Sixty years ago this year an important thoroughbred stallion was conceived, one that would later prove to carry an exceptional set of genes. Although a winning horse in its own right, Nearctic is better known as the sire of the most influential stallion of modern time, the great Northern Dancer.
In the same year that Nearctic first stirred in his mother’s womb, 1953, a scientific paper was published that transformed our understanding of genetic inheritance. Effectively it made it possible for today’s scientists to search for a “high performance gene” in thoroughbreds and suggest whether a horse had the potential to be another Northern Dancer.
The scientific paper in question, which provided the first explanation of the double-helix structure of DNA, was published in the journal Nature on April 25th, 1953; its publication changed everything about our understanding of the science of genetics.
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It didn’t just affect horse breeding. It explained how genetic inheritance worked and how the human genetic blueprint could reproduce itself again and again in every cell in our bodies with so few copying errors.
It led to DNA-based advances seen in forensic science, helping to solve decades-old cold cases. It completely altered drug production, to the extent that a third of all drugs today are produced using genetic technologies. Being able to study what genes were doing and the proteins they produced opened up new ways to diagnose diseases and in some cases identify patients who would be likely to respond to a treatment and patients who wouldn’t.
Knowing the structure of DNA led to the ability to find horse meat hidden in beef products. It allows us to use genetic engineering to change foods or modify animals.
We use it to make flu and other vaccines, and it provides the method to make insulin using engineered bacteria. It is the force behind the growing study of stem cells to produce replacement tissues and fix damage after a heart attack.
There is also a murky side to the genetic technologies, given the potential to deliver “designer babies”, exerting genetic control over height or hair and eye colour. It opens up the potential for bioterrorism, turning an otherwise harmless virus into a killer by making a few changes in its DNA. It has led to court battles over the patenting of life and provided a bonanza for charlatans who claim to provide cures for patients using unproven and unsafe methods loosely based on genetic methods.
The understanding provided by that single research paper provided a jumping-off point for all subsequent advances in the science of genetics. The paper, written by James Watson and Francis Crick, ended years of speculation about how we inherit characteristics from our forebears and provided an explanation for the biochemistry behind it.
Beautiful idea
"It is such a beautiful and simple idea," says Prof Fergus Shanahan, head of the department of medicine at University College Cork and director of Cork's Alimentary and Pharmbiotic Centre. "Once it was shown to us it became obvious. The discovery for me affirmed the exquisite beauty when the truth of nature is revealed."
The Cork centre studies the billions of life forms that reside in the human gut, mining these bacteria for useful substances such as natural antibiotics, probiotics, targets for drug production and even bugs that can clean up oil slicks, he says. “Every day we use the fundamental information traced back to Watson and Crick to make new advances in selecting beneficial microbes.”
The "speed gene" in thoroughbreds was discovered by Dr Emmeline Hill and her team at University College Dublin's school of agriculture and food science. She located a gene that, when present, tells the owner or trainer about whether the horse is suited to long or short races. She developed a test for the gene and launched a spin-out company, Equinome, that offers these gene tests to the global thoroughbred industry.
In a research paper published only last year – also in Nature – she and her team pinpointed Nearctic as the point of proliferation of the speed gene that, because of the horse's reputation, quickly moved into the thoroughbred population. Clearly his progeny Northern Dancer had the gene, something that contributed to his performance on the track.
Sixty years ago, on publication of the Watson and Crick paper, breeders would only have been guessing about the quality of a horse, she says. Now an aspect of performance can be read in the horse’s genes.
Hindsight provides a very clear view of the importance of the Watson and Crick paper, but it wasn’t an immediate success, says Prof Luke O’Neill, professor of biochemistry at Trinity College Dublin’s Biomedical Sciences Institute. It took 10 years for it to catch on.
“It wasn’t until the 1960s that DNA was accepted as the secret of life.” Even so, it did provide immediate clarity on how DNA copies itself so accurately. “Before that structure, nobody knew how inheritance worked,” he says. “This image of the double helix swept all before it.”
Researchers had long known about DNA, deoxyribonucleic acid, and about genes, but the structure of the molecule and how it worked remained hidden. The Watson- Crick model revealed DNA as having a helical shape, like a ladder where the long rails have been twisted.
Importantly, the connecting rungs are made up of just four chemicals, the nucleotides known by the letters A, T, G and C. There is only one way for them to connect, with A attaching to T and G attaching to C. If you pull the two rails apart, as when a cell divides, there is only one way for the ladder to be made whole again, with a perfect match-up between A and T and between G and C.
Identifying the structure immediately makes it clear how DNA duplicates itself, like an exceptionally good biological photocopier. “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material,” the authors wrote at the end of their research paper.
“It changed our understanding of life fundamentally,” says Prof David McConnell, professor of genetics at the Smurfit Institute of Genetics at Trinity. Scientists of the time “knew about genes and inheritance, but they had no idea what was going on in chemical terms”.
Even so, it is difficult to comprehend the complexity of DNA and its ability to scrunch down into a tiny package to fit inside the cell. You would need a microscope to see the DNA, but each complete copy of the human genome has a ladder with three billion rungs, or base pairs. Given we have trillions of cells, if all of the DNA from a single person could be straightened out and connected end to end, there would be enough to get to the sun and back 90 times.
Each cell contains two complete copies of this blueprint for life, and as each cell replicates the DNA is copied faithfully over and over again. When things do go wrong, and errors occur, mutations arise. Copying mistakes can be caused by too much sun, by smoking, or as we age, and disease can be the consequence.
Medical transformation
Being able to watch our genes in action in a biochemical sense has transformed diagnostics and medical treatments, McConnell says. Scientists search for markers, indicators in the genes or, for example, in blood or saliva that point towards a specific disease.
Blood samples can give an early warning about the presence of prostate cancer using the PSA test. Doctors assess gene profiles in breast cancers, looking for variants of the BRCS-1 gene that show an inherited risk of breast cancer.
NUI Galway’s Regenerative Medicine Institute, Remedi, uses stem cells to tackle difficult diseases and to provide replacement bone and cartilage tissues, work that is based on the use of genetic technologies at a fundamental level. It involves turning back the clock on adult cells and encouraging them to act like the cells found in an embryo. This means they can be changed into other adult cell forms, for example to provide replacement heart muscle after a heart attack.
You don't have to watch the popular CSI television programme to see cold cases solved, with breakthroughs brought about by DNA analysis. John Crerar was found guilty in 2002 of the murder of Phyllis Murphy, who had disappeared on December 22nd, 1979. Her body was recovered a month later near the Wicklow Gap. He was questioned and denied the murder, but almost 23 years later he was convicted when samples of his DNA matched those collected from Murphy's body. He was given a mandatory life sentence.
The technology has advanced so rapidly that it is outpacing the development of an ethical framework that could provide guidance in its application. Parents whose genes would leave their children at risk of genetic diseases can already do a DNA check on stored embryos in order to use only those free from the disease. The others are then discarded.
This is not available here, but demand for such services will increase as the methods improve. The problem is that it is a simple matter to select embryos not for disease but for height or other characteristics, says Dr Fiachra Ó Brolcháin, a researcher at the Institute of Ethics at Dublin City University. The issue relates to “reproductive autonomy”, he says, and whether people should be allowed to produce designer babies.
“The benefits of this are higher if you can avoid cancer or heart disease,” he explains. “The range of that technology might be problematic. If you select for disease you might also select for hair or eye colour. There is a risk of turning your baby into a product.”
Human enhancement, for example altering DNA to enhance athletic performance, could also become available in time. “It changes the goals of medicine, in that now it is therapeutic but in future it could be aimed towards enhancing people.”
He argues that it is important to establish an ethical framework before you begin introducing laws or government policy. Unfortunately, these frameworks are not being created, and it leaves room for abuse. “The current situation is that we let the free market decide. If we apply that to genetic engineering or cloning, these services become available if there is a market.”
Prof Luke O’Neill agrees that these issues can arise. “Clearly there is the capacity to mess with life, to ‘play God’, as it is called. That capacity exists. It becomes an ethical question how it should be used.”
It may take years before many of these techniques can be perfected and turned into services for sale. Many of the advances promised by genetic technologies have taken longer than expected to come to fruition. The introduction of stem-cell therapies is an example, as scientists work to ensure treatments are safe.
This is not to imply that genetic technologies have failed to deliver. They are being used in so many fields and in so many ways that it is difficult in a single article to encompass them all.
For this reason many scientists suggest that the Watson and Crick paper from 1953 is the single most important biological discovery of the 20th century. It is difficult to argue with this view.
