Nobel laureate Hamilton Smith, who discovered molecular 'scissors' to cut DNA, dies at 94

Johns Hopkins University School of Medicine alumnus and former faculty member Hamilton O. Smith, whose 1978 Nobel Prize-winning discovery of restriction enzymes revolutionized genetic engineering, died Oct. 25 at his son's home in Ellicott City, Maryland. He was 94.

The discovery of restriction enzymes—molecular "scissors" for cutting DNA—laid the foundation for advances in biotechnology, including genome sequencing and genetic recombination. Smith's co-winners of the Nobel Prize were Daniel Nathans, also a professor at the Johns Hopkins University School of Medicine, who died in 1999, and Swiss researcher Werner Arber.

Image caption: Hamilton O. Smith

"Ham embodied a spirit of adventure in science," says Jeremy Nathans, professor of molecular biology and genetics at Johns Hopkins, who followed his father Daniel Nathans to a career in biomedical research.

Smith graduated from medical school at Johns Hopkins in 1956 and did residency training in internal medicine. He served as a physician in the Navy for two years, and during that time he developed an interest in genetics.

In 1962, Smith began a postdoctoral fellowship in genetics at the University of Michigan. There, he worked with scientist Myron Levine to understand 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.

In 1967, after Daniel Nathans invited Smith to give a presentation at Johns Hopkins about his bacterial DNA research, Smith joined the Johns Hopkins faculty as an assistant professor in the Department of Microbiology—now the Department of Molecular Biology and Genetics.

In his early days at Johns Hopkins, Smith focused on genetic recombination—when different segments of DNA are swapped. Such genetic switching occurs in nature, sometimes producing a survival advantage, such as drug resistance in bacteria.

Smith decided to study the gene-mixing properties of the bacterium Haemophilus influenzae, which he described as an efficient system for integrating molecules into its genome. The bacteria, found in the lining of nasal passages, is linked with respiratory illnesses such as bronchitis and pneumonia.

Smith and graduate student Kent Wilcox made what they described as a "chance discovery": an enzyme from Haemophilus influenzae that could not cut Haemophilus influenzae DNA but could cut viral DNA derived from other bacteria. They correctly surmised that this enzyme—the first type II bacterial restriction enzyme to be discovered and purified—was part of a defense system used by Haemophilus influenzae to destroy the DNA of infecting viruses.

Smith and Thomas Kelly, a postdoctoral fellow at the time, then showed that the new enzyme cut DNA at specific sequences. The discovery of this enzyme, named Hind II, together with its DNA cleavage properties, was described in two research papers published in 1970. Kelly subsequently joined JHU's School of Medicine as a faculty member and later served as director of the Department of Molecular Biology and Genetics.

"Ham was a warm and generous colleague," Kelly says, "and he had a profound influence on the Department of Molecular Biology and Genetics, helping to promote the collegial atmosphere that we all know and enjoy."

Image caption: Daniel Nathans (left) and Hamilton O. Smith

Over the past 50 years, thousands of restriction enzymes have been discovered, enabling scientists to clip DNA at precise points for analysis and further experiments. They have been used to insert the insulin gene into bacteria and make insulin for people with diabetes, and to diagnose genetic diseases, such as sickle cell anemia.

Biomedical researchers have continued to use restriction enzymes, as well as modern DNA cutting tools such as CRISPR. While CRISPR facilitates DNA cutting inside living cells, restriction enzymes manipulate DNA that has been removed from cells—and often to check if CRISPR edits were successful.

In the 1990s, Smith collaborated with J. Craig Venter's group at the Institute for Genomic Research and played a key role in determining the first complete genome sequence of a free-living organism, the bacterium Haemophilus influenza—the same bacterium that had yielded the Hind II restriction enzyme.

After Smith retired from Johns Hopkins in 1998, he joined Venter at Celera Genomics and, later, the J. Craig Venter Institute, working on genome sequencing advances, including major contributions to the sequencing of the human genome. He then transitioned into the new field of synthetic biology and participated in the Venter Institute's design and construction of a minimal synthetic bacterial cell containing only 473 genes.

In Smith's honor, the Johns Hopkins University School of Medicine in 2015 established the Hamilton Smith Award for Innovative Research, given annually to outstanding early-career scientists in the Johns Hopkins Institute for Basic Biomedical Sciences. The award has been given to 13 scientists since its inception.

Smith was preceded in death by his wife, Elizabeth Ann, and his son Barrett James. He is survived by children Joel, Derek, Bryan, and Kirsten, 12 grandchildren, and 15 great-grandchildren.