The 10 greatest discoveries in genetics have taken less than two centuries since an Augustinian Monk in Czechoslovakia started to unravel the mysteries of genetic inheritance. It took a further 50 years to coin the word ‘gene’. But thanks to the work of many scientists, the second half of the 20th century saw an acceleration in the understanding of genetics and how genes influence all of life.
1 – The Rules of Heredity
It was the inquisitive mind of Gregor Mendel that kick-started the study of genetics. Although humans had been selectively breeding plants and domestic animals for thousands of years, no-one had researched it in detail. Gregor Mendel decided to see what happened when he cross-bred peas in the monastery garden, systematically recording his findings.
Amongst the many experiments he carried out was to look at the type of pea seed produced. One type of pea produced round seeds whilst another produced wrinkled seeds. When the two were cross-bred, he found that they always produced rounded seeds. But when he bred these first generation offspring, some of the second generation peas produced wrinkled seeds but most produced rounded seeds. The ratio was always 1:3.
Similarly, in the other experiments he carried out, the lost characteristic of the first generation always returned in the second generation in a ratio of 1:3. He worked out that this would happen if each characteristic was governed by two ‘factors’, one from each parent. One factor was dominant and the other recessive. Half a century later, when twentieth century science re-discovered his work, Mendel’s ‘factors’ were named ‘genes’ by Thomas Hunt Morgan and the study of genetics really got under way.
2 – Genes are Located on Chromosomes
Morgan was sceptical of Mendelian inheritance and of Charles Darwin’s ideas of natural selection – that is, until he had carried out many experiments on the fruit fly, Drosophila melanogaster. He chose these as they had a very short generation time and produced huge numbers of offspring so he could obtain statistically valid results quickly.
Amongst his experiments to create inheritable mutations, he noticed flies with white eyes instead of the normal red eyes. When he bred them with red-eyed flies, the first generation all had red eyes, showing the red eyed gene was dominant. White eyes reappeared in the second generation, as expected, but what he noticed was that all of the white eyed flies were male.
This unlocked our second greatest discovery in genetics. He knew how gender was governed by chromosomes and realised that the gene controlling the white eye colour must be recessive and found on the chromosomes. He found several other sex linked mutations too and also noticed some where the gene seemed to have crossed from one chromosome to the other. Now that geneticists knew where the genes were found, it would be only a matter of time before their workings were discovered.
3 – Genes Control Biochemistry
This discovery was made in 1941 by George Beadle working with Edward Tatum. Beadle had an inkling that eye colour may have been caused by genetically controlled biochemical reactions. Beadle had been working with Morgan on Drosophila but found that fly genetics were too complex to verify his theory. So he and Tatum used bread mould as its simple genetics made it easy to study specific products of metabolism directly.
Radiation induced mutations created some spores that would not grow unless a specific amino acid (arginine) was added. They produced other arginine dependent strains and thus showed that the mould could lose the use of a specific gene that produced an enzyme which was central to the production of the arginine.
The concept of genes producing enzymes had first been suggested by Archibald Garrod in 1901, however, his work had largely been ignored. When Beadle and Tatum were awarded the Nobel Prize in 1958 for their work, they had the grace to acknowledge that Garrod had been the real pioneer. Their findings have been augmented and modified and it is now realised that each gene is responsible for the production of a polypeptide (protein or part of a protein) rather than an enzyme. Two or more genes can therefore contribute to the synthesis of a particular enzyme and some products of genes are not enzymes but structural proteins.
4 – Transposons
Barbara Mclintock had developed a method of staining that allowed her to see the chromosomes in maize. She was working on a variety in which the kernel was either purple, blotchy purple, white or yellow. She thought that the variations could be linked to chromosome breakage during division of the cells responsible for making the outer coating of the seed. She discovered that the position of the chromosome breakage was controlled by a ‘Dissociator’ which was itself controlled by an ‘Activator’.
She tracked down the gene to chromosome 9 and reasoned that, if during cell division, the Dissociator inserted itself into the purple gene, the latter would be deactivated and no colour whould show in that particular cell. At some point in the process, she believed that the Activator could destabilise the Dissociator and cause it to jump to a different location. This would then re-activate the purple gene in a group of daughter cells, giving rise to some cells that were purple, some which were not i.e. the blotchy kernel.
She called this ‘Transposition’ and it made the patterns of colouration she was seeing easily understandable. This discovery was groundbreaking as it showed firstly that inherited features can be modified during the growth and development of an organism and secondly, it is possible to switch genes on and off. Prior to acceptance of the ‘jumping gene’ chromosomes were seen as fixed and unchanging entities.
Although her work was largely shunned at the time, it was eventually accepted years later and she was rewarded with a Nobel Prize in 1983. It marked the beginning of the science of epigenetics which may hold the key to beating inherited diseases and cancer.
5 – DNA is the Genetic Material
Prior to this discovery, it was believed that heredity was controlled by proteins. Swiss scientist Friedrich Miescher discovered several phosporous rich chemicals from analyses of the nucleii of white blood cells. He had no idea that one of these was central to life when he published his findings in 1871.
In 1944, A team led by Oswald Avery carried out experiments using bacteria. They showed that DNA could cause one strain to transform into another. This could not be done using any other chemicals so DNA was identified as a ‘transforming factor’ and was from that point seen as a good candidate as being the hereditary material of cells.
Within a decade, Alfred Hershey and Martha Chase studied how the T2 bacteriophage was able to ‘transform’ bacteria to produce replica viruses. Somehow, the virus hijacked the internal mechanisms of the bacteria it attacked, forcing it to manufacture a batch of new viruses. The bacteriophage comprises a protein outer coat protecting a strand of DNA. Using radioactive labelling (and a food blender!!), they discovered that only the DNA directed the host cell to produce more virus.
The race was on to work out the structure of DNA which is the subject of our next greatest discovery in Genetics …
6 – The Double Helix
The double helix of DNA has become one of the icons of 20th century science. The chemical composition was known to comprise just four bases – cytosine, guanine, adenine and thymine. X-ray crystallography had been carried out and showed hints of the structure.
Several groups were in the race to discover the structure of DNA but it was British team Crick and Watson who published first. Their research was not original, they simply pulled together the fragments of information that existed and built a model of a pair of sugar phosphate ‘backbones’ joined together via the four bases using their knowledge of biochemistry.
They were awarded the Nobel Prize in 1962 for the discovery, along with Maurice Wilkins, who gave them crystallographic information prepared by Rosalind Franklin. The Nobel Prize can only be awarded to a maximum of three living scientists so Franklin missed out as she died in 1958 of ovarian cancer. Had she still been alive, the awards committe would have had to make a decision between her or Wilkins.
Franklin was never really given credit for her part in the discovery, it was still an era where science was male dominated. Five years after the Nobel Prize, Watson wrote his book The Double Helix in which he gave a very personal account of the discovery. The book met with mixed reviews and was criticised for underplaying the work of Rosalind Franklin although he did try to make amends in the epilogue by acknowledging her skills and the enormous barriers that were in place to women scientists of the era.
7 – Messenger RNA
By the mid 1950s, scientists were aware that genes contained the coding for producing the proteins required for an organism to function properly. They had identified that proteins were made on the ribosomes, structures found in the cytoplasm. Trouble was, the genes were in the nucleus and so the mechanism by which they directed protein synthesis was unknown. Some speculated that ribosomes were made in the nucleus and migrated to the cytoplasm; others postulated that the RNA was involved since ribosomes were largely RNA.
Elliot Volkin and Waldo Cohn carried out a series of experiments using radioactive markers and enzymatic hydrolysis and were able to detemine the composition of RNA. Then, working with Larry Astrachan on the way that bacteriophages use e.coli bacteria to make the proteins needed to replicate themselves, they discovered messenger RNA. They found that short-lived RNA strands were created in the nucleus of the host, transported into the cytoplasm where the code they carried was translated into proteins. They called this ‘DNA-like RNA’.
As often seems to happen with genetic research, the original findings were not immediately accepted and the ‘glory’ was bestowed on a variety of other big names in the field, including Francis Crick.
8 – Cracking the Genetic Code
Now that it was realised that RNA was the key to the biochemical reactions in cells, the mechanism remained to be discovered. Since DNA and RNA are made up from sequences of bases, it was surmised that the order of bases would be the codons. A codon is a sequence of bases on RNA that directs the production of a protein molecule. They originate from the DNA in the nucleus of cells. Amongst others, George Gamow suggested that codons would be triplets of bases which would mean there were 64 codons.
The first experimental evidence came from work by Crick, Brenner and others but needed confirmation. This arrived in 1961 as a result of the experiments carried out by Marshall Nirenberg and Heinrich Matthaei. They extracted the cytoplasm from the bacteria e. coli, destroyed the bacterial DNA and introduced synthetic RNA strands. When they introduced poly-U (a strand comprising only the base urecil), they found that the cytoplasm produced phenylalanine. After considerable further experimentation, they cracked over 50 of the codons.
We now know that there are 64 codons, the order of which on a strand of RNA determines the complex protein that is synthesised.
9 – Restriction enzymes
In the 1950s, Salvador Luria and Giuseppe Bertani found that bacteriophages that had grown in a particular strain of e.coli would show limited growth in other strains. In the 1960s, this was shown by Werner Arber and Matthew Meselson to be caused by enzymatic cleavage of the DNA of the virus. Since this cleavage restricted the growth of the bateriophages, the enzymes were called restriction enzymes or more specifically restriction endonucleases where an endonuclease is an enzyme that slices through the ‘backbone’ of DNA.
Subsequent work has found that some are indiscriminate and will cut the DNA anywhere but others will cut only at specific points. This, the penultimate of our ten greatest discoveries in biology has had a major impact on our society. Whatever you feel about the ethics, restriction enzymes have given humankind the ability to carry out genetic engineering. It is possible to use them to cut DNA and then recombine the slices to form new DNA in specific and predictable ways.
10 – 300,000 Genes?
Cracking the genetic code was the first step on the route to our final greatest discovery, the human genome. The race began during the 1990s between two teams. At the time, the belief was that there could be up to 300,000 genes to discover and the two teams amalgamated in 2000. Eventually, they completed their task, having found considerably fewer genes, around 26,000. Recent work in the same field indicates that there may actually be fewer than 20,000 so this discovery is by no means complete as yet.
What has become clear is that the difference between individuals is incredibly small, we are all essentially the same. Indeed, all mammals, humans included, share pretty much the same genes in the same order, the function of most of which is currently unknown, so there is still plenty left to discover.