2021 Curt Stern Award: Studying the biology of “junk”

Summary

This article is based on the address given by the author at the 2021 virtual meeting of the American Society of Human Genetics (ASHG). The video of the original address can be found at the ASHG website

Main text

I feel honored and humbled by Stylianos’ introduction but even more by the nomination and selection by the awards committee to receive this prestigious and unique award. Since I started attending the ASHG meeting in 2000, I was always impressed by the quality of the awardees, and it feels really special to be part of this group of scientists. This award is clearly the recognition of the work of so many colleagues and collaborators over the years that I was fortunate to work with.

My history in science has been relatively traditional, starting from the University of Crete, where I did my bachelors and master’s degrees in biology, but the big transition was the move to the US in 1997 to do my PhD at Penn State University with Andrew Clark. It is there I was first exposed to the world-leading science and realized the excitement, but also the challenges, to be operating at that level. For my post-doc, I moved back to Europe and the University of Geneva in Stylianos Antonarakis’ lab, and after a relatively short post-doc of 2.5 years, I moved to my first faculty position at the Wellcome Sanger Institute, where I stayed for 5 years. In 2009, I moved to the University of Geneva as full professor, where I stayed for 12 years until I recently moved to GlaxoSmithKline (GSK). At every single step in my career I was fortunate to have great colleagues, and I made a lot of friends and had a lot of fun doing science.

My whole career I have worked in the interphase of population genomics, functional genomics, and computational biology. The complexity behind the population variability of a phenotype is fascinating—combining information from the genome as well as the interactions of the environment. These interactions and effects occur in cells, tissues, and organs and cumulatively result, over time, in the manifestation of diseases, in most cases complex and multifactorial. In order to disentangle the specific effects, understand their pathophysiology and make predictions about possible therapeutic hypotheses, we need to study the molecular underpinnings of these interactions and their progression from risk to disease manifestation in disease-relevant tissues.¹

It has been demonstrated that the vast majority of genetic effects driving complex disease impact non-coding regulatory DNA,² so my research has been focused on understanding the degree of variability of regulatory DNA,^3,4 its tissue specificity,^5,6 and its relevance to disease manifestation.^7,8 From the beginning of my career, even during my undergraduate years, I was fascinated by the role of non-coding DNA in the function of the cell and the subsequent biological interactions. Even at that time, non-coding DNA was considered “junk,”⁹ and in many cases it was considered not relevant for exploration and further analysis. We can all agree that by now we have realized the value of non-coding DNA not only to the overall functionality of the cell but also with respect to driving evolutionary change.

My laboratory over the last 10 years has focused heavily on understanding the contribution of genetic variability in regulatory DNA to phenotypic variability and disease risk. We have employed innovative methods to disentangle these relationships, such as expression QTL analysis, and have extended these methods to other molecular phenotypes beyond expression such as chromatin modifications,¹⁰ methylation, and proteomics. We have used all this information to build models that bridge genetic variability with the ultimate disease manifestation, contributing not only to the understanding of the molecular underpinnings of disease but also providing therapeutic hypotheses via modulation of key genes in this process (Figure 1).

Figure 1.

Propagation of signal from genetic variation to regulatory phenotypes (chromatin, gene expression) to regulatory networks leading to disease risk and manifestation

It is true that my career has brought a lot of successes, a lot of moments of celebration, such as this one today. However, we tend to forget that success is not a linear road but rather a bumpy road sprinkled with failures and setbacks. I want to take the opportunity from this position to highlight how failures in my life have been the foundation of any successes. Many of my failures, such as requiring a second attempt to enter university in Greece, getting low grades at university, failing to obtain an EMBO post-doc fellowship, or having several rejected grant proposals and papers, have facilitated my development, maturity, and realization of my strengths and weaknesses. These were the triggers that allowed for further development and improvement. And I want to make sure that junior colleagues that are listening today are aware that their setbacks are by no means an obstacle for future success but rather the foundation of future success.

There are so many people I would like to thank today, and there is no time to mention all of them one by one by name. I would like to start by thanking all the colleagues in my laboratory over the years, and in particular the last 10 years, who have honored me with their collaboration and have contributed significantly to all these successes that brought this award. I would also like to thank my mentors over the years, and in particular Lefteri Zouros, Andrew Clark, and Stylianos Antonarakis, for giving me the foundations to become a scientist. I have been blessed with many collaborators internationally, and I want to thank them all today for all the things I learned from them, and of course the funding agencies that supported our work over the years.

I would like to also thank my parents and my sister, who have always supported my career, my explorations around the world, and have always encouraged me to go after my ambitions and passion.

But more importantly, I would like to thank my wife and my three children who are a continuous source of inspiration for all the work I have been doing and for being next to me and supporting me in this exciting adventure.

In normal conditions, I would be celebrating tonight with all my friends from ASHG like we have celebrated previous awards and other occasions in the past. But I want to promise everyone that we will be able to celebrate in 2022 when we are hopefully back to normality.

Again, I want to thank the Society and the committee for giving me this honor, which I will always cherish as one of the most important moments of my scientific life. Thank you all for your attention.