Treating disease with cold atmospheric plasmas

Graves with students in the section of his lab where research is conducted on plasma applications for semiconductor etching and thin-film deposition.

David Graves still remembers the first time he saw the Bay Area. “I had just graduated with a B.S. in ChemE,” he recalls. “It was 1978 and the petrochemical industry was booming. I had 13 offers for plant visits, including one with Chevron Research in Richmond. They put me up in the St. Francis Hotel in San Francisco. I fell in love with the Bay Area—it was so beautiful.”

It would take Graves another eight years to make the Bay Area his home, but along with his plasma research, it has become an anchor in a life and career that have been peripatetic both geographically and intellectually.

Graves was born in 1955 in Daytona Beach, FL. His father coowned a restaurant with his stepfather, but later joined the U.S. Air Force. By age seven, Graves was living in Homestead AFB, an hour’s drive southwest of Miami, one of the handful of air force bases he would call home as he was growing up.

Graves started high school in North Bay, Ontario, the location of a joint U.S./Canadian base, but graduated in 1973 from Dysart High School in a western suburb of Phoenix near Luke AFB. He started at the University of Arizona in Tucson as a chemistry major. But he switched his major to chemical engineering as a second-semester junior because he had heard that “ChemE had lots of jobs.” With his newly minted B.S. he began working for Chevron Research in June 1978. “I joined the computer process control group where I was the youngest member of the computer control team,” Graves says. “My first project was at the Chevron Chemical ammonia plant in Fort Madison, Iowa.”

Chevron next assigned him to Pascagoula, MS, where he realized he didn’t want to be a process engineer. In late 1979, Graves called his former professor James White, who had taught him computer process control at the University of Arizona. “He told me he could get me into the spring grad school courses, and he did.” Graves earned his M.S. in ChemE in 1981 for his research on pulverized coal combustion, working with Jost Wendt. He moved on to a ChemE Ph.D. program at the University of Minnesota. There he worked with Klavs Jensen on low-temperature plasmas.

At the time low-temperature plasmas were a new and risky area of research. “I was warned not to study them because their physics and chemistry were so little understood. But plasmas had potential and I was curious about them.” Graves completed his Ph.D. in 1986, was married to his wife Sue, and joined the Berkeley faculty later that year. Their three children were born at Alta Bates Hospital in Berkeley. He says, “The plasmas I study are not the variety found inside stars or fusion reactors. Those are superheated, completely ionized gases. I study low-temperature, partially ionized gases which are also known as cold atmospheric plasmas. Common examples are neon or fluorescent lights and, in the natural world, lightning.”

Ten percent of the world’s adult population have fungal nail infections. Graves and colleagues have demonstrated that cold atmospheric plasma (CAP) can penetrate a nail-like barrier and kill underlying bacteria and fungus within minutes of treatment. While more testing and development to be done, CAP offers the promise of a safe and effective therapy for fungal infections of the nail and perhaps other tissues as well.

Graves adds, “A main area of research for my group has been the fundamentals and applications of low-temperature plasmas to the microelectronics industry. There plasmas are used for etching the silicon wafers used to make computer chips and for thin-film deposition techniques. We typically combine various types of plasma modeling and simulation methods with well-controlled experiments to develop insights into mechanisms governing the processes.”

Silicon Valley has been grateful for Graves’s research, and his group started a long and fruitful relationship with Lam Research, headquartered in Fremont, CA, a leading supplier of wafer fabrication equipment. Lam endowed the Lam Research Distinguished Chair in Semiconductor Processing, a chair held by Graves from 2011–16. After more than 30 years at Berkeley, Graves could be content to wind down his career. Instead, like that young man who lived on many different air force bases while growing up, he is still moving. He is now exploring another expanding area for plasma research, one that has tremendous potential but is also poorly understood.

“Plasma biomedicine started in the mid-1990s with studies of plasma decontamination of surfaces. By the early 2000s, Eva Stoffels and colleagues at the Eindhoven University showed that atmospheric pressure low-temperature plasmas alter mammalian cells without causing necrosis and under some conditions even leading to apoptosis, programmed cell death,” says Graves. “From that starting point the medical applications have grown. I began to hear about plasmas being used in Europe for wound sterilization and wound healing. More research showed that plasmas could shrink tumors.”

There was a whole new area being explored on the biological effects of plasmas. Graves and others suspected it had something to do with the reactive oxygen and nitrogen species (RONS) created when the plasmas reacted with the Earth’s atmosphere.

Says Graves, “We used to think that RONS were just ‘bad guys,’ damaging by-products of cellular metabolism. But now we know they are often ‘good guys’ that play important roles in immune response, tissue repair and cell signaling. I documented this by spending hundreds of hours researching the biology and medical literature for a 2012 review article in the Journal of Physics D.”

Berkeley chemistry professors Judith Klinman, Michael Marletta and Chris Chang have also made fundamental discoveries about RONS—Klinman on how enzymes control the formation of radical oxygen species, Marletta on the role of nitric oxide in immune response, and Chang on the cellular signaling role of hydrogen peroxide.

Although the therapeutic benefits of plasmas may seem farfetched, the possibilities are taken more seriously in Europe and in Asia. This emerging field has several journals, including Clinical Plasma Medicine, published by Elsevier. Graves is now senior editor of a new journal in the field—Transactions on Radiation and Plasma Medical Science, published by IEEE. In Germany, several commercial plasma medical devices, including the kINPen MED, have been approved for clinical use, primarily for wound healing.

Notes Graves, “Plasma is a well-established treatment for wound healing and tissue decontamination. There is also growing evidence that in the treatment of cancer, tumors respond to external applications of RONS in a manner similar to how they respond to interior exposures from radiation and chemotherapies. Recently, we worked with a Bay Area startup to investigate using plasma to treat toenail fungus. The preliminary results look pretty good.”

But Graves cautions, “What has not been shown is that plasmas are consistently better than existing drugs or medical devices, or that they can work synergistically with them. A tremendous amount of research still needs to be done both on exactly which RONS are generated by plasma devices, and on the specific therapeutic benefits of each of them.”

Unfortunately, research funding budgets are shrinking in the United States, so Graves finds himself once again on the move. The French language he begrudgingly studied while attending high school in Canada has come in handy. He has polished his language skills and after several trips to confer with European researchers, he can now give scientific talks in his “near-fluent” French.

“I cut my teeth early in my career doing process control,” Graves concludes. “When I apply that perspective to biology, I’m amazed at how sophisticated the process control mechanisms are even in single cells. “It turns out my new research interest is more complicated than I thought, but I’m far from the first researcher to make that observation. Humans have a tendency to overestimate scientific progress in the short run, but to underestimate it in the long run. Science tends to work that way. I wish I could live 300 years just to see how this all turns out.”