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A Spirit of Scientific Adventure

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A Spirit of Scientific Adventure

A Spirit of Scientific Adventure

By Catherine Gara

Edited by Vanessa Wasta

April 2018 --Once you’ve won a Nobel Prize, people are apt to refer to you as “Nobel laureate So-and-So” — as if the prize redefines your identity. And maybe it does for some, but for Hamilton “Ham” Smith, the Nobel Prize he won at age 47 didn’t change his interactions with people, and his prize-winning discovery involving one of the first molecular “scissors” — made just a year after joining Johns Hopkins’ faculty—was just the first of many landscape-altering discoveries. Though he now spends his days in a laboratory on the other side of the country, his influence is still keenly felt at Johns Hopkins — and around the world.

The Thrill of an Experiment

“Ham likes nothing better than to think of experiments and go into the lab and do them with his own hands,” says Thomas Kelly, Smith’s first postdoctoral fellow, who later became his boss as director of the Department of Molecular Biology and Genetics (MBG) and who founded the Johns Hopkins Institute for Basic Biomedical Sciences (IBBS).

In a lecture at the school of medicine a few years ago, Smith recounted a telling anecdote: “One day, I came into the lab pretty early on a Saturday morning,” he says, “and there was Dan Nathans, unshaven and haggard looking. I asked him, ‘What’s wrong?!’ And he says, ‘Nothing. I was just up all night doing an experiment.’ I thought, ‘Darn! I wish [my wife] would let me do that!’”

Smith — whose parents thought his first name should be distinctive since his last name wasn’t — says he’s always had an inquiring mind and wanted to know how things work. Born in 1931, he was the second of two boys. His parents were both educators and often entertained the boys with math problems and a chemistry set. Smith also studied piano from the age of 8 and developed a deep appreciation for classical music — after fighting it for several years — when he heard a recording of Beethoven’s Pathétique Sonata.

Biology, as he knew it, was too descriptive for his liking, but his interest in the quantitative sciences deepened in high school thanks to some outstanding teachers. He studied mathematics in college, where he was exposed for the first time to biology topics that really captured his imagination, like neural circuits involved in vision. So, he decided to go to medical school and began at Johns Hopkins in 1952. After graduating and fulfilling his draft duty with the Navy, he went to the Henry Ford Hospital for residency, and there, in the library, he found the topic that has occupied his professional life ever since: DNA.

“I left medicine when I learned about Watson and Crick,” says Smith. “I had to get in on working with DNA.”

testimg Hamilton “Ham” Smith.

Stephen Desiderio, the current director of the IBBS and a former colleague of Smith’s in MBG, says that Smith “has always been committed to the most fundamental questions — questions you could ‘own,’ that you could answer definitely and not just qualitatively describe. That philosophy had an enormous influence on the department. We all tried to apply it to our own areas of study.”

Home at Hopkins

In 1962, Smith began a postdoctoral fellowship in genetics at the University of Michigan under Myron Levine. His research group was trying to figure out how viruses merge their own DNA with their host’s, using a virus called P22 that infects bacteria such as Salmonella, which causes food-borne illnesses. Five years later, Daniel Nathans, a recently hired professor, called Smith and asked him to give a talk at Johns Hopkins about his work.

Smith recalls that as soon as he gave that seminar, he knew he had found a home. The department at the time was a tight-knit group of five faculty members who talked to each other every day and had dinners together every week.

Jeff Corden, who arrived at Johns Hopkins in 1980 and is now a professor of molecular biology and genetics, recalls that Smith drove the conversations at the departmental dinners by asking simple questions that put everyone at ease. Corden says, “Ham used to say, ‘There are no stupid questions, except for the ones you don’t ask.’”

A Game-Changing Discovery

When Smith started his lab, he decided to study genetic recombination, which occurs when two different segments of DNA, usually on different chromosomes, swap places. Some bacteria, like the Haemophilus influenzae Smith chose to study, can take in pieces of DNA from other species, which sometimes confer advantages such as drug resistance.

Smith asked his new graduate student, Kent Wilcox, to mix Haemophilus bacteria with radioactively labeled DNA from the P22 virus. The P22 DNA disappeared and Wilcox immediately thought of a departmental presentation Smith had given the week before that might explain the “missing” virus. Smith had described how DNA could be chopped up by self-defense enzymes within the bacteria. Scientists at Harvard University called this self-defense mechanism “restriction enzymes.”

Smith was skeptical of Wilcox’s explanation at first, but he still thought about the idea and came up with a simple way to test it.

The next morning, May 28, 1968, Smith and Wilcox did the experiment. Jeremy Nathans, an MBG professor whose father, Daniel Nathans, shared the Nobel Prize with Smith and Swiss scientist Werner Arber, explains it this way: “DNA molecules are a bit like spaghetti. The longer they are, the more they impede the flow of the liquid in which they are dissolved.  You can measure the approximate length of DNA by putting it in a solution in a thin, open-ended tube and measuring how fast the drips come out of the tube. Ham figured that if there was a restriction enzyme in the Haemophilus bacteria, it would cut the P22 DNA and decrease the viscosity of the solution.” 

They prepared two solutions, both containing cellular contents from Haemophilus. To one they added Haemophilus DNA, to the other, P22 DNA. And sure enough, the solution with P22 DNA ran faster.

testimg Daniel Nathans (L) and Ham Smith (R).

Smith says there was luck involved — a paper he had just read, Wilcox’s mysterious result — but to this, Nathans responds with a quote from Louis Pasteur, who said, “Luck favors the prepared mind.” In Smith’s honor, Nathans in 2015 created the Hamilton Smith Award for Innovative Research, which is given annually to an early career faculty member in the IBBS. “Ham embodied a spirit of adventure in science that is increasingly rare,” says Nathans. “We want to encourage that spirit.”

Scientific Reverberations

Now restriction enzymes are a staple in the fields of genetics and molecular biology, thanks in large part to the insights of Daniel Nathans, who was on sabbatical in Israel at the time of Smith and Wilcox’s discovery but heard about it from Smith. Nathans thought the enzyme could be used to cut viral DNA into specific fragments that could be pieced together in a map showing which genes corresponded to which viral traits. Smith gave him some of the enzyme, and it worked.

Since then, more than 3,600 restriction enzymes have been discovered. Together, they cut at more than 250 specific DNA sequences, allowing scientists to clip DNA at precise points for analysis and further experiments. They have been used to “trick” bacteria into making insulin for people with diabetes by cutting open bacterial DNA to make room for the insulin gene. They are used to diagnose certain genetic diseases, such as sickle cell anemia, and to identify close relatives — and criminals—through “DNA fingerprinting.” They have even been used to exonerate the innocent.

Some 50 years have passed, and the discovery of restriction enzymes that were described by the Nobel Committee as “chemical knives” still has a major impact on the field of molecular biology.

“It’s hard to imagine a world without restriction enzymes,” says Geraldine Seydoux, vice dean for basic research at the Johns Hopkins University School of Medicine.

“Restriction enzymes ushered in the recombinant DNA technology era,” says Srinivasan Chandrasegaran, describing the field of combining genetic material from more than one source. A Bloomberg School of Public Health professor and U.S. Fulbright Scholar at the Indian Institute of Science, Chandrasegaran created zinc finger nucleases in 1996, the first among designer or programmable enzymes that cut DNA.

These and other discoveries, says Chandrasegaran, “ushered in the era of genome editing.” New to the scene of such DNA manipulation is the highly publicized gene cutting tool known as CRISPR.

“CRISPR has democratized genome editing by making it cheaper, easier and simpler,” says Chandrasegaran.

Yet, Seydoux says, scientific laboratories will continue to use restriction enzymes, as well as modern tools such as CRISPR. The difference between the two is that restriction enzymes are used to manipulate DNA that has been removed from cells, and CRISPR facilitates the modification of DNA inside living cells.

“When we use CRISPR to manipulate DNA in animals, we also use restriction enzymes as a quick way to see if our editing was successful,” says Seydoux, who recently published efficiency rules for CRISPR editing.

Not the End of the Story

Smith went on to learn computer coding and use his mathematics training to figure out the first full DNA sequence of a living organism, Haemophilus influenzae, with help from J. Craig Venter at the Institute for Genomic Research. In 1998, Smith left Johns Hopkins and academia and joined Venter at the company Celera Genomics, where he played a key role in developing some of the methods used to sequence the first draft of the human genome and other model organisms, including the fruit fly, mouse and rat.

Smith, 86, still works with Venter at the J. Craig Venter Institute in San Diego, California. In March 2016 they published another seminal paper: They synthesized from scratch the most basic set of genes (438, it turned out) needed to sustain a single-celled organism. “Those genes are all the bacterium needs to continuously grow and divide in the lab,” says Smith. “Now we want to know what every one of those genes does in the cell.”

Those who know him aren’t surprised by Smith’s latest success. “He has always been ambitious in his scientific pursuits but unassuming in person,” Kelly says. Maybe most telling is an anecdote from the day he won the Nobel Prize. He went to Kelly’s office to hide for a few minutes from all of the reporters and TV cameras — and to call his mom … to tell her he hadn’t been wasting his time all those years.