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It is a rare honor to be selected as a Nobel laureate in chemistry by The Royal Swedish Academy of Sciences. An even greater tribute is to be selected as a Nobel Laureate twice. Frederick Sanger, the winner of the Nobel Prize in Chemistry in 1958 and 1980, is a scientist whose research embodies the tireless spirit of Alfred Nobel. Sanger first began studying the problems associated with determining the structure of proteins in 1943, but, following the receipt of his first Nobel Prize, his focus shifted from proteins to nucleic acids. In 1980 he received his second Nobel Prize for developing a technique for determining the base sequence in nucleic acids. His work with both proteins and nucleic acids has greatly contributed to science and has helped put molecular genetic studies at the forefront. When Sanger first began studying the structure of proteins in the 1940s, the field was still in its nascent years. In fact, the word “protein” hadn’t even entered the scientific vocabulary until 1838, only 100 years prior to the start of Sanger’s work. While scientists had been studying these mysterious compounds since the early 19th century, there were no significant advances until the end of that century when the German chemist Emil Fischer, also a Nobel laureate, found that proteins were composed of smaller compounds called amino acids. Fischer’s early studies revolved around his discovery of phenylhydrazine, as well as the properties of caffeine and theobromine. He determined the organization of many of these compounds and was later able to synthesize them. The work for which he received his Nobel Prize in 1902 involved the study of purines and sugars. Fischer proved that substances such as adenine, caffeine, uric acid and guanine are all related and all contain hydroxyl and amino groups. This knowledge enabled him to produce many artificial compounds that are chemically similar to their naturally-occurring counterparts in addition to synthesizing purine. It also showed that there was a family of compounds, all chemically similar, that consisted of amino and hydroxyl groups. This work was revolutionary because it explored previously little known substances and furthered the study of proteins. Fischer’s discovery that proteins are composed of amino acid chains led to a better understanding of proteins which helped Frederick Sanger study the structure of insulin. Sanger’s work with insulin, which garnered him his first Nobel Prize, would not have been possible without the technological and scientific advances during the 1930s and 1940s. The first major advancement was made in 1934, when Desmond Bernal showed that large molecules, such as proteins, could be studied using x-ray crystallography. This technique involves the diffraction of x-rays through the atoms of a crystal which helps reveal the structure of the molecule. Following Bernal’s discovery, scientists began to study proteins and DNA in an effort to determine which molecule contained the hereditary information. These efforts led to more sophistication in the processes by which proteins are separated and purified. With the aid of these discoveries, Sanger developed an ingenious method that “marked” the amino acid group at the end of the protein chain. A dye reagent (2,4-dinitrofluorobenzene), now known as Sanger’s Reagent, was used to “mark” the end. When he boiled insulin with acids, Sanger found that there were actually two distinct chains: one of 31 amino acids, the other of 20. In 1947, Martin and Synge, both future Nobel laureates, developed a paper chromatography method that allowed for the sequencing of large proteins. Sanger used this technique to determine the sequence of amino acids in the two isolated chains of insulin. Not only was he able to make a model of the protein on paper, but he was also able to carefully reconstruct it in the laboratory from its constituent amino acids, thus confirming its structure. Sanger was the first person to determine the precise amino acid sequence and structure of a protein, a discovery that greatly influenced scientific studies that followed. Professor Arne Tiselius said in his 1958 presentation speech for Sanger’s Nobel Prize in Chemistry, “The procedure he used so successfully can be applied to proteins in general, in attempts to determine their structure. Already now, many research workers are engaged in such investigations, and important results appear to be on the way in the exploration of how proteins play their role as key substances in the chemical processes of Life.” In 1958, Sanger received his first Nobel Prize in Chemistry “for his work on the structure of proteins, especially that of insulin.” When Sanger moved in 1962 to the new Laboratory of Molecular Biology in Cambridge, UK his focus began to shift from the sequencing of proteins to the sequencing of nucleic acids. Since the study of proteins and DNA is linked because the nucleotide sequence in DNA determines the amino acid sequence in a protein, Sanger felt that his next pursuit should be the sequencing of nucleic acids. A critical breakthrough that encouraged Sanger to change his focus had occurred in 1957, when Francis Crick and George Gamov hypothesized that the nucleic acid sequence in DNA specifies the amino acid sequence in a protein. Nine years later in 1966, Nirenburg, Mathaei and Ochoa discovered that three adjacent nucleotides (a codon) codes for each amino acid. Then, in 1972, Paul Berg isolated and used ligase to repair DNA that had previously been cut by restriction enzymes. This procedure allowed scientists to mass-produce proteins by inserting the gene that codes for that protein into rapidly growing bacteria. Building upon all these developments, Sanger created the dideoxy-sequencing technique for determining nucleic acid sequences. This technique, which later became known as the Sanger Sequencing Method, used small concentrations of dideoxy bases in tubes copying target strands of DNA. When the dideoxy nucleic acid was integrated into an elongating strand of DNA, the process terminated. The resulting partial strands of DNA can be run through an acrylamide gel and simply viewed with the naked eye to determine the nucleotide sequence. Until Sanger’s process, the technology didn’t exist to sequence even the shortest genome. In the 1980 Nobel Prize in Chemistry presentation speech, Professor Bo G. Malmström said that Sanger’s method “should become important means in our efforts to understand the nature of cancer, as in this disease there is a malfunction in the control by the genetic material of the growth and division of a cell.” Sanger’s work with DNA sequencing has influenced molecular genetics and medicine in ways far beyond this suggestion and has had a major impact on the fields of proteomics and genomics that have dominated science in the last decade. In 1980, Sanger, along with Paul Berg and Walter Gilbert, received the Nobel Prize in Chemistry “for contributions concerning the determination of base sequences in nucleic acids.” Sanger’s work with protein and nucleic acid sequencing was monumental in the relatively new field of biochemistry and allowed for many major scientific advances. During the same year that Sanger received his second Nobel Prize, Kary Mullis, a future Nobel laureate, along with other employees of Cetus Corporation invented the polymerase chain reaction (PCR), a method by which fragments of DNA can be multiplied at great speeds. The development of PCR is considered to be one of the most important advances in biochemistry and paired with Sanger’s work with sequencing nucleotides made possible the entire genomics revolution. Two years later, Michael Smith of the University of British Columbia-Vancouver developed a technique that allowed amino acids to be substituted anywhere in a protein. Also that year, Applied Biosystems, Inc. developed the first commercial gas phase protein sequencer, which made it much easier to sequence a protein. This technology can be traced directly back to Sanger’s work in sequencing insulin. His work in the 1940s and 1950s enabled Eli Lilly, in 1983, to become the first company to receive a license to artificially manufacture insulin, a product that proved vital to the well-being of people with diabetes. Sanger’s study of nucleic acid sequences has led directly to the techniques that propelled the Human Genome Project, the most ambitious project ever undertaken in the biological sciences. Begun in 1987 by the United States Department of Energy, the Human Genome Project soon evolved into the National Center for Human Genome Research (NCHGR) led by James Watson. In 1990, the Center set the goal of sequencing the entire human genome by 2005, but, in fact, finished two years ahead of schedule. A similar research center was founded in the United Kingdom in 1993, appropriately named the Wellcome Trust Sanger Institute. The institute worked with the NCHGR and was responsible for sequencing one-third of the human genome. Ultimately the Project involved thousands of scientists working in six countries around the world. Once the techniques for rapid sequencing were in place, the genomes of many other organisms have been partially or entirely sequenced. Scientists agree that the potential benefits in the fields of medicine and biotechnology are only beginning to be appreciated. The future developments resulting from Sanger’s contributions to biochemistry are virtually endless. Already, scientists have been able to genetically engineer plants and animals that are more nutritious and hardier. Similarly, transgenic bacteria and mammalian cell cultures are used to mass produce proteins such as insulin. In the future, organisms may be used to mass produce vaccines or other life-enhancing products. It is possible that scientists will be able to create cures for complex diseases with genetic components such as cancer and Alzheimer’s. Through gene therapy, scientists hope that within the next couple of decades they will be able to target a defective gene inside a human and replace it with one that works properly. The potential benefits from this therapy are enormous; previously intractable disorders such as Huntington’s disease may finally be ameliorated or prevented. In 1997, a sheep named Dolly became the first mammal ever to be cloned individually through nuclear transplant from an adult cell source. Parallel work with human stem cells holds the potential to regenerate lost limbs or organs. Molecular genetics not only has health benefits, but also aids in catching criminals. DNA fingerprinting, a process by which a sample of DNA is converted into a bar-code-like fingerprint, was first used in court in 1985. Like a normal fingerprint, a person’s DNA fingerprint is unique and is now being used by police around the world to identify criminals and to exonerate those wrongfully-convicted. With the sequencing of the human genome complete, there is some speculation that someday everyone will have his/her DNA sequenced and recorded by the government. While this may make catching criminals easier and allow for improved methods of identifying people at locations such as border crossings, it leaves many concerned about possible misuse of this sensitive information by the government, employers, and insurers. In the future, society must take care to avoid using genetic technology as a new form of genetic discrimination or eugenics programs. The possible uses of genetics may be endless, but as it begins to involve human experimentation it raises complicated issues involving ethics and morals. Frederick Sanger was a chemistry pioneer, whose work with proteins and nucleic acids helped make possible the burgeoning fields of genomics and biotechnology. His work was instrumental in advancing DNA studies and his methods are still used today, twenty-five years after he received his second Nobel Prize. Sanger’s legacy lives on at the Sanger Institute and other laboratories around the world. While he has now retired from the scientific spotlight, spending a great deal of his time gardening, Sanger, sometimes now called “the father of genomics,” has significantly influenced, and will continue to influence, both science and society. Works Cited |
Chemistry,
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