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Hamilton O. Smith (Figure 1), together with Werner Arber and
Daniel Nathans, is the recipient of the 1978 Nobel Prize in
Physiology or Medicine for the discovery of restriction enzymes
and their application to molecular genetics.
Early Life
Born on August 23, 1931 on New York City, NY,
USA to school teachers originally from Panama City,
Florida, Smith spend his early childhood commuting
between the two states until his family moved to
Champaign-Urbana, Illinois in 1937. His father joined the
faculty of the Department of Education at the University
of Illinois and worked there until his retirement. Smith
grew up in this small academic community where
intellectualism was maintained. Smith and his brother
received private French and music lessons during their preteen years. As a young boy, his interests include football,
basketball, music, chemistry, electricity, and electronics.

Figure 1. Hamilton O. Smith

Background and Education

Smith attended University High School, a small college preparatory school for exceptional
students. Within three years, he was able to finish high school and was admitted at the University of
Illinois in which he majored in Mathematics. In his sophomore year, he came across a book on
mathematical modeling of the central nervous system circuits. This sparked his interest in the medical
field in which he pursued by taking up courses in cell physiology, biochemistry, and biology in the
University of California at Berkeley. Finally, he began his studies at the Johns Hopkins University
Medical School in Baltimore, Maryland in 1952. He received his M. D. degree in 1956 and continued a
conventional medical career. He interned at Barnes Hospital in St. Louis where he met Elizabeth Anne
Bolton, a young nursing student, who later became his wife. In 1957, he took a break from his medical
career and received a two year assignment as a Navy officer in San Diego, California to fulfill his
service obligation. In his free time, he began reading on researches and found one about human
chromosomal abnormalities which caught his interest. His newfound interest led him to his area of
research, the field of genetics. With a postdoctoral fellowship, he began his research career with Myron
Levine in the Department of Human Genetics at the University of Michigan in 1962. Smith and Levine
studied Salmonella Phage P22 lysogeny and discovered the gene controlling prophage attachment, int
gene. Later, Smith learned about Werner Arbers work on restriction and modification phenomenon in
bacteria. After working with Levine, Smith returned to Johns Hopkins as an Assistant Professor of
Microbiology. He continued his research, this time, about restriction and modification enzymes,
enzymology of genetic recombination, mechanism of bacterial transformation, and genetic regulation in
prokaryotes and eukaryotes.
Work on Restriction Enzymes
Smith verified Arbers hypothesis on the existence of restriction enzymes, a special class of
DNA-cutting enzymes found in many bacteria. A type of restriction enzyme can recognize, cut or digests
only one particular sequence of nucleotide bases in DNA. Figure 2 shows some restriction enzymes and

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their restriction sites. Restriction enzymes that cut both DNA strands on the same place create blunt ends
while those that do not, create staggered or sticky ends. Restriction enzymes can be used as tools to (1)
determine the order of genes on chromosomes, (2) to analyze the chemical structure of genes and, (3)
recombine genes chemically. Through these enzymes, the function of a specific DNA fragment can be
analyzed, exploring the connection of hereditary and function. Restriction enzymes also paved way for
the emergence of recombinant technology which can offer new and exciting medical and research
applications.
Observations of restriction
enzymes started as early as 1950s
when bacteriophage grown on two
different strains of bacteria showed
different behavior: phage on one
strain were found to have a
restricted growth while other phage
did not exhibit this restriction.
Arber and his colleagues showed
that the host-specific modification
was carried on the phage DNA.
This led him to postulate the
existence
of
site-specific
Figure 2. Action of Restriction Enzymes
restriction enzymes and the
modification might be produced by DNA methylases. Smith and a young graduate student, Kent Wilcox,
were able to verify Arbers postulate by isolating a restriction enzyme in Haemophilus influenza Rd,
HindII. Smith and Wilcoxs experiment made use of DNA from a bacterial virus, phage P22. Surprisingly,
they couldnt retrieve the foreign DNA from the cells. The duo speculated that it might be restricted. To
verify this, the endonucleolytic cleavage of the DNA by cell extracts was measured using a viscometer.
Two viscometers were set up: one contained P22 DNA and the other, Haemophilus DNA. A cell extract
was added to each viscometer and measurements were taken. The viscosity of the Haemophilus DNA was
constant, while that of the P22 DNA decreased. This proved the existence of the restriction enzyme. They
began to focus their work on the isolation and study of the new enzyme. After successfully isolating the
enzyme, they used sucrose gradient centrifugation to show that the enzyme selectively degraded P22
DNA to fragments while Haemophilus DNA was not. The site-specific cleavage action of the enzyme was
demonstrated by sequencing the termini of the cleavage fragments. Furthermore, Smith also confirmed
the role of DNA methylases as a modification system, as hypothesized by Arber.
Other Works
In 1995, Smith, together with his team at The Institute of Genomic Research, sequenced the first
bacterial genome of Haemophilus influenza. He also joined Celera Genomics Corporation in the
sequencing of Drosophila and human genomes in 1998. In 2002, he joined J. Craig Venter Institute where
he is currently leading the synthetic biology and biological energy groups.
References
Smith, H. O. (2014). Hamilton O. Smith - Biographical. Retrieved January 25, 2017, from
https://www.nobelprize.org/nobel_prizes/medicine/laureates/1978/smith-bio.html
Smith, H. O. (1992). Nucleotide Sequence Specificity of Restriction Endonucleases. In Nobel Lecture
(Physiology or Medicine 1971-1980, pp. 523-541). Singapore: World Scientific Publishing Co.
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Tortora, G. J., Funke, B. R., & Case, C. L. (2010). Microbiology: An Introduction. San Francisco, CA:
Pearson Benjamin Cummings.

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