History of DNA cont'd

1953 - James Watson and Francis Crick discover the double helix structure of DNA

In 1951, James Watson visited Cambridge University and happened to meet Francis Crick. Despite an age difference of 12 years, the pair immediately hit it off and Watson remained at the university to study the structure of DNA at Cavendish Laboratory.

Using available X-ray data and model building, they were able to solve the puzzle that had baffled scientists for decades. They published the now-famous paper in Nature in April, 1953 and in 1962 they were awarded the Nobel Prize for Physiology or Medicine along with Maurice Wilkins.

Despite the fact that her photographs had been critical to Watson and Crick's solution, Rosalind Franklin was not honoured, as only three scientists could share the prize. She died in 1958, after a short battle with cancer.

1953 - George Gamow and the “RNA Tie Club”

Following Watson and Crick's discovery, scientists entered a period of frenzy, in which they rushed to be the first to decipher the genetic code. Theoretical physicist and astronomer George Gamow decided to make the race more interesting - he created an exclusive club known as the “RNA Tie Club”, in which each member would put forward their ideas about how nucleotide bases were transformed into proteins by the body's cells.

He handpicked 20 members - one for each amino acid - and they each wore a tie carrying the symbol of their allocated amino acid. Ironically, the man who was to discover the genetic code, Marshall Nirenberg, was not a member.

1959 - An additional copy of chromosome 21 linked to Down's syndrome

Today, scientists routinely use our growing understanding of genetics for disease diagnosis and prognosis. However, it took decades for cytogenetics (the study of chromosomes) to be recognised as a medical discipline.

Cytogenetics first had a major impact on disease diagnosis in 1959, when an additional copy of chromosome 21 was linked to Down's syndrome. In the late 1960s and early 70s, stains such as Giemsa were introduced, which bind to chromosomes in a non-uniform fashion, creating bands of light and dark areas. The invention transformed the discipline, making it possible to identify individual chromosomes, as well as sections within chromosomes, and formed the basis of early clinical genetic diagnosis.

1965 - Marshall Nirenberg is the first person to sequence the bases in each codon

In 1957, Marshall Nirenberg arrived at the National Institute of Health as a postdoctoral fellow in Dr. DeWitt Stetten, Jr.'s laboratory. He decided to focus his research on nucleic acids and protein synthesis in the hope of cracking 'life's code'.

The following few years were taken up with experiments, as Nirenberg tried to show that RNA could trigger protein synthesis. By 1960, Nirenberg and his post-doctoral fellow, Heinrich Matthaei were well on the way to solving the coding problem.

Nirenberg and Matthaei ground up E.Coli bacteria cells, in order to rupture their walls and release the cytoplasm, which they then used in their experiments. These experiments used 20 test tubes, each filled with a different amino acid - the scientists wanted to know which amino acid would be incorporated into a protein after the addition of a particular type of synthetic RNA.

In 1961, the pair performed an experiment which showed that a chain of the repeating bases uracil forced a protein chain made of one repeating amino acid, phenylalanine. This was a breakthrough experiment which proved that the code could be broken.

Nirenberg and Matthaei conducted further experiments with other strands of synthetic RNA, before preparing papers for publication. However, there was still much work to do - the scientists now needed to determine which bases made up each codon, as well as the sequence of bases within the codons.

Around the same time, Nobel laureate Severo Ochoa was also working on the coding problem. This sparked intense competition between the laboratories, as the two scientists raced to be the first to the finish line. In the hope of ensuring that the first NIH scientist won the Nobel Prize, Nirenberg's colleagues put their own work on hold to help him achieve his goal.

Finally, in 1965, Nirenberg became the first person to sequence the code. In 1968, his efforts were rewarded when he, Robert W. Holley and Har Gobind Khorana were jointly awarded the Nobel Prize.

1977 - Frederick Sanger develops rapid DNA sequencing techniques

By the early 1970s, molecular biologists had made incredible advances. They could now decipher the genetic code and spell out the sequence of amino acids in proteins. However, further developments in the field were being held back by the inability to easily read the precise nucleotide sequences of DNA.

In 1943, Cambridge graduate Frederick Sanger started working for A. C. Chibnall, identifying the free amino groups in insulin. Through this work, he became the first person to order the amino acids and obtain a protein sequence, for which he later won a Nobel Prize. He deduced that if proteins were ordered molecules, then the DNA that makes them must have an order as well.

In 1962, Sanger moved with the Medical Research Council to the Laboratory of Molecular Biology in Cambridge, where DNA sequencing became a natural extension of his work with proteins. He initially began working on sequencing RNA, as it was smaller, but these techniques were soon applicable to DNA and eventually became the dideoxy method used in sequencing reactions today.

For his breakthrough in rapid sequencing techniques, Sanger earned a second Nobel Prize for Chemistry in 1980, which he shared with Walter Gilbert and Paul Berg.

1983 - Huntington's disease is the first mapped genetic disease

HD is a rare, progressive neurodegenerative disease which usually manifests itself between 30 and 45 years of age . It's characterised by a loss of motor control, jerky movements, psychiatric symptoms, dementia, altered personality and a decline in cognitive function. As the disease is adult onset, many people have already had children before they are diagnosed and have passed the mutant gene onto the next generation.

In 1983, a genetic marker linked to HD was found on Chromosome 4, making it the first genetic disease to be mapped using DNA polymorphisms. However, the gene was not finally isolated until 1993.

1990 - The first gene found to be associated with increased susceptibility to familial breast and ovarian cancer is identified

In 1990, the first gene to be associated with increased susceptibility to familial breast and ovarian cancer was identified. Scientists had performed DNA linkage studies on large families who showed characteristics related to hereditary breast ovarian cancer (HBOC) syndrome.

They named the gene they identified, which was located on chromosome 17, BRCA1. However, it was clear that not all breast cancer families were linked to BRCA1, and, with continued research, a second gene BRCA2 was located on chromosome 13.

Everyone has 2 copies of both BRCA1 and BRCA2, which are tumour suppressor genes. If a person has 1 altered copy of either gene it can lead to an accumulation of mutations, which can then lead to tumour formation.

1990 - The Human Genome Project begins

In 1988, The National Research Council recommended a program to map the human genome. The Human Genome Project officially started in 1990, with the U.S. Department of Energy (DOE) and the National Institutes of Health (NIH) publishing a plan for the first five years of the anticipated 15 year project.

Many organisations had a long-standing interest in mapping the human genome for the sake of advancing medicine, but also for purposes such as the detection of mutations that nuclear radiation might cause.

The project's goals included: mapping the human genome and determining all 3.2 billion letters in it, mapping and sequencing the genomes of other organisms, if it would be useful to the study of biology, developing technology for the purpose of analysing DNA and studying the social, ethical and legal implications of genome research.

1995 - Haemophilus Influenzae is the first bacterium genome sequenced

In 1995, to demonstrate the new strategy of "shotgun" sequencing, J. Craig Venter and colleagues published the first completely sequenced genome of a self-replicating, free-living organism - Haemophilus Influenzae.

Known as H.flu, Haemophilus Influenzae is a bacterium that can cause meningitis and ear and respiratory infections in children. Prior to this breakthrough, scientists had only managed to sequence the genome of a few viruses, which are around ten times shorter than that of H.flu.

The project took around a year and was a remarkable achievement. Its success proved that the random shotgun technique could be applied to whole genomes quickly and accurately, paving the way for future discoveries.

1996 - Dolly the sheep is cloned

The world famous Dolly the sheep was the first mammal to be cloned from an adult cell. The feat was ground-breaking - whilst animals such as cows had previously been cloned from embryo cells, Dolly demonstrated that even when DNA had specialised, it could still be used to create an entire organism.

Dolly was created by scientists working at the Roslin Institute in Scotland, from the udder cell of a six-year-old Finn Dorset white sheep. By altering the growth medium, the scientists found a way to 'reprogram' the cell, which was then injected into an unfertilised egg that had had its nucleus removed. The egg was then cultured to reach the embryo stage, before being implanted into a surrogate mother.

Cloning from adult cells is a difficult process and out of 277 attempts, Dolly was the only lamb to survive. She went on to live a pampered existence at the Roslin Institute and was able to produce normal offspring. Following her death, she was stuffed and put on display, as can be seen in the accompanying image.

1996 - 'Bermuda Principles' established

In 1996, the leaders of the Human Genome Project met in Bermuda and agreed that genome sequence data should be made freely available in the public domain within 24 hours of generation.

Known as the 'Bermuda Principles', the agreement was designed to ensure that sequence information led as rapidly as possible to advances in healthcare and research.

In order to co-ordinate the process, it was also agreed that large-scale sequencing centres would inform the Human Genome Organisation (HUGO) of any intentions to sequence particular regions of the genome. HUGO would then place this information on their website and direct visitors to the specific centres for more detailed information regarding the current status of sequencing.

1999 - First human chromosome is decoded

In 1999, an international team of researchers reached a major milestone when they unravelled for the first time the full genetic code of a human chromosome. The chromosome in question was chromosome 22, which contained 33.5 million "letters," or chemical components.

At the time, the sequence was the longest continuous stretch of DNA ever deciphered and assembled. However, it was only the first deciphered chapter of the human genetic instruction book - the rest was still to come.

2000 – Genetic code of the fruit fly is decoded

In March 2000, scientists from a number of laboratories successfully decoded the genetic makeup of the fruit fly. The collaborative effort had major implications for the sequencing of the human genome, as fly cell biology and development has much in common with mammals.

During their research, the scientists discovered that every fruit fly cell contains 13,601 genes, making it by far the most complex organism decoded at the time. However, by contrast, human cells contain 70,000 genes. Whilst the Human Genome Project still had a long way to go to achieve its ultimate objective, this was an important milestone along the way.