Tuesday, February 06, 2007

Nobel Laureates: Arber, Nathans, and Smith

The Nobel Prize in Physiology or Medicine 1978.

"for the discovery of restriction enzymes and their application to problems of molecular genetics"

Werner Arber, Daniel Nathans, and Hamilton O. Smith received the Nobel Prize in 1978 for working out the mechanism of restriction enzymes (see Restriction, Modification, and Epigenetics).

By the time the Nobel Prize was awarded it was quite clear that the discovery of restriction enzymes was transforming biology and the new era of recombinant DNA technology was upon us. Read what this meant for Hamilton Smith below the fold.

The short history of this remarkable transformation was nicely summarized in the presentation speech by Peter Reichard.
Restriction enzymes are the tools which make it possible to open the sealed book. Werner Arber discovered these enzymes in the early 1960s when he analyzed an apparently obscure phenomenon in bacteria, discovered 10 years earlier by Bertani and Weigle, called host-controlled modification. In a series of simple but elegant experiments Arber showed that this phenomenon was caused by a change in DNA and apparently served to protect the host from foreign genes. Foreign DNA is degraded, and Arber postulated that bacteria contain restriction enzymes with the capacity to recognize and bind to recurring structural elements of DNA. At these locations the DNA-helix is severed: the pages of the book are separated.

Hamilton Smith verified Arber's hypothesis. He purified one restriction enzyme and showed that it could cleave foreign DNA. He determined the chemical structure of the regions of DNA which were severed by the enzyme and discovered certain rules which later could be applied to other restriction enzymes. Today maybe 100 such enzymes are known. They all cleave DNA, each at different, defined regions. With their aid, these giant molecules can be dissected into well-defined segments which subsequently can be used for structural investigations or in genetic experiments.

'The last step in this development was taken by Dan Nathans. He pioneered the application of restriction enzymes in genetics and his work has been a source of inspiration for scientists all over the world. He constructed the first genetic map using restriction enzymes by cleaving the DNA from a monkey virus. The methodology devised by him for this purpose was later used by others to construct increasingly more complicated maps. Today we can write the complete chemical formula for the genes of the monkey virus that Nathans started to investigate.
By the early 1990's the revolution had passed Hamilton Smith by. He lost his funding in 1989 and was relegated to sitting on committees and puttering in the lab on small projects. Then he met Craig Venter.

Venter was about to fund TIGR (The Institute for Genome Research) and he needed a man like Hamilton Smith. Now only did Smith have the magic hands of a brilliant bench scientist, he also had a Nobel Prize. It's not clear which of these was more important to Ventor but the result was astounding.

Smith was responsible for making the libraries that allowed genome sequencing. He was very good at it and that's why TIGR turned out the sequence of Haemophilus influenzae in record time. (H. influenzae was the organism that Smith had worked on all his life. Later on Smith built many more bacteria libraries and in 1998 he made the Drosophila melanogaster (fruit fly) library that really put TIGR on the map and led to the creation of Celera.

Craig Venter and Celara could not have entered the race to sequence the human genome without the technical expertise of Nobel Laureate Hamilton Smith. I recommend The Genome War by James Shreeve. It's a wonderful account of Venter, Celera, and the race to sequence the human genome. Here's an excerpt,
On the morning of July 7, 1998, Hamilton Smith drove down from his farm in Howard County and pulled into the TIGR parking lot. His 1987 Mercury Grand Marquis rumbled along the rows of cherry Corollas and silver Civics like an old tug trying to dock in a marina. The car had a long piece of trim missing on the driver's side, exposing a parallel row of rusted holes, as if the car had been strafed long ago. The odometer read 244,000 miles. The radio was playing—the knob had stuck in the "on" position a couple of months before—and a sucking sound was emanating from somewhere deep in the steering column. Smith didn't mind, because he had his hearing aid turned down low. The Mercury was among his most beloved possessions. He was more ambivalent about his Nobel Prize.

Smith maneuvered the car into a spot, gathered up his briefcase, and quietly made his way through TIGR's elegant lobby. He was on his way to pop in on Craig when the receptionist called out to him, "Something came for you FedEx, Dr. Smith," she said.


  1. I've always liked to use the discovery of restriction / modification systems as a stellar example of why it's not possible to plan for basic scientific advances that will produce societal benefits. At the time it was pretty obscure and recondite stuff- exactly the sort of research topic pinheaded politicians love to make fun of- and nobody could conceivably have predicted the massive technological advances to which it would lead. Sadly, politicians and bureaucrats seem eternally incapable of learning this lesson...

  2. Stebe LaBonne says,

    Sadly, politicians and bureaucrats seem eternally incapable of learning this lesson...

    I couldn't agree more. Even more sadly, many of our colleagues have lost sight of this important fact. And wost of all, most of our colleagues continue to buy into the idea that scientific research must have some societal/technological benefit even if it's only indirect.

    Those of us who are interested in evolution have a tough time convincing fellow scientists that the research is worthwhile.