Interview with our new honorary doctor Zoltán Ivics

Interview with our new honorary doctor Zoltán Ivics HU
Zoltán Ivics is the Head of the Medical Biotechnology Division of the Paul Ehrlich Institute (in Langen, Germany), a research professor studying the evolution, molecular biology and genetic technology applications of mobile genetic elements (transposons). He is one of the inventors of the Sleeping Beauty transposon system, which revolutionized the technological platforms of genetic modifications in vertebrate model systems. He is a leading figure in the gene and cell therapy scientific community in Germany and Europe, a recognized lecturer at Goethe University in Frankfurt, organizer and lecturer at numerous international conferences.

Why did you choose an agricultural university (today, the Hungarian University of Agriculture and Life Sciences, Gödöllő)?

Already as a kid I loved plants and animals and was deeply interested in them (which, at the time, did not go beyond collecting them and keeping them at home as pets. As many, if not most, 18-year-olds, who are confronted with the dilemma of choosing a university for higher education, I was pretty unsure in which direction I should go, except that I was certain that it had to do something with biology. I chose agriculture, because it corresponded better to my interest in learning something that offered hands-on contact with plants and animals, rather than theoretical research.

What ambitions did you start your career with, what was your first research interest, and how did you get to studying "jumping genes"?

The turning point in my interest was when I joined a professor at the university (Laszlo Horvath) as a 4th year student for my diploma project, which led me to a Hungarian consortium (also including Erno Duda from the Biological Research Centre in Szeged) aiming at establishing new methods for genetic engineering in fish. This project was still driven by my interests in agriculture (fish as a food source), but opened up a completely new world to me, represented by genetics and biotechnology. The concept of inserting a new gene into the genome of an animal in the hope that this would fundamentally alter some of the characteristics of the animal not only appealed to me, but fascinated me. Interest in establishing technologies for genetic engineering was the very topic that later brought me to America. There, as the main topic of my PhD project, I began to work with retroviral proteins as potential tools for gene delivery in fish. Retroviruses were particularly interesting, because they evolved, over the course of millions of years of evolution, a molecular machinery that efficiently inserts their DNA into the genomes of their host cells. From here, bumping into transposons was practically inevitable. Transposons have molecular mechanisms of inserting themselves into the genome that are very similar to retroviruses, but their structures and components are far less complex. Transposons have been described from bacteria, plants, worms and flies, but their existence in the genomes of vertebrate animals (including fish) was completely unknown at the time. Therefore, developing a transposon-based method for genetic engineering in fish (and hopefully in mammals including humans) appeared a challenging, but at the same time extremely exciting research project.

You went to the United States as a doctoral student, then returned to Europe as a postdoctoral fellow and finally became a renowned researcher and teacher in Germany. What was the significance of the "peregrine years" for you, and what is the significance of the "peregrine years" for a young researcher in molecular biology in general?

The early years are decisive. These are the years for an early-career scientist when theoretical knowledge, practical laboratory skills and early confidence solidify. There are three equally important aspects of these early years: enthusiasm and passion, endurance and perseverance, finally an environment that is nurturing both scientifically and personally. I believe that success in research is difficult to reach without any one of these factors. I was extremely lucky, because in addition to enthusiasm and endurance, I ended up in a lab in Minnesota led by Perry Hackett, which offered freedom in scientific exploration and a collaborative, friendly environment.

When you returned to Europe, what could have been the reason that you did not end up in Hungary and did not become a leading researcher and professor here?

When I returned to Europe, my choice for a location was not driven by personal feelings at all. One of the European experts on transposon biology (Ronald Plasterk) was based in Amsterdam in the Netherlands. The reason that I joined his lab was mainly the specific expertise in that lab, coupled with my interest in deepening my knowledge in the basic molecular mechanisms involved in DNA transposition. After a two-year postdoctoral period in Amsterdam, I received my first independent leadership appointment in Berlin at a research institute that offered me an opportunity to develop my invention for human gene therapy. Again, this choice was driven by a very specific scientific interest, rather than by any other consideration. Having said that, returning to Hungary in some capacity and at some point during my scientific career has always been a distinct possibility in my thinking.

Please try to outline the significance of the artificial transposon "Sleeping Beauty" developed by you and your wife, Zsuzsanna Izsvák, in a comprehensible way even for non-specialist readers.

The most outstanding potential for the application of Sleeping Beauty for genetic engineering is in curing genetic diseases in humans. Very roughly speaking, gene therapy is based on inserting a functional copy of a gene into cells, where the cells' own gene is defective. In other words, when a baby is born with a defective gene due to mutations leading to a disease, gene therapy offers a solution to cure that disease by adding a functional copy of that particular gene to the cells, thereby restoring its function. The most frequently used method for gene addition relies on retroviruses that I mentioned before. However, retroviruses are complex to manufacture and thus very expensive to produce as drugs. Moreover, they require a special environment to protect both the personnel that work with them as well as the environment from unwantedly getting infected and, very importantly, they can have serious side effects when applied in humans. In contrast, transposons, especially Sleeping Beauty, are propagated, maintained and manufactured as pure DNA in a laboratory, and they are far safer to work with than with a retrovirus, because transposons by nature cannot infect cells. In addition, Sleeping Beauty inserts therapeutic genes into the human genome in a far safer manner than retroviral vectors. Thus, therapeutic cell engineering with Sleeping Beauty is altogether simpler, safer and more economical than with retroviral vectors.

There have been and are ongoing serious ethical debates worldwide regarding the use of gene technology, and there are many misconceptions about it in the general public. In the light of your own research, how do you see the present and the future of these often truly revolutionary methods?

At the dawn of gene technology, at the time when recombinant DNA technologies first offered ways of altering the genetic makeup of living organisms, the Asilomar conference, organized by leading scientists in 1975, outlined the rules and guidelines to work with such technologies in the interest of protecting public health and the environment. Decades of research that followed have delivered strong evidence that recombinant DNA technology is harmless, if those guidelines and regulations are strictly observed. Significant discussions revolve today around genetically engineered plants and animals as a food source. Policy makers often refer to the potential risks of GMO food, but I have the feeling the main arguments are in fact fueled by economic considerations, rather than by scientific ones. Recent developments in gene editing technologies offer an unprecedented level of precision at which the genetic code in an organism can be altered. Unfortunately, legislation classifies gene edited organisms as GMOs, despite the fact that the edit may actually be limited to the exchange of a single nucleotide in the DNA. I agree that caution is warranted every time a new technology emerges and reveals its potentials, but at the same time, I strongly believe that decisions should primarily be based on scientific arguments. Perhaps the greatest ethical dilemma out there today is whether gene editing should be applied to the germline of humans (often referred to as "designer babies"). The society, following a thorough discussion led by scientists, had put a moratorium on human gene editing. I fully agree with this, because the impact of such genetic interventions on humans is currently unpredictable. What is, I believe, ethically fully justified is the use of genetic engineering in human somatic cells to cure genetic diseases. In such applications, the human germline is not affected, and therefore genetic changes are not inherited by the next generation. Because somatic cell gene therapy is actually used to combat devastating diseases, manipulating the genome in those instances are lifesaving and therefore fully justified.

What kind of professional relations do you maintain with the Hungarian research community, including with the Faculty of Natural Sciences of ELTE?

I always maintained a very strong scientific exchange and contact to colleagues in Hungary. I always attend scientific conferences organized in Hungary and I myself organized two such conferences in Budapest, the latest being the Spring School of the European Society of Gene and Cell Therapy, where 150 international PhD students attended. I applied for joint funding together with Hungarian scientists on multiple occasions, which provided a formal framework for deepening the scientific exchange with these partners. My earliest contacts with ELTE-TTK were established with the Department of Genetics, where we pursued a fascinating idea and experimental observation relating to transposon activity in worms and its impact on ageing. This collaborative work has recently resulted in a joint publication. I was then invited by the Department of Biochemistry to contribute to the university's curriculum with a lecture course on genetic engineering and biotechnology. Because I love teaching, I happily accepted and already accomplished two rounds of the course. Finally, recent efforts together with the Department of Immunology focus on strengthening our interactions to establish a nucleus of gene therapy research at ELTE-TTK.

What will you talk about in your honorary doctorate lecture, which is entitled: "Digging in the dirt: How archeogenetics and synthetic biology impacted gene therapy"?

I will cover briefly how I discovered the Sleeping Beauty transposon (with some personal elements of my career as side notes), how we developed this system as a useful tool for genetic engineering, and how it is currently used for human gene therapy. I will also mention the challenges that are ahead of us.

What is your message to the young generation studying molecular biology and biotechnology, what should they focus on, what should they train themselves in, to cope with the many challenges of the present and the future and become successful researchers?

My first message to them is to follow their hearts. Enthusiasm and passion are prerequisites for becoming a successful scientist. My second message is that failure is an integral and natural part of the discovery process. This requires endurance and patience. If enthusiasm and patience are there, then success will inevitably come their way.