Stylianos Antonarakis opens the era of personalised genetic in Lake Geneva Region
The Lake Geneva Region is blessed with pharmaceutical and medical technology industries, and with two university hospitals combining both basic and clinical research and universities of applied sciences. With that background you might think that the area long ago started to develop expertise in the amazing disciplines opened by the decoding of the human genome. Far from it. If Geneva’s institutions are now among the best ones in genetics, they have to thank for it one man who decided, some twenty years ago, to choose Geneva instead of Oxford, London or Cambridge to set up the foundations of a science then still in its infancy in Europe.
In 1979, a newly graduated doctor from the University of Athens Medical School was taking a break in a hospital in the Greek capital, absentmindedly watching television over a steaming cup of coffee. Still on duty and exhausted after the long hours already spent working, he could not concentrate on the reporter’s voice. The doctor was Stylianos Antonarakis, and he was about to qualify as a paediatrician. He chose that specialism in order to be able to “work in a field where everything remains to be done or to be discovered”, explains the man who still admits to “disliking what is known”. The young physician was concerned by a disease that is particularly common around the Mediterranean – thalassaemia, a kind of anaemia whose cause was still a mystery.All of a sudden, he picked up a sentence from the television, and his whole world was turned upside down: no more daydreaming, no more certainties. “The journalist was announcing that an American scientist had found evidence that a beta globulin gene was strongly suspected to be one of the triggers of thalassaemia,” recalls Stylianos Antonarakis with a hint of excitement in his voice. “At that exact moment, I knew my goal in life. I wanted to become a researcher.”On the shoulders of giants
Straight away he started looking for a research institution. Sufficiently well read in genetics to begin a new academic career, he found it far from his native Greece – in Baltimore on the U.S. East Coast, which he had never visited. Baltimore’s Johns Hopkins University had the best researchers in the field, though he didn’t know it at the time. He applied for a position as a post-doctoral assistant and got the job quite easily. That began an exceptionally prolific period for the junior researcher. “Each mutation revealed ended up with an article in Nature, written in collaboration with the most prestigious genetic scientists of Harvard and Johns Hopkins University – all the names that matter in the field,” he says.
It was a productive time, but by no means a smooth one. At first Stylianos Antonarakis had to deal with criticism from numerous top scientists who undervalued the importance of his research. “I was told that clinical genetics had no future and would remain in the shadow of fundamental research. My belief was that genetics would inform all medical specialisms and that one day it would benefit patients personally. So I decided to keep going.” In 1983, he was working his way up the Johns Hopkins hierarchy. In a move that proved crucial for his career, his research on thalassaemia led him to focus on other genetic diseases, especially haemophilia. Haemophilia is a kind of benchmark disease. All the genetic variations that are expressed in patients with the disease are related to a single chromosome – the X chromosome – and haemophilia involves the whole spectrum of genetic mutations that are found in other more complex diseases.
LAB TO BED For Antonarakis, time has come for the patients to benefit from genetic
A fresh start
With the help of genetic cloning carried out by other research teams, Stylianos Antonarakis and his group discovered the role of a deficiency in the gene for blood factor VIII and, thereby, the cause of the “common” form of haemophilia. They then proved the potential of genetic engineering by curing a mouse deliberately infected with the coagulation disorder. It was a kind of prelude to gene therapy. “A very decisive victory,” says the researcher. “After this success we no longer had to fight to prove the benefits of genetics for therapeutic purposes.”
After haemophilia, Stylianos Antonarakis focused on another mysterious disorder: trisomy 21 – where instead of the normal two copies of human chromosome 21, there are three copies. It was his work on this chromosomal disease that brought the Greek scientist international recognition. First he had to read and decode all the genes related to chromosome 21, which is the smallest human chromosome in order to discover the function of each one of them. It was an essential step in the search for a therapy, but it was also a Herculean task: in 1984, sequencing techniques were still rudimentary and extremely expensive. Again, the researcher’s determination and scientific efficiency paid off with a major breakthrough: the conclusion that the genetic disorder is inherited in most cases from the mother, just as with haemophilia. In the midst of all this, Stylianos Antonarakis, already full professor at John Hopkins, started to dream of another life for his wife and four children. He considered moving back to Europe. But where? London? Cambridge? The odds might have seemed to favour the British capitals of knowledge. Curiously, Stylianos Antonarakis opted for an outsider that had no a priori right to be selected.
“So many opportunities were put forward, I didn’t know what to choose,” he remembers. “Then I received an offer from the University of Geneva that finally caught my attention. What I knew about Geneva was that it was a city with all the assets of a bigger metropolis but without the drawbacks. Genetics was not the main concern there. When I realised I could create my special venture from scratch, I couldn’t resist and decided to go for Geneva.” With Guy-Olivier Segond, by then health minister of Geneva, committing himself to release “significant” funds and the possibility to work closely with immunologist star professor Bernard Mach the researcher’s last doubts were put to an end.
In 1992, Stylianos Antonarakis made a fresh start in Geneva, researching into molecular genetics, or more precisely into DNA. It was direction that from the beginning expressed clinical intent, combining diagnosis and treatment. He focused on genetic diseases that are not chromosomal disorders, but related to genetic variations requiring more painstaking research. The knowledge he had gained from studying trisomy 21 proved invaluable. “Progressively we found genes responsible for other diseases, such as one form of deafness, one form of hereditary epilepsy, one form of autoimmunity, among the 30 million nucleotides that make up chromosome 21. The challenge became how to move to the clinical trial phase so as to locate a molecular pathway that could act on the third chromosome,” he remembers.
Stylianos Antonarakis was part of the Human Genome Project, and so he understood that one in 1000 genes differs between individuals, that the function of around 3% of the genes is still unidentified and at the same time that 1,5% of the genome has remained unchanged through evolution, exactly the same as it was at the dawn of humanity. He deduced from this that the causes of genetic diseases have to be found within each individual in order to detect the tiny variations between the patients and the rest of the population. “Going from genotype [the genetic constitution of a cell] to phenotype [the observable result of the genes],” the scientist concludes. This is a real challenge for so-called “multigenic” disorders, such as Alzheimer’s disease or premature ageing, where not one but several different genetic variations are involved.Genetic enters the clinic
Professor Antonarakis is now about to launch a project that will put the Lake Geneva Region into the big league. In 2011, the University of Geneva will inaugurate the first “genome clinic”, in cooperation with other major research institutions. Its objective: to sequence the genome of some 100 000 people so as to read their entire genetic code and to trace the slightest gene variations. It is a huge task that will take more than 10 years, but at the end it should produce hope against all the odds. “Our job is changing. People who come to see us will no longer be ‘diagnosed patients’, but ordinary people who want to understand the mysteries of their DNA,” he says.
But has the time for predictive genetics now come? “It’s far too soon to tell,” says Stylianos Antonarakis, who doesn’t really trust the commercial companies seeking to exploit the market for genetic tests. “We have certainly reached a landmark in research on genetic inheritance. We know that some diseases have a 100% chance of developing when a specific gene has a mutation. Others are not so clearly evident, for example, the breast cancer type 1 gene, BRCA 1. When the markers are present in a patient, we know that the disease is seven times as likely to develop as in an average person. It’s this type of information we need to find and share so that the public might do its best to prevent the disease.”
Illusion or real hope? Stylianos Antonarakis cites some figures as evidence. “In 2004, it took nearly 3 billion dollars, that is to say $1 per letter of our genetic code, to crack the human genome. Today, it takes less than 25 000 dollars. That’s better than Moore’s law [which predicts a doubling of computer power each year].” The era of personalised genetics has just begun.