Designing the Future of Medicine

by Deirdre Schwiesow

Viruses such as influenza and chicken pox have existed throughout human history, but their ability to wreak devastation on a large scale is a relatively recent phenomenon.

David Baker, Ph.D., and Michelle Scalley-Kim, Ph.D. ’03, are colleagues and co-adventurers in the promising new world of protein design. All photos: Clare McLean.

“With the invention of agriculture 10,000 years ago, transmission of diseases from domesticated animals to humans became more common,” explains Trisha Davis, Ph.D., UW professor and acting chair of the Department of Biochemistry. And increased population density meant that diseases could be communicated easily across broad populations, before humans developed resistance.

Baker, Scalley-Kim and their colleagues at the UW Institute for Protein Design recently moved into new, high-tech space on campus.

While millennia have passed, the basic problem of disease hasn’t changed: it still takes time to develop resistance. And time, points out Davis, is at a premium in a world that grows ever more crowded.

“Viruses are emerging — like SARS — that we don’t have resistance to,” says Davis. “They could have a devastating effect, unless we find ways to develop therapeutics quickly, in months rather than years.”

The answer to developing a quick fix for a virus? (Or the answers to a whole host of other medical issues?) It might be found in proteins.

Proteins, which fulfill the instructions of DNA, are the workhorses of all biological processes. Diseases result from protein malfunctions. Therefore, figured David Baker, Ph.D., UW professor in the Department of Biochemistry and a Howard Hughes Medical Institute Investigator, adapting or designing proteins could be the key to preventing and curing disease.

This idea has led to the creation of the University of Washington’s Institute for Protein Design (IPD) — a new endeavor with the potential to revolutionize medicine and other fields.

Solving 21st-century problems, like flu

“Simply looking at the range of things that proteins do in living systems gives you a hint of what proteins could do if you designed them to order,” says Baker, a pioneer of protein design and the IPD’s director. “So the prospect of being able to design new proteins to solve 21st-century health problems is very exciting.”

“A lot of strides have been made lately in this new field,” says Michelle Scalley-Kim, Ph.D. ’03, director of research and strategy for the IPD. “These are built on an understanding of how a protein folds into its unique structure — whether it’s catalyzing a reaction or communicating between cells.” Much of that understanding has come from Baker’s work with a computer program called Rosetta, which analyzes proteins’ structures based on their amino acid sequences. (Read more about Rosetta.)

One of the premises behind the medical use of designed proteins, says Davis, is that bigger is better. When researchers design drugs to combat disease, they are designing molecular structures that bind with the body’s proteins. When it comes to therapeutics, proteins have an advantage over small molecules — proteins are bigger, have more sites where they can bind with malfunctioning proteins, and contain more information than small molecules — which gives them tremendous potential.

“There’s a tremendous possibility to do good and help humankind.”— Trisha Davis, Ph.D.

“Big pharma has invested a lot of money into small-molecule discovery — things like aspirin,” Scalley-Kim explains. “But small molecules are not very specific, so you can’t treat all the disease you want to treat. We want to design synthetic proteins that have exquisite specificity and are cheaper to produce.”

The Institute for Protein Design already has made a significant step forward: the development of a novel protein that binds to the flu virus and blocks it from infecting cells. This protein has been licensed by a large pharmaceutical company for translation into a therapeutic to treat flu infections. Davis calls this work “stunning,” saying, “they’ve basically developed the proof of principle” for the use of protein design for therapeutics.

“The field of protein design is so new that industry views making therapeutics based on protein design as too risky,” Scalley-Kim explains. “So creating the institute is really critical to moving this industry forward. Protein design just needs this push to make a big difference.”

How do proteins work against the flu? Binding!

Visual courtesy of the UW Institute for Protein Design

Medicine, the environment, and more

The IPD recently received federal funding in the form of a three-year grant from the Defense Threat Reduction Agency. In collaboration with researchers from UW’s Applied Physics Lab, IPD investigators will work to shorten the timeframe for developing proteins, similar to the fluinhibitors, as countermeasures to bio-warfare infections. It can take years to move therapeutics through development and FDA approval; increasing the speed of the process could be critical to effective bio-defense.

“Looking at the range of things that proteins do in living systems gives you a hint of what proteins could do if you designed them to order.”— David Baker, Ph.D.

Baker’s group is also exploring protein design for disease diagnostics. Currently, diseases are diagnosed using antibodies designed to respond to specific viruses and biomarkers in the body; because designed proteins are more stable and cheaper to produce than antibodies, they could be ideal for use in developing countries.

“Our Department of Biochemistry has been an international leader in research related to proteins for more than 50 years,” says Paul G. Ramsey, M.D., CEO of UW Medicine. “With David Baker’s groundbreaking research, the IPD will be able to build on long-standing UW leadership to design approaches for diagnoses and therapeutics that will be much faster and substantially more cost-effective. The IPD will make a tremendous contribution to our mission of improving health.”

In addition to its use for therapeutics and vaccines — several of which are in the works at the labs of Baker and his collaborators — protein design has exciting applications in other areas, such as detecting and breaking down toxic compounds in the environment, creating new forms of fuel, producing new types of polymers that could replace materials like silk or wool, and, possibly, revolutionizing the creation of electronic devices.

Many experts, many resources

Like other areas of research at UW Medicine, protein design thrives on collaboration — and on contributions from trainees. Shown: IPD Director David Baker, Ph.D., and post-doc fellow Possu Huang, Ph.D. (below), and graduate student Yu-Ru Lin (above).

Tapping the remarkable potential of protein design requires close collaboration among scientists from many different fields.

“The IPD is a fascinating idea whose time has come,” says Davis. “Having David lead it is really what makes the difference, because of his genius in protein design and his ability to attract the top young researchers in the world to work in this area.”

“Collaboration is definitely key to the success of the institute,” says Scalley-Kim. “All of these [uses for protein design] require collaborators who can follow through with the experimentation that will be necessary to validate our proof of concept.”

Fortunately, Baker is also an adjunct professor in genome sciences, physics, computer science, chemical engineering and bioengineering. Working with researchers from these and other disciplines, as well as with scientists at various organizations around Seattle and beyond, IPD investigators are developing and testing new designs and then partnering with industry to produce therapeutics.

“At some stage, [Seattle] will be a huge breeding ground for small companies who will take these therapeutics to market,” Davis predicts. “The institute has tremendous potential to enhance not only the biochemistry department, but also the local economy.”

This is a prospect that University of Washington President Michael K. Young awaits with a great deal of anticipation.

“The UW has a history of making important discoveries and translating them into business opportunities — in order to take the extraordinary work we do in the laboratory out into the community to improve the lives of real people,” says Young. “Having spent time with David and his colleagues, I have absolutely no doubt they’ll do the same, and I’m very excited about the prospect.”

Helping humankind

To harness the power of protein design, the IPD must develop not just new proteins, but also train and nurture the next generation of protein designers.

Most of the research in Baker’s lab is conducted by graduate students and post-doctoral fellows in advanced training. “They are just here a couple years and then they move on, so there’s no long-term institutional memory other than me,” Baker says. “To bring the vision for the IPD into reality, we need to recruit new faculty members to bring new perspectives to this problem.”

The UW Institute for Protein Design, notes Baker, also needs the infrastructure to sustain the work — including state-of-the-art computing capability.

“No place else is going to do it,” says Davis. “I have no doubt that, with resources, great things for modern medicine will come out of the IPD. There’s a tremendous possibility to do good and help humankind.”

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