Pioneering the Future

Adopting Nature’s Chemistry

High atop mountains and deep in the sea, animals make molecules that help them thrive in their ecological niches. Many of those, it turns out, make good medicines. But when it comes to getting medicines based on natural products to patients, discovering compounds with useful properties is just the beginning. It’s not usually practical to retrieve enough of a natural compound from the organism in which it was first found to enable drug development and testing, so scientists must find a way to scale up production.

To protect themselves against predators, soft corals make a diverse array of chemicals called terpenes. Many of these defensive compounds show promise as potential therapies for cancer or chronic pain. Paul Scesa, PhD, a scuba-diving scientist working in the lab of medicinal chemist Eric Schmidt, PhD, studied a soft coral that makes an anti-inflammatory terpene, pseudopterosin. By analyzing the animal’s genome, as well as the genomes of related corals, Schmidt’s team was able to identify enzymes that are used for pseudopterosin production in nature.

By programing microbes to make the same enzymes, scientists can now bring the production of these compounds into the lab, rather than harvesting them from the ocean’s corals. “My hope is to one day hand these to a doctor,” Scesa says. “I think of it as going from the bottom of the ocean to bench to bedside.” Scesa now leads his own lab and is continuing this research at the University of South Florida.

Schmidt’s team also studies chemicals called polyketides, many of which treat cancers or infections. Most polyketides were found in microbes, but new work reveals a previously hidden world of potential drugs in animals. Working with biochemist Chris Hill, DPhil, vice dean of research for the Spencer Fox Eccles School of Medicine at the University of Utah, research professor Heidi Schubert, PhD, and postdoctoral scientist Feng Li, PhD, captured detailed images of two polyketide-making enzymes from sea slugs. Like a robotic assembly line, the enzymes use an arm to move pieces into place. By understanding those motions, the team defined a key step in molecule building in animals, aiding the discovery and creation of new biotech tools and pharmaceutical leads.

Protecting Fatty Livers

Liver cancer is one of the leading causes of cancer deaths worldwide. In the United States, rising rates of liver cancer have been tied to an increased prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), a condition in which excess fat accumulates in the liver. As obesity, diabetes, and other metabolic disorders become increasingly common, MASLD does too, putting more and more people at risk of progressing to serious liver disease and liver cancer.

Scientists led by Mei Koh, PhD, have identified a protein that appears to protect the liver from the changes that link fat accumulation to cancer development. This protein, called HAF, is present in healthy livers.

But when Koh and her team examined livers with excess fat from humans or mice, they found that HAF was depleted. In experiments with mice, they showed that low levels of HAF put animals at higher risk for fatty livers, which ultimately progressed to liver cancer. Then they worked out why. They learned that HAF acts on a growth-regulating pathway that is notorious for driving cancer progression. In livers where HAF levels are low, deregulation of this pathway spurs cell death and inflammation, which can cause tumors to develop.

For Koh, who founded the biotechnology company Kuda Therapeutics to translate her lab’s findings into cancer therapies, elucidating the changes that drive cancer development is about more than satisfying her scientific curiosity. “My research is focused on identifying novel therapeutic targets to make patients’ lives better,” says Koh, associate professor in the Department of Pharmacology and Toxicology at the College of Pharmacy. “We have identified key pro-oncogenic proteins that are suppressed by the liver-protecting HAF. When HAF is lost, levels of these proteins increase leading to liver disease, suggesting that these proteins could serve as therapeutic targets.”

Her team’s work suggests that manipulating these proteins might be a way to protect vulnerable livers from cancer development or to treat liver cancer after it is diagnosed.

Monitoring Metabolism

The molecules inside our bodies are in constant flux as our cells break down food, produce and store energy, and generate the materials they need to keep us healthy. Amidst all this metabolic activity, one particularly influential molecule is acetyl-CoA. Cells depend on acetyl-CoA to produce structural materials, signaling molecules, and energy. It may also help cells monitor and adjust their own metabolism by regulating gene activity, which is vital for ensuring essential molecules are available when and where they are needed.

Scientists can now get a clear picture of acetyl-CoA inside human cells, thanks to a new sensor developed by Katharine Diehl, PhD, and her team. The sensor glows green under a microscope, lighting up living cells with color that intensifies as acetyl-CoA levels rise and fades when they fall. That gives scientists a way to track acetyl-coA in real time.

Acetyl-CoA is part of so many metabolic pathways, its disruption is known to have wide-ranging consequences for health. “Being able to visualize this molecule will allow us and others to study its many important roles within cells, particularly in diseases like cancer and neurodegeneration,” says Diehl, assistant professor in the Department of Medicinal Chemistry at the U’s College of Pharmacy. Her team also ensured the sensor works well in bacterial cells, meaning scientists can use it to monitor bacteria whose metabolic pathways have been engineered to generate useful products, such as biofuels.