Hopkins Medicine Magazine - go home
Current Issue Past Issues Talk to Us About the Magazine Search
an online version of the magazine Fall 2008
Where Are They Now?

After the Prize

In Texas, Stobo tried on a new hat—medical school president—and loved it.
> Smith’s advice: “Stay active as long as you’re alive.”

Frustrated by the NIH’s increasing bureaucracy, Nobel laureate Hamilton Smith left Hopkins to become a for-profit researcher. But the old days were best, he says.


If there is such a thing as a scientific mold, Hamilton O. Smith broke it. In 1968, Smith, was an assistant professor at Johns Hopkins when he discovered restriction enzymes, a tool so pivotal to the study of human genetics that it opened new avenues for understanding disease. Swiftly on the heels of that discovery—rather than decades later as is usually the case—Smith shared in the 1978 Nobel Prize in Medicine. He then demonstrated that there’s life for a laboratory researcher beyond the prize. There’s life even after NIH money dries up. And there’s also life after academia. That is, if you’re brilliant, lucky, and willing to take a risk.

Today, at age 77, Ham Smith is still breaking the mold, still taking risks. Living in San Diego and co-directing two laboratories—one in Rockville, Md., one in San Diego—in collaboration with entrepreneur-geneticist J. Craig Venter, he is leading the search for the “trillion dollar organism,” the cell that will mean synthetic, renewable biofuel.

Still, despite considerable financial and scientific success in the for-profit world, Smith calls “the old days at

Johns Hopkins,” where he was on the full-time faculty in the Department of Microbiology from 1967 to 1997, “the best years” of his life. “To be young and making discoveries, you can’t beat that,” says the 1956 graduate of the School of Medicine. “Today is second best. I’m coasting on what I know.”

It was frustration that finally pushed Smith out of Hopkins and into Venter’s nexus. The NIH’s increasing bureaucracy, as well as its unwillingness to fund out-of-the-box ideas, eventually just got to Smith, by then a full professor of molecular biology and genetics. “I didn’t like to spend time writing grants. I found it a chore,” he admits, particularly when the funding didn’t come through.

Academic research has changed, Smith makes clear. At the beginning of his career, there was a lot of money flowing into research, and “I’d just write a draft and send it down.” By the early ’90s, with the NIH rejecting his grant applications, the Nobel laureate was forced to borrow equipment and material from colleagues “down the hall” for his studies of Haemophilus influenzae, an infection-causing bacteria that had been key to his discovery of restriction enzymes. When a colleague suggested they sequence Haemophilus, he recalls, “I told him no academic lab could sequence a genome.” The resources just weren’t there. 

It was at that point that Smith met Venter, then considered the bad boy of science because of his zeal for privatizing genomic research and trying to profit from it. “I was mildly depressed,” Smith remembers. “My research didn’t seem as exciting, and I was worried about funding. When I teamed with Craig, I felt I was working on something exciting again.” They were sequencing H. influenzae.

In his autobiography, Venter credits Smith with suggesting that project. And Smith almost chortles when he remembers how the NIH turned down as “not feasible” Venter’s application for a grant to sequence H. influenzae using the technique known as whole genome shotgun sequencing and assembly.

“We knew we could do it,” Smith says. “We’d already started. And a few months later we published our results!” That breakthrough marked the first sequence of a cellular—not viral—genome.

Since then, the various Venter labs, with Smith as a lead player, have gone on to conquer one genomic challenge after the next. Articles trumpeting each latest accomplishment generally note that it is Hamilton Smith who directed the scientific team. It was Smith, for instance, who constructed all the DNA libraries at Celera for human genome sequencing.

These days Smith is focusing on synthetic genomics. “We can fairly routinely take a sequence and make it synthetically,” he explains. “We recently published the synthesis of an entire bacterial chromosome.  [The January 2008 announcement was a blockbuster.]  Now I’m trying to answer the question of the minimum set of genes necessary to operate a bacterial cell independently. I think it’s about 400 genes for any cell. My goal for the next several years is to create such a cell synthetically.”

Of course, the ultimate goal of Synthetic Genomics, the latest spin-off company from the J. Craig Venter Institute, is to engineer synthetic plant cells to make fuels. Smith, in addition to being the privately-held company’s co-chief scientific officer, is one of its founders, along with Venter and two others.

Was it hard to move from a pure basic science environment to an entrepreneurial one?  “No,” Smith says, “although they have different styles. At Hopkins, if I had an idea, I could just take off and pursue it—if I had my own money. With Craig, I need to stay on a critical path, so in a sense, I’m less independent now. We have large-scale projects that require large teams, and we have the resources to do things you couldn’t in academia. But my years at Hopkins were more creative with more discoveries. The Hopkins model is the best.”

During the heady days when he and the late Dan Nathans (with whom he and Swiss scientist Werner Arber shared the Nobel Prize) first used restriction enzymes, Smith says that neither he nor Nathans even considered patenting. “We were young idealists and didn’t think about profiting from our work. We’d rather be overworked and underpaid. The climate then was that commercialization was a bad thing.”

So strong was that orientation that Smith recalls feeling shocked when one of his post-doctoral fellows proposed a business venture. “This guy was from a business-oriented family.  He came into my office one morning and said he’d like to start a company to sell restriction enzymes. I bawled him out. ‘Why do that,’ I asked, ‘when you can have a career in academic medicine and do research, the ultimate thing you can do?’”  Now, Smith admits, “you’d almost be forced to patent.”

Smith’s move this year to San Diego to set up a branch of the Synthetic Genomics lab was prompted by Venter’s desire to get back to California. But Smith was ready for a warmer climate after falling on the icy driveway of his North Baltimore County farm several years ago and cracking his hip and pelvis. Elizabeth, his wife of more than 50 years, however, preferred to stay on the farm. “So we made a deal. We each live where we want to and spend one week each month together at one place or the other. She’s happy and I’m happy.”

Meanwhile, Smith keeps in touch with his main laboratory in Rockville, Md., via regular teleconferences, directing the research. “Craig protects me from administrative burdens, and I work primarily in the lab. It’s a simple life, and I like it.”

His advice to others: “Stay active as long as you’re alive.” He’s heeding his own counsel: “I’m pretty much financially well off now. That’s a big plus you don’t get in academia, but there’s no slowing down yet. I’m still at my peak. I’m doing exciting things now, even if not worthy of another Nobel.”

And when will that trillion dollar organism leading to synthetic fuel be ready? Ever aware of his entrepreneurial obligations, Smith laughs. “Oh, it’s not something I can talk about publicly. Anything affecting the company is under very tight control.”star


Elaine K. Freeman 

 Get a Life!?
 Washing Out My Distressed Genes
 Guardians of the Heart
 Sleep Interrupted
 Circling the Dome
 Medical Rounds
 Annals of Hopkins
Class Notes
 After the Prize
 Learning Curve
Johns Hopkins Medicine

© The Johns Hopkins University 2008