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Computational Protein Designer Stephen Mayo Works to Create Drugs to Treat Diseases

headshot of Steve Mayo
Stephen Mayo, Ph.D.

If amino acids are the building blocks of proteins – and proteins comprise the foundation of life – biochemist Stephen Mayo, Ph.D., is an architect of sorts, carefully drafting teeny-tiny organic blueprints capable of solving the world’s problems.

Mayo, a 2021 AAAS Fellow, pioneered the field of computational protein design. He leverages software programs with complex equations to design proteins – from the ground up – with many uses, from new therapies for diseases to improved enzymes for converting plant material to biofuel.

Using the same technology, Mayo also applies mathematical modeling to predict a protein’s atomic properties based on its amino acid sequence. Amino acid chains go through a process called “folding” to become 3D, biologically active protein structures capable of performing different functions.

“Once you can reliably design sequences that fold and function the way you want, all bets are off,” says Mayo, the Bren Professor of Biology and Chemistry and Merkin Institute Professor at the California Institute of Technology. “You can do anything you want.”

To manipulate proteins is to harness the force of nature in your own hands – a power Mayo wields to tackle the biggest health crises of modern times. His latest project involves engineering therapeutic antibodies against SARS-CoV-2, the potentially deadly virus that leads to COVID-19. These antibodies, he adds, are used in passive immunization therapy, injected directly into someone who already has the virus or into an uninfected individual to protect against infection. This differs from preventative vaccines and boosters, which train the body to create its own antibodies.

The project is a collaboration with fellow Caltech biochemist Pamela Björkman, Ph.D., and Protabit, a start-up co-founded by Mayo. Their challenge with SARS-CoV-2 is a race against the clock, as the virus quickly evolves into multiple variants.

“We’re trying to engineer these antibodies so that they are less susceptible to mutations in the virus,” Mayo explains.

In an early small study with animals, he adds, the engineered antibodies show promise to fight against both Delta and Omicron variants.

Besides this recent pandemic-related work, Mayo’s lab is committed to creating better treatments for diseases like cancer as well – especially ones that wreak less havoc on healthy parts of the body.

“One of the drawbacks of traditional chemotherapy drugs is that they are not specific enough to kill only cancer cells,” Mayo notes. “They will get into other cells and cause massive side effects.”

For example, some cancer patients lose their hair or experience skin irritation as the chemo drugs attack hair roots and other rapidly growing cells outside of the cancerous area. To solve for this, Mayo’s research focuses on designing a new class of “antibody drug conjugate” – an antibody coupled to a small molecule drug – that simultaneously exploits the unique binding abilities of both molecules. Carefully crafted antibody drug conjugates can be designed to enhance the drug’s ability to bind in a more targeted manner.

“It’s a lot of fun thinking about designing and building interesting and weird molecules and using computational approaches to help you do that,” Mayo says.

Mayo credits this enthusiasm for the intersection of biology, chemistry and technology to his parents, who never stopped nurturing his curiosity. His father, active in the U.S. Air Force during the Korean War, later worked as Director of the U.S. Army Communications Command.

“He was the kind of guy that would buy a kit to build a television or a computer,” Mayo says. “I got exposed to a lot of electronics stuff when I was younger.”

After high school, Mayo attended the Pennsylvania State University, where he worked with professor of chemistry Roy Olofson for three years conducting small molecule organic synthesis and crystallography, a technique that uses X-ray diffraction to study the atomic and molecular structure of material.

“I remember solving the structure of some small molecule,” Mayo says. “It was awesome. I solved it in the middle of the night … I was the first person on the planet to know the structure of that molecule. How awesome is that?”

To visualize molecular structures, Mayo says, people would build physical models – a time-consuming task. In the early 1980s, computer imaging wasn’t as sophisticated as it is today. After taking a graduate-level computer graphics course, Mayo wrote a program that allowed him to input the coordinates of a molecule to produce an on-screen 3D rendering capable of real time movement and manipulation.

The program, called SMURF – Steve Mayo Undergraduate Research Fotos – was the product of his honors thesis. Later iterations of this software became the basis for Molecular Simulations Inc., a company Mayo co-founded while studying for his Ph.D. at Caltech.

Outside of academia, Mayo is an entrepreneur. In 1997, he founded Xencor, a publicly traded antibody engineering company. He’s also active on many boards, having served on President Barack Obama’s National Science Board and the board of AAAS. His latest board appointments to pharmaceutical companies Merck and Sarepta Therapeutics tie-in with his ambition for seeing science pipelined into real world solutions.

“I have a strong desire to make molecules that might benefit the world in one way or another,” he says. “I also have a real passion for helping to promote the translation of basic science for the benefit of society.”

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