Famous last words in the world of science? “We totally figured that out.”
At least that’s the case with metabolism research, where it seemed that all the important metabolic pathways had been defined and mapped decades ago. The instructions for how living things generate energy from food and oxygen, how they produce building blocks of the body, and how they repair or recycle themselves were all captured in those labyrinthine diagrams found in any biochemistry textbook.
Turns out we spoke too soon.
At a Nov. 22 meeting of the Wisconsin Tech Council (WTC), scientists at the Morgridge Institute for Research described the renaissance taking place in metabolism research, which is revealing newfound connections to disease and entirely new roads to treatment and prevention.
“Metabolism may help address such things as cancer, heart disease, kidney failure and other diseases.”Brad Schwartz
“As we’ve learned more about it, we have come to recognize that virtually any disorder in any system in the body involves a significant change in some metabolic pathway,” says Brad Schwartz, CEO of the Morgridge Institute. “And for most of them, we don’t know if the metabolic changes are the cause, or the effect, or if it’s both.
“Metabolism may help address such things as cancer, heart disease, kidney failure and other diseases,” Schwartz adds. “A number of diseases that we used to think were undruggable may now be treatable once we figure out what needs to be targeted.”
At the University of Wisconsin–Madison alone, a community of more than 500 scientists are studying metabolism in some form, whether it relates to aging, early development, disease or creating biofuels (which is a metabolic transformation). At the Tech Council Innovation Luncheon, two Morgridge scientists described their pursuits that may transform how we study biology and how we treat cancer.
Jason Cantor, Morgridge metabolism investigator and UW–Madison assistant professor of biochemistry, is taking a new approach to another one of those taken-for-granted aspects of science: The cell growth medium.
It turns out that the common media that scientists have used for decades to study cells in a dish — while highly effective at supporting the survival and rapid growth in culture — poorly simulate the nutrient conditions that cells see in the human body. So, Cantor set out to develop a reagent called Human Plasma-Like Medium (HPLM) that more closely mimics nutrient levels in human blood circulation. As a postdoctoral fellow at the Whitehead Institute/MIT, he achieved this by filtering from among the thousands of metabolites that have been detected and quantified in human blood to a final collection of about 75 defined components.
The result was the first systematically designed physiologic growth medium – HPLM – which is now being used in labs all over the world thanks to a commercialization agreement with Thermo Fisher Scientific.
“One aspect that’s received maybe a renewed appreciation over the past 10 years is that the cell environment has a massive impact on how cells behave,” Cantor says. Many studies using HPLM are showing that scientists generate different results by using the more physiologic model than they do in the conventional growth media.
While mice and rats remain critical in vivo (“within the living”) models across different areas of human biology, Cantor argues that in vitro (“in glass”) models still offer several unique advantages in terms of control and flexibility to gaining essential molecular insights into how cell behavior and how their responses to changes in their growth conditions.
“The overarching hypothesis of our lab is that conventional models have likely masked our understanding of key aspects of human cell biology, and by extension, drug sensitivity,” he says. “We can erroneously conclude that we’ve already discovered ‘everything’ of importance in cell biology, but in fact you can only make discoveries based on how you’ve looked for them . So if we now put a completely different lens on things, I think there’s likely a lot that we haven’t even scratched the surface of yet.”
Amani Gillette, a Morgridge postdoctoral researcher in Melissa Skala’s lab, described her work on an imaging technology that may help significantly improve the success rate of immunotherapies for fighting cancer. The lab uses a technology called autofluorescence imaging, which tracks the light given off naturally by cells, to determine metabolic activity without having to perturb the cells in any way. This makes the technology especially beneficial for potential therapies.
Gillette’s focus is improving CAR T Cell therapies, a revolutionary new treatment that is producing great outcomes for some cancer patients but is still in its infancy. CAR T cell therapies involve taking immune cells from patients, growing and optimizing them in a manufacturing process, and putting them back in the patient to super-charge the immune response to cancer.
“There are more than 1,000 CAR T cell therapies currently in clinical development, but there are some challenges,” Gillette says. “As you can imagine, when you take T cells from a patient who’s already sick, they may not be in the best state to start with and are very stressed out.”
Adding to the challenge is the T Cell manufacturing process currently takes multiple weeks — a long time for a sick patient — and still about 50 percent of patients relapse after immunotherapy. “Right now there’s a big need for technologies to better evaluate T cell quality in real time with high sensitivity, minimal sample perturbation, and easy integration into current CAR T cell manufacturing systems,” Gillette says.
Enter SeLight, LLC a company Gillette is leading to help address these challenges. SeLight systems can be used to sort through T cell samples in real time and determine which cells are active and ready to fight cancer, and which are in a quiescent state and unlikely to provide health benefit.
With the help of a machine learning system developed by Morgridge scientist Anthony Gitter, the SeLight technology has a 97 percent predictive accuracy. While early work was done on massive, expensive machines, the SeLight prototype is 20 times less costly and 40 times smaller than a research-grade microscope, allowing it to be integrated into the clinical setting.
“For CAR T manufacturing, it leads to decreased time and cost — which is very important for patients — and it can enable intervention to actually improve the quality of the therapy,” Gillette says.
The Wisconsin Technology Council is the science and technology advisor to the Governor and the Legislature. It is an independent, nonprofit and nonpartisan board with members from tech companies, venture capital firms, higher education, research institutions, government and law. Its Innovation Luncheon is held monthly in Madison.