The Foundation for Polish Science (FNP) celebrates its 25th anniversary this year. To mark the occasion, we have invited 25 beneficiaries of our programmes to tell us about how they “practise” science. What fascinates them? What is so exciting, compelling and important in their particular field that they have decided to devote a major part of their lives to it? How does one achieve success?
The interviewees are researchers representing many very different fields, at different stages of their scientific careers, with diverse experience. But they have one thing in common: they practise science of the highest world standard, they have impressive achievements to their credit and different kinds of FNP support in their extensive CVs. We are launching the publication of our cycle; successive interviews will appear regularly on the FNP website.
They Built a Bridge between Poland and the United States
Dr Alexander Wlodawer and Prof. Mariusz Jaskólski, whose joint research has contributed to the development of new treatments for diseases such as AIDS and childhood leukaemia, talk to Aleksandra Stanisławska.
ALEKSANDRA STANISŁAWSKA: Nobel Prize winner Ada Yonath called Dr Wlodawer “the godfather of the Polish mafia of crystallographers”. How did you come to deserve the name?
ALEXANDER WLODAWER: It’s true, the name has stuck, most probably because my example encouraged so many scientists in Poland to take up crystallography. Of course many scientists before me conducted such research, including the famous Rosalind Franklin whose work enabled Crick and Watson to discover the DNA double helix. After that, however, many scientists from Poland, their number reaching at least thirty now, have been developing this field of knowledge, especially as regards research on the structure of proteins. I was simply the first to start working in this field. The crystallography lab I set up at the National Cancer Institute in the United States became a leading centre of this work. I invited Prof. Mariusz Jaskólski to work there, and a dozen or so other scientists from Poland, including Dr Maria Miller who has contributed very significantly to the success of our research. This is the group which made our main discoveries.
How did the two of you meet?
AW: Since 1968, when I was forced to emigrate, I’ve been living in the United States, where I was given an opportunity to head a laboratory and conduct research of a standard that no one in communist Poland even dreamed of. I wasn’t looking for excuses to return to the country that didn’t want me, but when the possibility of attending a conference there emerged in the mid-1980s, I took the opportunity. A meeting of crystallographers was being held at the time in Wrocław, where I met Prof. Zofia Kosturkiewicz from Adam Mickiewicz University in Poznań, a specialist in crystallography. She was the one who recommended Dr Jaskólski as a candidate for a visiting scientist in my lab.
MARIUSZ JASKÓLSKI: Dr Wlodawer was looking for someone to work in his lab on the crystallography of proteins, which are the “molecules of life”, true giants in the molecular world, with a highly complicated structure. At the time, I was studying the crystallography of small molecules. I was really dedicated to my own small world of small molecules and didn’t dream, unlike many other Polish scientists, of a traineeship abroad. But for some reason Dr Wlodawer decided to give me a try. I agreed to go to the United States on condition that he would let me continue my “fiddling” with small molecules. I went there, and… in a very short time I became fascinated with the macromolecular research being conducted by Dr Wlodawer’s team. Within three weeks I was converted: I became a protein crystallographer.
What proteins did you study?
MJ: It was the mid-1980s and – as many people will remember – the world was starting to panic about the spread of AIDS, a disease which at the time meant a death sentence. When its cause was discovered in the early 1980s to be the HIV retrovirus, many research centres and pharmaceutical companies brought all hands on deck to work on finding the weak points of the virus that could become targets for anti-HIV drugs. Dr Wlodawer and his team were also working on this subject when I joined them. The task I received was to use crystallographic methods to study the three-dimensional structure of a retroviral protein called protease. This is one of the three enzymes of the HIV-1 retrovirus, essential for its replication; it functions like a pair of scissors, cutting other retroviral proteins into appropriate fragments. We suspected that HIV protease was similar to other known enzymes of cellular origin, which is why we focused on this particular protein. Our goal was to understand the mechanism of those scissors and to find a molecular trick to block their “blades”. The idea was that this would halt the replication of the retrovirus thus providing an excellent opportunity for developing an effective AIDS drug.
Why was research on an HIV virus protein conducted at the National Cancer Institute?
AW: Obtaining an amount of HIV retrovirus proteins required for crystallography back then verged on the miraculous, or at least was extremely expensive. We didn’t have that kind of funding, but we managed to obtain a similar protein, a protease of the Rous sarcoma virus, ASV for short. This virus causes cancer in poultry, and that’s a topic well within the competence of the National Cancer Institute. This retrovirus is related to HIV-1 and very similar to it. As it turned out, scientists from the pharma giant Merck Sharp and Dohme in New Jersey were also working on the structure of the actual HIV-1 virus protein.
Could you feel an atmosphere of a race, rivalry?
AW: Oh yes, we were taking part in a race driven by endless questions from the media about the results of our work. We were working under great pressure from public opinion.
MJ: I became so engrossed in this research that I spent over a dozen hours at the lab every day. Luckily I wasn’t directly exposed to questions from the press – Alex handled that extremely well, but I felt pressure when scientists working on AIDS drugs, who frequently visited us, practically snatched our results from our hands, even very preliminary ones. Everything happened extremely quickly. Largely thanks to the pressure, we obtained reliable and well-checked results within a record time of several months from the start of our project. It was a huge achievement. But if we were to ask, “do we go fast or carefully?”, at Dr Wlodawer’s lab the answer is always the same: “the latter”.
AW: Our paper on the structure of the ASV protease was published in Nature in early February 1989, and a week later the team from Merck Sharp and Dohme published the results of their research on HIV-1 protease in the same journal. It turned out that although the two structures looked roughly the same, they differed in one significant area.
MJ: It was an extremely embarrassing situation, because without a generally accepted correct model of HIV-1 protease there was no question of rationally developing inhibitors that could become the drugs so desperately needed by AIDS patients. We, at Dr Wlodawer’s lab were certain we hadn’t made a mistake and that our model was correct. But the competition stuck to their results just as strongly…
How did you manage to prove you were right?
AW: We could only do it experimentally. The problem was how to get hold of HIV-1 protease for the study. That’s where we were helped by Dr Stephen Kent from Caltech, who developed a chemical method of protein synthesis and provided us with a microscopic amount of this synthetic HIV-1 protease. The invaluable Dr Maria Miller managed to grow appropriate crystals within a short time, which in itself was a great achievement because it proved that protein chains can fold correctly and crystallize without prior contact with any biological environment.
MJ: We went through the same research process as before, only even faster, and this time with a genuine protein from the HIV virus. And we proved beyond the shadow of a doubt that our structure of the retroviral protease was the right one. We published the results in August 1989 in Science.
Dr Alexander Wlodawer and prof. Mariusz Jaskolski / private archive
Were AIDS drugs developed thanks to this research?
AW: Yes, especially since we’d made it easier by showing the retrovirus protease structure in complex with an inhibitor, which is a compound capable of attaching itself to the protein and blocking its function; such an inhibitor molecule is the best starting point for developing a drug that could stop the virus from replicating. On that basis pharmaceutical companies have so far managed to develop 12 drugs targeting HIV-1 protease. The first one, saquinavir, appeared on the market just seven years after our structure was published. That is an extremely short time for the process of developing and producing a completely new drug. Even today, it may take pharmaceutical companies a dozen or more years to develop a new drug.
MJ: A few years later we also studied the structure of integrase, another member of the trio of retroviral enzymes. But designing drugs targeting this enzyme is a laborious process. Recently, research on integrase has progressed significantly, so we hope that also in this area drugs for AIDS patients will soon be developed. Later we continued studying the structure of proteins of other retroviruses, including HTLV which causes leukaemia.
You also studied a drug fighting leukaemia in children…
AW: It’s true that in the 1990s we were able to describe the chemical mechanism of action of asparaginase, a protein that is important in treating acute lymphoblastic leukaemia in children. In this case the sequence of events was different than for HIV-1 drugs. It had been discovered by accident that asparaginase was effective in treating this type of cancer, but for a long time no one knew why. By studying the structure, we were able to explain this, which helped uncover the mechanism of action of this drug, including minimizing its side effects, and facilitated efforts to create new drugs.
Are you currently working on any projects together?
AW: We are working on improving the quality standards for the Protein Data Bank, which is a huge database containing experimental information on the three-dimensional structure of proteins and nucleic acids. There are about 130,000 structures deposited there, but the quality of some of them leaves a lot to be desired. Since these data are of key importance for many biomedical research projects, including the development of medicines, they should represent the highest possible level of quality, and the research process leading to them should conform to the best standards, to guarantee reliability and reproducibility.
MJ: We are working on this project in two teams – in Poland and the United States. Validation of the quality of protein structures in the Protein Data Bank is one of the research tasks of a National Science Centre (NCN) research grant that I hold together with Dr Zbigniew Dauter, who is a member of Dr Wlodawer’s team. The nature of our research enables us to keep in touch from a distance, which we do mostly over the internet or by phone, though of course meetings in person are also desirable. It so happens that recently Dr Wlodawer has been coming to Poland more often – he is here even several times a year. This gives us an opportunity to freely exchange thoughts, sum up the ongoing work, and draft our joint publications.
You have been collaborating for almost 30 years, living in two different parts of the world. How did you manage to conduct all this joint research in times when the internet didn’t exist?
MJ: I first visited the United States in 1988 to help with the research on HIV-1 protease. I went there for a few months but stayed for almost a year and a half. After that I returned many times to the National Cancer Institute to conduct research with Dr Wlodawer’s team. My subsequent visits lasted a few months each. It was a requirement of that particular research, in which team work is absolutely key. It also needs emphasizing that 30 years ago my trips to the United States were necessary also because it was only there that I had access to the lab equipment needed for this type of research. Today we have equally good equipment at our disposal in Poznań and in other large scientific centres in Poland and in Europe, so it’s much more convenient to do our research right here. Moreover, I’m also proud to say that the Center for Biocrystallographic Research at the Institute of Bioorganic Chemistry of the Polish Academy of Sciences, which I set up and head, is just as open as Dr Wlodawer’s laboratory. We are happy to welcome associates from different countries, enabling them to conduct world-standard research.
Is the work of research teams in Poland and the United States significantly different today?
MJ: I see the main difference in the organization of scientific centres: efficient in the United States, but still wanting in Poland. The biggest trouble in Poland is that we do not have the position of a postdoctoral fellow (we don’t even have a Polish word for “postdoc”), i.e. a middle-level research post that is the “work horse” of scientific research in the West. Postdocs are junior researchers who have already obtained a PhD and over a period of two to five years gain research experience working in good teams worldwide, learning the trade and how to be independent. All research groups in the United States are based on such people. In Poland a similar hiring system is starting to emerge, mainly thanks to the grant system. However, the employment contract system still dominates at universities and Polish Academy of Sciences institutes, encouraging people to stay put, which is very unhealthy in science, particularly at the “apprentice” stage. It results in poor exchange of people and ideas as well as stagnation. Such exchanges are extremely invigorating and important for scientific development. Going far and wide on postdoctoral fellowships, leaving behind a safe, cushy job, has a very stimulating effect on scientists, which is why I regret we don’t have a system like that.
Were you never tempted, back in those tough times when you were collaborating with Dr Wlodawer at the turn of the 1980s and 1990s, to stay in the United States for good?
MJ: I had strong family ties at the time, so I had motivation to return to Poland. Today I don’t regret that decision, because it turned out that doing research on two continents not only is possible but also creates the synergy that is so desirable in science. I don’t know what would have happened had I stayed in the U.S., but looking back on my career I can say that we were able to solve exceptionally difficult problems in a way that is intellectually extremely stimulating. In addition – upon returning to Poland – I set up the country’s first strong centre for crystallographic studies of biological macromolecules. This was a completely new quality. I can say immodestly: I’m really proud of it. But I will also add that I have never abandoned my original scientific roots, the crystallography of small molecules from which I started. Even today, I am still interested in this subject. I view crystallography as a whole, without artificial divisions into “small” and “large”.
And you, Dr Wlodawer, did you ever consider returning to Poland?
AW: I didn’t have such plans because I was too deeply immersed in life and research in the United States. For me, returning to Poland would have meant giving up the enormous opportunities that U.S. research institutes offer. But I’ve maintained close scientific contacts with Poland and the centres here. I am a foreign member of the Polish Academy of Sciences, I support Polish scientists in their activity, I collaborate with many laboratories, share the results of my research, and my door is always open to Poles wishing to do research in my team. I’d like Polish science to become more competitive and the work of research centres to be reviewed according to international, transparent criteria. This is already happening, for example in a more competitive and motivating system of grants, but it’s still not enough. More vigorous actions in this respect could encourage many gifted young Polish scientists to return to Poland and develop their careers here. The fact that many of them remain abroad is a huge problem of Polish science.
What about those who did research in your lab, did they come back or stay in the United States?
AW: A dozen or so came to my lab and most of them later returned to Poland. All of them were and still are truly great specialists.
And is it precisely for building this bridge between Poland and the United States that the two of you received the Poland-U.S. Science Award?
MJ: This is an award of which I am especially proud, because we were the very first people to receive it from two extremely prestigious organizations: the Foundation for Polish Science together with the American Association for the Advancement of Science, AAAS for short. It is of note that the AAAS is the largest U.S. organization for the promotion of science and for bringing together scientists from many different fields. I’m honoured that having so many researchers and so many fields of science to choose from, they chose us. It is a true distinction and source of great satisfaction. Yes, I do think that the chapter of the award considered not only our particular achievements and particular discipline, but also the fact of building lasting scientific cooperation between Poland and the United States.
AW: The achievements of Prof. Jaskólski and myself are documented by over 40 joint publications on the subject of protein crystallography. That’s more than many scientists working in one country and one research centre can boast. For us, distance is not an obstacle but extra motivation to make an effort.
DR ALEXANDER WLODAWER (born 1946 in Ząbkowice Śląskie), heads the Macromolecular Crystallography Laboratory at the National Cancer Institute (NCI) in the United States. Together with Prof. Jaskólski he is a recipient of the Poland-U.S. Science Award (2015).
PROF. MARIUSZ JASKÓLSKI (born 1952 in Inowrocław), heads the Center for Biocrystallographic Research at the Institute of Bioorganic Chemistry of the Polish Academy of Sciences in Poznań and works at the Faculty of Chemistry of Adam Mickiewicz University. He is a recipient of the FNP Prize (2002) and a beneficiary of other FNP programmes: SUBIN (2000 and 2003), MISTRZ (2003), NOVUM (2007), MPD (2008).