Section 4：Double Helix
Doctor Frederick Sanger. It sometimes happens that an important scientific discovery is made so to say “overnight” – if the time is ripe and the necessary background is there. Yours is not of that kind. The first successful determination of the structure of a protein is the result of many years of persistent and zealous work, in which the final solution of the problem has been approached step by step. You knew when you began to look into the structure of the insulin molecule 15 years ago that the problem was a formidable one.... Without your wholehearted devotion to the task you had set before you, many obstacles on your way would have appeared insurmountable.
The Nobel Prize Award ceremony speech by Professor A. Tiselius in 1958
Arthur Kornberg (1918-2007)
Arthur Kornberg (March 3, 1918 – October 26, 2007) was an American biochemist who won the Nobel Prize in Physiology or Medicine 1959. Kornberg was born in Brooklyn, New York, as the son of parents who had emigrated from Eastern Europe and ran a small hardware store. He majored in chemistry and biology at City College of New York and received an M.D. from the University of Rochester in 1941. After briefly serving as a physician in the US Navy, Kornberg joined in the research institute of National Institutes of Health (NIH) in 1942. In 1953, Kornberg became the chairman of the Department of Microbiology at Washington University, and in 1959 he became the Professor and Executive Head of the Biochemistry Department at the newly established Stanford Medical School.
When at the NIH, Kornberg spent a year with Severo Ochoa (1903-1993) at New York University Medical School and studied with Carl and Gerty Cori (1986-1984, 1896-1957) at Washington University School of Medicine in 1947. That made Kornberg turn to the study of enzymes and start searching for an enzyme that could synthesize the polynucleotide chain. As a biochemist, Kornberg felt that he could reconstitute any cellular event in a test tube and set up a reaction containing DNA, radioactive thymidine (a nucleoside), and protein fractions obtained by breaking open Escherichia coli. Kornberg eventually managed to synthesize DNA in a tube and found an enzyme, DNA polymerase. However, when Kornberg reported his results to The Journal of Biological Chemistry in 1957, the reviewers rejected him and refused to acknowledge the product as DNA. In the spring of 1958, a new editor stepped in and accepted the papers. And in 1959, Kornberg’s discovery, together with Ochoa’s independent work on the synthesis of RNA, were recognized by the Nobel Prize in Physiology or Medicine.
François Jacob（1920-2013）
François Jacob (17 June 1920 – 19 April 2013) was a French molecular biologist who was awarded the 1965 Nobel Prize in Medicine with Jacques Monod (1910-1976) and André Lwoff (1902-1994). Jacob was born to a Jewish family and went to the University of Paris to study medicine, but his education was interrupted in 1940 when Germans invaded France. Jacob managed to escape from Paris and served Charles de Gaulle’s Free French forces until 1944 when he got seriously injured. The wounds prevented Jacob from becoming a surgeon and he went back to finish his medical degree in 1947 and received a doctorate in science in 1954 at Sorbonne University. In the meantime, Jacob became so interested in researching about phage and bacteria that he applied to work with Lwoff at the Pasteur Institute, and Lwoff agreed in 1950.
In the late 1950s, Jacob collaborated with another fellow Pastorien, Jacques Monod, and experimented on the bacteria Escherichia coli (E. coli). Monod discovered that when the sugar lactose is added to growing E. coli, E. coli produces the enzyme β-galactosidase for digestion. Monod wondered how β-galactosidase appears suddenly. With the help of the visiting scientist Arthur Pardee (1921-2019), the researchers found that the lacZ gene, which is responsible for coding β-galactosidase, can be oppressed by the gene lacl. Jacob and Lwoff provided more evidences that the gene lacl acts as a repressor by using bacteriophage λ to infect E. Coli and inhibit the gene lacl. The repressor model in gene expression brought the three scientists Noble Prize in Medicine in 1965.
Sydney Brenner（1927-2019）
Sydney Brenner (13 January 1927 – 5 April 2019) was a South African biologist and the laurate of the Nobel Prize in Physiology or Medicine in 2002. Brenner was born in Germiston, South Africa, to poor immigrant parents. He completed his first 3 years of primary school in a year, and joined the University of Witwatersrand in Johannesburg, South Africa, at the age of fifteen. Because he was too young to practice medicine, Brenner earned a B.Sc. Honours in histology in 1946 and a M.Sc. degree in anatomy in 1947, before receiving a medical degree in 1951. Next year Brenner won a scholarship to the Department of Physical Chemistry at Oxford and received his doctorate in 1954. He paid a visit to Cambridge in April 1953, and was among the first to view James Watson and Francis Crick’s double helix model of DNA– a defining moment in life as Brenner recalled.
After a postdoc at the University of California, Berkeley, Brenner joined the Medical Research Council in Cambridge, England, which became the Laboratory of Molecular Biology (LMB) in 1962. In the 1950s, Brenner proved theoretically that DNA bases are read in groups of three– every three nucleotides specify one amino acid that constitutes proteins, and he confirmed this in lab with Crick in 1961. In the same year, with François Jacob (1920-2013) and Matthew Meselson (1930-), Brenner demonstrated the existence of messenger RNA. In the mid-1960s, Brenner decided to focus on whole organism and picked Caenorhabditis elegans, from which he deciphered the genetics of programmed cell death and animal development. It is for this pioneering work on C. elegans that Brenner received the 2002 Noble Prize in Physiology or Medicine together with two colleagues Bob Horvitz (1947-) and John Sulston (1942-2018). Brenner maintained that it should have been his second Nobel Prize for his earlier work on genetic coding having been equally worthy.
Frederick Sanger (1918-2013)
Frederick Sanger (13 August 1918 –19 November 2013) was an English biochemist who twice won the Nobel Prize in Chemistry, and the fourth person with two Nobel Prizes. Sanger was born in Gloucestershire, UK. Raised as a Quaker, Sanger learned self-reliance and practical manual skills as a school boy. Sanger received his bachelor’s degree in biochemistry in 1939 and his doctorate in 1943, both from the University of Cambridge. Meanwhile, Sanger married Margaret Joan Howe, an economics graduate at Cambridge, in 1940. They had two sons and one daughter and remained married until her death in 2012.
Sanger joined Albert Chibnall’s (1894-1988) research group in 1943 at Cambridge and tried to determine the exact chemical structure of proteins, which was controversial at that time as most scientists believed the arrangement of different amino acids in a protein to be random. Sanger chose to work on insulin and eventually figured out the complete amino acid sequence of the two polypeptide chains of insulin, A and B, in 1952 and 1951, and this brought him the Noble Prize in 1958. Sanger joined the Medical Research Council (MRC) Laboratory of Molecular Biology in 1962 and began to develop methods for sequencing RNA and DNA. He first came up with the “plus and minus” method in 1974, and the chain terminator sequencing in 1977 – the latter adds a terminator, the dideoxy derivatives or the arabino nucleosides, to terminate the replication of DNA. The chain terminator sequencing is also known as “Sanger sequencing”, and it enables to sequence several hundred DNA bases within one day, a process that previously took many years. And Sanger received a second Noble Prize in 1980, along with Walter Gilbert (1932-) and Paul Berg (1926-).
Sanger retired in 1985. According to Sydney Brenner (1927-2019), when Sanger was asked whether he would like to keep his office at MRC after retirement, he answered: “No. I have had enough. I want to build a boat and spend some time messing about in my garden.” And he did spend most of the time working in the garden ever since.
Wu Rui（1928-2008）
Rui Wu(1928-2008), whose family origin was Fuzhou, was born in Beijing on August 14th, 1928. Biochemist, one of the most vital pioneering scholars in the fields of DNA sequencing, genetic engineering, and biotechnology, academician of the "Academia Sinica" in Taiwan, a foreign academician of the Chinese Academy of Engineering, and a professor at Cornell University.
From 1968, after three years of hard work, he established the world's first DNA nucleotide sequence analysis method successfully. Subsequently, the study of making the primer extension method a basic method for DNA sequencing was successful. Using this method developed by Rui Wu, many scientists have confirmed the DNA sequences of numerous genes. To date, more than a billion nucleotide sequences have been verified, and the information contained in them has been widely used throughout the fields of bioscience and bioengineering, including medicine, agriculture, and industry. Rui Wu became an important subject leader in DNA sequencing.
In addition, Rui Wu and his colleagues also pioneered the method of using synthetic oligonucleotides as adaptors and linkers to improve the efficiency of blunt-ended DNA cloning in the process of gene cloning. This method has become an efficient routine method in bioengineering.
In 1988, Rui Wu's laboratory successfully cultivated transgenic rice. Thanks to the right decision, his lab overtook other labs in just two years and became one of the world's leaders in the field of genetically modified rice. There are two important contributions of Rui Wu in rice research: First, the first use of particle guns in transgenic technology of plants has greatly improved the success rate of plant transformation/regeneration. The second is to use genetic engineering methods for the first time to transfer drought and salt tolerance genes from different species into rice cells, and cultivate transgenic rice plants with drought and salt tolerance.
Walter Gilbert (1932-)
Walter Gilbert (born March 21, 1932) is an American biochemist, physicist, molecular biology pioneer, and the winner of 1980 Nobel laureate in chemistry. Gilbert entered Harvard University in 1949 and earned a baccalaureate degree with a major in chemistry and physics in 1953, and a master’s degree in physics in 1954. He then went to Cambridge University to pursue a doctorate degree in mathematics, where he met James D. Watson (1928- ) and Francis H. C. Crick (1916-2004), who had just claimed the double-helix structure of DNA. At Watson’s invitation, Gilbert joined him and his colleagues in isolating the messenger RNA and developed an interest in molecular biology. While Gilbert received his Ph.D. in 1957 and returned to Harvard as an assistant professor in physics in 1959, he worked hard to make up for his lack of formal training in biochemistry and became a tenured associate professor of biophysics at Harvard in 1964, and a full professor in 1968.
Just as François Jacob (1920-2013), Gilbert worked on the bacteria Escherichia coli (E. coli) and became interested in a substance which represses the gene lac from producing β-galactosidase in the absence of the milk sugar lactose; by 1970 he determined the precise region of the gene lac to which the repressor bonds. Moreover, working with graduate student Allan Maxam (1946-), Gilbert successfully used gel electrophoresis and X-ray exposure to determine the sequences of DNA fragments. For that, Gilbert shared half of the 1980 Nobel Prize in chemistry with the British scientist Fredrick Sanger who also developed a sequencing technique (1918-2013), with the other half going to American biochemist Paul Berg (1926-).
In addition to a renowned scientist, Gilbert is also famous for capitalizing molecular biology – developing and selling biochemical technologies. He started a biotechnology firm, Biogen, with a group of venture capitalists in 1978. In 1987 he announced to create his own company, which would sequence human DNA, copyright the information, and sell it. Though he failed to get adequate funds for that project, he did win a two-million-dollar annual grant from the U.S. government, before the Human Genome Project formally launched in 1900.
Beckman System 1 Plus DNA Synthesizer，Circa 1985
This combination of hardware and software allowed users to program a sequence, check reagent levels, and perform DNA synthesis using phosphoramidite chemistry. The control module in the color photograph included an IBM PC with a color monitor, keyboard, light pen, system interface with a strip chart recorder, and the Beckman DNA synthesis software on a disk.
Illig, Russell. “Beckman System 1 Plus DNA Synthesizer,” circa 1985. Beckman Historical Collection, Box 59, Folder 121. Science History Institute. Philadelphia.
Beckman Instruments released the Oligo 1000M in 1995
“Beckman Oligo 1000M DNA Synthesizer,” 1990–1999.
Beckman Historical Collection, Box 84. Science History Institute. Philadelphia.