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Biotechnology and Society---Part XI

The scientific world celebrated the 50th anniversary of the human genome early this year. That marked the fifty years that have passed since the determination of the structure of DNA which has spawned an immense scientific revolution in the areas of medicine, agriculture, and industry contributing to society in multifarious ways. The end of World War II ushered in an era of peace and prosperity and the decades of the 1950s, 1960s and ‘70s saw the advancement of all fields of science including physics, chemistry, biology and space science.

1950s: The Golden Age of Biology began in the 1950s. In 1952 Rosalind E. Franklin at King’s College in England obtained X-ray diffraction images of DNA which were ultimately used by James Watson and Francis Crick to intuitively arrive at the structure of DNA which was published in 1953. Severo Ochoa, in 1955, discovered an enzyme called RNA polymerase which made ribonucleic acid (RNA) from DNA. In 1956, using electron microscopy, it was determined that there are cellular structures termed “ribosomes” which contained RNA. Arthur Kornberg at Washington University (St. Louis) discovered DNA polymerase, which was involved in DNA synthesis. In the next couple of years, the replication (copying) of DNA was explained. With the discovery of another RNA, called tRNA, in 1957 at Harvard University, the jigsaw puzzle of how DNA was doing its job of controlling cellular processes was solved. In 1958 the “Central Dogma” of molecular biology was propounded. The transfer of genetic information occurred in a one-way process, namely “DNA makes RNA makes Protein”. We will see later on how this “inviolable” dogma was violated under specific circumstances.

1960s: Despite all the furor over the determination of the structure of DNA and the processing of the genetic information, DNA was still a “molecule without a mission”. It was still a puzzle as to how the genes made proteins. The role of the mediator, RNA, in making the proteins was obvious but the details were still missing. It was not until 1960 that a synthetic RNA created by Marshall Nirenberg and Heinrich Matthaei at the National Institutes of Health and used it in a cell-free system to synthesize a novel protein, the Genetic Code revealed itself. In the next few years it was established that there was a unique triplet codon (a string of 3 letters) for each specific amino acid (that formed part of a protein) and the codons for all the 20 amino acids that constituted the proteins in the biological systems were identified. This Genetic Code was demonstrated to be universal for all biological species, from the lowly bacteria to the most intelligent human life form.

The Trojan horse: Biology can borrow from mythology to explain certain phenomena. When bacteria share some of their genetic information with other bacteria, they use a shuttle known as plasmid, which functions in a manner quite similar to the wooden horse (with soldiers hidden inside) that was used in the legendary Trojan War the Greeks fought against the city of Troy. Typically a plasmid is just a circular piece of DNA (see figure). They replicate (multiply) independently of the chromosome in the cell. Hence each cell has multiple copies of such plasmids.

Bacteria possess several such elements for some specific purposes like warding off their microbial enemies or drugs designed to kill them. They also share such elements with their friends through exchange. This behavior is reminiscent of the Thamizh maxim, “yAm peRRa inbam peruga ivvaiyagam” (Let the world share the pleasure that we have obtained). The bacteria which possess such functional plasmids transfer these units to other bacteria through a process known as conjugation. It was Joshua Lederberg who coined the term ‘plasmids’ in the early fifties to denote extra-chromosomal genetic material. He also demonstrated that bacteria can reproduce through sexual recombination. This would turn out to be crucial to genetic engineering and biotechnology.

Restriction Enzymes: The second important tool in molecular biology after the plasmids was the isolation of restriction nucleases in 1968--- which as the term implies are enzymes which can cut nucleic acids at specified locations. They were called restriction enzymes because they ‘restricted’ the entry of foreign DNA into the bacterial cell. Several restriction enzymes were isolated and characterized which would all go into the tool box of the molecular biologist. These restriction enzymes can be considered as ‘molecular scissors’.

With yet another discovery of an enzyme called DNA ligase (1966), it was possible to attach two or more DNA molecules to one another. With the previously discovered DNA polymerase, it now became possible to synthesize stretches of DNA, cut DNA molecules where needed, and then join different pieces together pretty much like a tailor who makes an elegant suit from various patches of cloth. The triumvirate of plasmids, restriction nucleases, and DNA ligase together constituted the toolbox with which cells can be manipulated to transfer genes from higher organisms to bacteria and produce recombinant proteins.

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By the late 1960s, complete genes were isolated from an organism and transferred to bacteria. The scientific community was thrilled as well as got somewhat apprehensive, similar to what the physicists felt in the early 1940s when the power of the atom was harnessed into a lethal bomb. The scientists, administrators and the press started getting cautious about the biotech genie that was to be unleashed. The overwhelming fear was what the genie could do and if the genie started misbehaving how the situation could be remedied. Moral issues such as the possibility of biological warfare were discussed along the same lines as the atomic warfare. From excitement to caution it is only a small step. Let us look at the measures instituted to handle this situation in our next article.