Throughout his 30-plus years as a physician-scientist, Stylianos Antonarakis, M.D., D.Sc., president of the Human Genome Organisation (HUGO), has sought better understanding of human disease. Originally trained as an M.D. in Athens, he went back to school to study genetics at The Johns Hopkins University, where he worked with genetic medicine pioneers Victor McCusick and Haig Kazazian. Now at the University of Geneva in Switzerland, Antonarakis has been prominent in genomics research since its early days, studying diseases such as thalassemias and trisomy 21 and investigating the relationships between genomic and phenotypic variation. In the following interview, Antonarakis discusses his new role with HUGO, what genomics means on a global scale and what may be genomics’ most difficult challenges.
It means I participate in a lot of conference calls! [Laughs] There are a lot of exchanges of ideas and organizational efforts with the HUGO council. In the larger context it means that I am heading an international organization whose main mission is to introduce genetics and genomics into healthcare on a global scale. A major advantage to HUGO is that it’s international and looks at the impact of genetics in everyday life around the globe. We work not just in the countries that produce the knowledge but also in the countries that can use the knowledge to improve human health.
Yes, disseminating the knowledge across borders is complicated and difficult. Working through ELSI [ethical, legal and social implications] in different countries and different cultures is very important, and it can take on a new meaning when you’re working in a nonindustrial society. What are the health needs in those societies? How much human suffering—health and disease—is related to genomes and how much is related to environment in those countries? It hasn’t been looked at in a comprehensive, scientific way, and it’s important to do a global study to assess it. WHO [World Health Organization] headquarters are near where I work in Geneva, and they’re asking just how important is the genome? Most of their budget is for infectious disease, and it’s been difficult to quantify the importance of genomics in public health worldwide.
We know that the genome plays an important role in diseases like cancer, diabetes, schizophrenia, obesity, asthma and so on, but it will be very helpful to quantify it on an international scale, to know exactly what we’re talking about in the next few years.
I started out as a pediatrician in Athens. During my years there I saw that genetic disorders are common but most are unknown and, as a doctor, I was unable to treat them. So I decided that the best thing to do was to study genetics, and I went to Johns Hopkins, where I worked with Victor McCusick and Haig Kazazian. We were doing research into thalassemia, a blood disease that is most common around the Mediterranean and caused by mutations in the beta globin genes. Just finding another mutation was sometimes enough to get a Nature paper—it was an exciting time. But in 1992 I decided to leave a full professorship to come back to Europe, because the coffee is better here! [laughs] Well, that’s not the reason I came back, but the coffee really is better!
At the University of Geneva we were looking at developing better research through more effective collaborations between research and clinical departments. So we created iGE3—GEnetics, GEnomics, GEneva—to promote research and teaching in genetics and genomic analysis. We now have about 65 members investigating the structure and function of the genome, working in genomics training, model organisms, ELSI and tying it all in to human health.
We’re very lucky in Switzerland; we have stable funding through an outstanding national funding agency. The evaluation is similar to that of the U.S., but here each investigator has a cap of how much money he or she can get. If you can write a good grant every three to four years, you don’t have a rat race of writing grants all the time—you know you can’t have more. Also in most European countries the PI’s baseline salary is supported by the institution, which also helps ease some of the grant pressure. Some people argue that it might make us too comfortable, that we won’t produce as much, but if you look at the productivity per investigator, Switzerland does very well.
I am looking at human genome variation and function. After I worked with thalassemia I became interested in trisomy 21, which is a difficult multigenic disorder to research with a complex phenotype. That led me to the human genome sequencing, and I was involved with sequencing chromosome 21. We published that in Nature in 2000. So I’ve participated with the groups working on genome sequencing, the HapMap and ENCODE—it was a natural evolution.
In the near future I see genomic analysis having an important impact for cancer care, identifying driver mutations, tracking tumor history, targeting tumor vulnerabilities and developing more focused therapies. I see every primary tumor and metastasis being sequenced and treatments based on the specific driver mutations.
Genomes will be able to give us better risk assessments over time. Right now they are based on very limited knowledge from GWAS [genome-wide association studies], so they will only improve in the future. So the question is how well we’ll be able to apply the knowledge from genome sequencing in industrialized societies. How quickly will it become a reality? How quickly will the greater scientific knowledge and lower costs of sequencing and informatics and analysis make the knowledge useful? I don’t know the answer to that.
Moving forward, I think the biggest scientific obstacle we face is understanding genome variation. Which variants are pathogenic, and which are neutral? What is of interest and will actually have an impact for patient care? It will take a long time to understand genome function at the nucleotide level, to know the pathogenicity or lack thereof for each variant.