Frederick Sanger, an outstanding English Biochemist has laid
the foundation for the field of Genomics. The field of science which has opened
a Pandora box and we continue to explore for decades to come. His technique of
protein sequencing has provided the scientists with tools to decode the
sequence of any protein in the body and led to the development of new drugs
like the Human Growth Hormone. Fred Sanger a two times Nobel Prize winner
and Pioneer of DNA sequencing died at the age of 95 in Britain on November 19th.
As of 2013, he is the only person to have received the Nobel Prize two times in
Chemistry. Other scientists who have received two Nobel Prizes are John Berdeen
for Physics (1956 and 1972), Marie Curie (for Physics in 1903 and Chemistry in
1911), Linus Pauling (for Chemistry 1954 and Peace 1962).
Sanger was born on August 13th 1918 in a family of
Quakers in Gloucestershire, England. His father was a medical practitioner.
Both his father and older brother Theodore have been a great influence on young
Sanger for his interest towards biology, science and the scientific method. At
school and all through his initial days of college he was above average but not
outstanding. He wanted to pursue a career in Medicine but then decided against
it as he would see his father visit patient after patient every day. Instead he
thought he would be suited for career where he could concentrate all his
activities and interests on a single goal. During that time Biochemistry was
recently introduced in the Cambridge University and he got interested in it when
he first heard about it through Ernst Baldwin. It was the time of Second World
War but he could obtain an exemption from the military service as a conscientious
objector.
Sanger began his PhD under A. Neuberger 1940 on lysine
metabolism and a more practical problem concerning the nitrogen of Potatoes. He
was awarded the Doctorate Degree in 1943. He started working under A.C.
Chibnall who succeeded F.C. Hopkins, Professor in the Department of
Biochemistry, Cambridge University and started working on proteins, especially
Bovine Insulin. Till 1943 he has to support himself on his own. From the year
1944 till 1951 he received Beit Memorial Fellowship for Medical Research. After
that he became staff member of Medical Research Council. This was most exciting
period for working on Protein Chemistry as several fractionation and
Chromatography techniques were developed. These techniques helped in
determining the fundamental components of living matter. What was known before
he sequenced the composition of the Insulin protein is that proteins are made
up of amino acids.
Sanger’s first triumph came when he sequenced Insulin protein
and revealed that it is made of two polypeptide chains A and B linked by three
disulphide bonds. Till then proteins were considered as amorphous substances. He
used a chemical fluorodinitrobenzene (FDNB) also called Sanger’s Reagent to
determine the composition of the polypeptide chains. Using Sanger’s technique
scientists have sequenced several proteins. This approach of Protein sequencing
has earned him Nobel Prize for Chemistry in 1958. This discovery has been
crucial for the sequence hypothesis proposed by Crick later, which states that
sequences of bases (A, G, T, C) in the genetic material determine the sequence
of amino acids of a particular protein. The Nobel prize has helped him to work
with more enthusiasm and interest as finding funding, facilities and
collaborators became little easy for him.
In 1962, Sanger has moved to Laboratory of Molecular Biology
in Cambridge where he contemplated the possibility of sequencing RNA using
specific nucleases (enzyme which chew nucleic acids). He developed several
methods for sequencing small sequences of RNA. By 1965, Robert Holley of
Cornell University for the first time sequenced the 77 ribonucleotides of Alanine
tRNA in Saccharomyces cerevisiae.
Sanger then took up
the task of sequencing the DNA. Scientists knew that like proteins, DNA is made
up of long chain of nitrogenous bases (Adenine, Guanine, Thymine and Cytosine
or simply ATGC). The order of these bases has to be determined to know the sequence
of the DNA template. In 1975, with Alan Coulson he published the sequence of
DNA using DNA Polymerase using the radiolabelled nucleotides. This technique
was called “Plus and minus” technique. This was an improvement over earlier
methods as it could sequence 80 nucleotides at a single stretch but was very
laborious. Later he came up with a more
fool proof, relatively rapid and stringent method which became popular as Dideoxy
chain termination method or Sanger method for sequencing DNA molecules. In
1977, he decoded the sequence of ΦΧ bacteriophage174 (5375 nucleotides), human
mitochondrial DNA (16,338 nucleotides) and of bacteriophage λ (48,500
nucleotides). This Sanger method of sequencing has increased the efficiency of
sequencing DNA by over thousand times. This discovery has earned him the second
Nobel Prize in Chemistry in 1980, which he shared with Walter Gilbert and Paul
Berg.
Fred Sanger with his colleagues has pioneered the use of thin
gels to provide for resolution of DNA bases and 30 years back he has developed
the first shot gun genome sequence of the bacterial virus lambda. Even now,
scientists around the World use this technique to attack the genome
3,000,000,000 base pairs long. He retired in 1983. He was awarded Order of Merit
by the British Government but declined the honour of Knighthood as he didn’t
want be addressed as “Sir”. He worked in laboratory throughout
his entire career and preferred to do the work on his own instead of assigning it
to juniors which is a common precedent in most of the labs. He has little aptitude
towards administration or teaching.
Sequencing is the only technique which enables us to decode
the genetic information stored in DNA. Since Sanger method is amenable for computer
automation, it has allowed scientists to decipher more complicated genomes. The
contributions made by Sanger are of par excellence- as the sequencing
techniques developed by him have enabled the scientists to determine the
building blocks of proteins and DNA. His research has allowed us to understand
the language of life. In lieu of his contributions towards the science of
genomics, Wellcome Trust has named their institute after him in the year 1993
that specialises in understanding Genomics. His contributions have opened up
the field of Molecular Biology, Genetics and Genomics. The modern day
biological science is dominated by Genomics which has revolutionised the field
of biomedical sciences with its transformative improvements in healthcare. “He
is the one the most important scientists of 20th century. He twice
changed the direction of scientific world” recalled, J. Craig Venter, the
scientist who first sequenced the human genome.
In a review published in Annual Reviews of Biochemistry in
1988 he commented, “Of the three activities involved in scientific research,
thinking, talking and doing I much prefer the last and am probably best at it.
I am right at thinking, but not much good at talking”.
It is my personal tribute to the great Biochemist, whose
sequencing technique has formed the backbone of my thesis work and without which
several of my observations would have been confounded. The thousands of the
gels which I ran day in and day out remind of the veracity of the Nobel Prize
winning discovery.
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