force the cell metabolism back to a normal state.
“We’re particularly interested in what happens to liver cells when they’re exposed to too much fat. Fatty acids and other lipids circulate in the blood. When a person is obese or diabetic, lipids become elevated and the liver soaks them up like a sponge,” he explains. “We’re interested in how liver cells respond to excess lipids… and how those metabolic changes cause stress and dysfunction to liver cells.”
He says cancer isn’t often considered a metabolic disease, but it does have metabolic drivers. Some genes—oncogenes—are known to have the potential to cause cancer. That leads Young down several tantalizing avenues of possible research. “When some of these genes get mutated or overexpressed, how does that reprogram the metabolism of the cells?” Young asks. “Would some of those metabolic processes be good targets for therapeutics to slow down the growth of the cell? Can we inhibit the metabolic pathways that cancer cells depend on for fuel and kill them, or at least slow them down?”
Plant World Promise in Fuel, Food
Plants also rely on metabolism to grow and Young works with researchers at Vanderbilt and elsewhere to explore ways to better understand that process. Because metabolic flux analysis is typically applied to organisms that grow by converting sugar to carbon dioxide, mapping metabolic fluxes in plants that carry out the reverse process of photosynthesis hasn’t been possible.
Young and others published a paper last year showing how metabolic fluxes in cyanobacteria—bacteria that obtain energy through photosynthesis—could be mapped. The outgrowth is a new research effort that aims to engineer carbon flow in cyanobacteria to produce biofuels.
It may be far-fetched, he says, but could bear fruit. “The issue right now is we have these cells that are producing a valuable product from air and sunlight but at a very small rate and in very small amounts. Can we apply some engineering approaches to figure out how to redirect more carbon into pathways that are producing the biofuels?” Young says. “The end goal for us is in developing strategies and methodologies. We’d like to come up with a tool kit that would enable you to take a photosynthetic organism like this cyanobacterium and figure out how to systematically drive more carbon into desirable pathways. We’re mostly interested not in some particular product but developing techniques for understanding the metabolic pathways of these cells and redirecting them.”
That already has led to another NSF-funded project in which Young serves as a co-principal investigator. He’s helping plant biologists at the Danforth Plant Science Center in St. Louis and Los Alamos National Laboratories discover how to enhance photosynthesis in plants and make them grow faster. The work has applications for both energy and food production.
Doug Allen, a biologist with the U.S. Department of Agriculture’s Agricultural Research Service and researcher at the Donald Danforth Plant Science Center, has worked closely with Young on the project. “The application that we’re working on together recognizes that our existence in this world is based on plants—what we eat . . . what animals eat,” Allen says. “The population of the world is going to increase and plants are going to continue to provide for us, so studying their basic biochemistry is an important and timely topic.” Young’s engineering background brings a diverse view focused on quantification of metabolism. “Being able to quantify metabolism at the cellular level is important to enable rational metabolic engineering,” the biologist says.
Teaming with Industry
Young’s research also shows potential for industrial uses and an NSF-funded GOALI (Grant Opportunities for Academic Liaison with Industry) grant has paired him with researchers at Centocor, a subsidiary of Johnson & Johnson that specializes in manufacturing therapeutic proteins called monoclonal antibodies.
Currently, Chinese hamster ovary (CHO) cells are widely used in pharmaceutical and biotechnology to produce monoclonal antibodies. When not producing the antibodies, CHO cells produce the byproduct lactate. Young is exploring what controls the production of lactate and whether this can be overcome, bypassed or redirected to enhance the growth and productivity of the CHO cells.
Collaborating with industry builds synergy, Young says. “You’re dealing with people who have a lot of experience and really know what problems are important for the industry,” he says. That helps academic researchers identify new problems to work on. “Drug manufacturing companies usually aren’t interested in basic science, but instead in process development that will get the product out the door. They may not have the inclination to do fundamental research, but because of their experience, they know the right questions to ask.”
With so much potential for so many applications, Young must balance opportunities with focus. “Engineers tend to be ambitious,” he says. “We think we can tackle everything. I try to achieve a balance between developing new methodologies that exploit my engineering expertise and applying those approaches to important scientific problems where they can have the greatest impact.”
At the same time, he sees the value of envisioning multiple applications for his metabolic engineering techniques. “As an academic investigator, I can pick and choose to apply our research methodologies to things I’m interested in,” he says.
“It’s very freeing from my perspective.”