„Žurnalistika kitaip“(“Different Journalism”) starts a series of articles, which will help you to get familiar with foremost recognized scientists in the world, get a closer look at them and find out, what is hidden behind the famous names. Our first interview - with Dr. Tony Hunter.
Dr. Hunter is one of the leading scientists in the field of cell growth control, growth factor receptors and their signal transduction pathways.
The scientist is well known for the discovery of tyrosine phosphorylation and established, that it is the fundamental mechanism by which growth factors via their receptors transduce their signal to the nucleus. He also laid a foundation for the research, showing that tyrosine phosphorylation is one of the important causes for the oncogenic transformation of the cells, eventually leading to cancer.
Five years ago he was awarded with the Wolf Prize in Medicine for the discovery of tyrosine kinases.
Other awards and honors:
* 1987 Fellow of the Royal Society;
* 1994 Charles S. Mott Prize by the General Motors Cancer Research Foundation;
* 2001 Keio Medical Science Prize;
* 2004 Louisa Gross Horwitz Prize from Columbia University;
* 2006 Pasarow Award in Cancer Research;
* Member of the US National Academy of Science.
The area of your research is molecular cell biology. Were you attracted to life sciences already at school?
I grew up in England near Canterbury. My father was an MD, and got me interested in biology, and at the age of 7 I started to study biology as one of my subjects in a private preparatory school in my hometown. When I went to public school (i.e. a private boarding school) at the age of 13, I specialized in science almost immediately, and in my final two years I was lucky enough to have a teacher who was very interested in biochemistry and taught me everything he knew. When I went up to Cambridge University to study Natural Sciences, I found biochemistry to be the most exciting subject. In my third year I took biochemistry as my honours course, which was given in the Department of Biochemistry. I did well in the final exam, and someone in the Department suggested that I apply for an MRC studentship to do my graduate work in the Department. I was awarded the studentship, and decided to work with Asher Korner, who was studying hormonal control of protein synthesis, and was really the only “molecular” biologist in the Department at the time.
When I finished my PhD in 1968, I was not certain what to do, although I knew I wanted to continue in research, and a colleague suggested that I apply for a college fellowship, which would provide support for four years while I continued to do research in the Department. Once again, luck was on my side, and I was awarded a research fellowship at Christ’s College, which enabled me to stay on in the same group in the Department. By this time, Asher Korner had moved to take up the Chair of Biology in Sussex, which left a small group of us with college fellowships to work together in the same space, including Tim Hunt and Richard Jackson. After two years, I accompanied my first wife Pippa Marrack, who had been a fellow graduate student in Alan Munro's lab a couple of years behind me, to La Jolla, where she was going to do a postdoc with Dick Dutton at UCSD. We were both intending to come back to Cambridge after two years, and I was not certain whom I should work with in La Jolla for this period. Coincidentally, Alan Munro, a new faculty member in the Department, who had become an unofficial mentor for me when Asher Korner left, had just got back from a one year sabbatical at the then brand new Salk Institute, and suggested that I go and work for Walter Eckhart, a new faculty member at the Salk, who was using polyomavirus as a model system to investigate the mechanisms underlying human cancer. At the end of two years, Pippa and I had split up, and she moved to Rochester, NY while I went back to Cambridge for the final year of my college fellowship and to look for a job. Before I left the Salk, Walter Eckhart had offered me an Assistant Professor position in the newly formed Tumor Virology Laboratory, which I had turned down. However, after a couple of discouraging rejections for jobs that I had applied for in England, I approached Walter to see if his offer was still good. It was, and the rest is history. In retrospect, I never made a conscious decision to embark on a career in research, and in many ways I seem to have taken the path of least resistance and have been fortunate on several occasions when a critical decision had to be made.
You have graduated from The University of Cambridge. What are the most memorable moments of your studies?
In Asher Korner’s group there were 9 graduate students (three per year all doing three-year PhD degrees). Among the students were Richard Jackson, Tim Hunt and Brigid Hogan, all of whom went on to have eminent careers in science, and become Fellows of the Royal Society.
In my second year, I started working with Tim Hunt, a fellow graduate student, to study how hemoglobin is synthesized in rabbit reticulocytes. There were many memorable moments scientifically in the course of this collaboration. We set out to test whether ribosomes on the globin mRNAs “paused” two thirds of the way along to await the insertion of the haem prosthetic group, as had been proposed. We did this by isolating polysomes from 3H-leuicne-labeled reticulocytes, and then analyzing the tryptic peptides generated from nascent chains afar mixing in uniformly labeled 14C-labeled globin by two-dimensional paper chromatography and electrophoresis, comparing the ratio of 3H/14C in each peptide. Because we knew the complete sequence of the alpha and beta globin chains, we could display the 3H/14C ratios along the length of the chains, and from the linearity of the plot establish that ribosomes do not pause. We also found that the polysomes for the beta chains are smaller on average than those for the alpha chain, and suggested that this was accounted for by a longer translation time for ribosomes traversing the coding region of the beta chain mRNA, which is essentially the same length as that of the alpha chain. It turned out that our interpretation of the experimental measurements of the translation times was flawed, and we were politely corrected by Harvey Lodish, who reported that the translation times for alpha and beta chains are the same, and that the polysome size difference is in fact due to a faster rate of initiation of ribosomes on the alpha chain mRNA.
Just after I got my PhD, I started working with Richard Jackson trying to determine how globin chain translation is initiated, testing if a specialized methionyl tRNA was used, as had just been shown to be the case in bacteria. Of course, there was no nucleotide sequence of the globin mRNAs, and so we could not be certain! This turned out to be a very competitive situation, and in the end we were one of three groups who showed that a methionine donated by an initiator tRNA is indeed used to initiate translation, but that it is cleaved off the nascent chain as it reaches a length of about 40 amino acids and emerges from the 60S subunit of the ribosome, which is why the initiating methionine is not present on the mature alpha and beta globin chains. In fact, we should have guessed earlier that the synthesis of the globin chains did not initiate at the mature N-terminus, because the only point in our nascent chain peptide mapping data that did not lie on the line, was the N-terminal peptide, which with hindsight was telling us that the peptide had to be different in some way as would be the case of there were an extra N-terminal residue, such as methionine.
One amusing anecdote from my time in Cambridge that comes to mind is the occasion when we wanted to make some 32P-labeled globin mRNA for ribosome binding studies. For this purpose, we decided to label an anemic rabbit by injecting it with 50 mCi 32P orthophosphate and isolate the labeled reticulocytes from the blood. What we had neglected to consider is that most of the 32P orthophosphate would be excreted in the urine, and we ended up with 32P contamination of pretty much everything in the radioactive suite! Another traumatic experience was the fire in our lab, which started late one Friday evening and burned for several hours before it was discovered. Almost everything, including all our lab notebooks was destroyed, but despite losing their vacuum the under bench liquid nitrogen canisters still had some liquid nitrogen and we were able to rescue most of our precious biological samples. Luckily, we were offered space in a new laboratory building on the New Addenbrooke’s site where the MRC Laboratory of Molecular Biology is located, and we were doing experiments again within a month! Max Perutz, the Director of the LMB at the time, very generously offered us dining rights in the LMB cafeteria on the top floor while we were refugees. It was a lunch meeting with the TMV group at LMB that led to a collaboration in which we showed that the viral coat protein is not synthesized as a result of translating the full length virion RNA, which has plus sense, but rather is made from a subgenomic RNA, representing a copy of the 3’ end of the genome, which is transcribed by the viral polymerase from the minus strand of replicative intermediates in the infected cell. This was the first example of a virus using what is a common subgenomic mRNA strategy to encode proteins from a multigenic genome.
You are the scientist. What does that mean to you?
To me being a scientist means developing and testing a hypothesis experimentally, and critically assessing the data to determine whether they support the hypothesis. It is important to have an open mind about your data, and, if they do not support your ideas, one must be willing to develop a new hypothesis to explain your results. An example would be the discovery of phosphotyrosine, which came out of an experiment where I was trying to determine whether polyomavirus middle T antigen was phosphorylated on serine or threonine in the in vitro kinase reaction. Since the radioactive spot generated upon hydrolysis of middle T did not comigrate with phosphoserine or phosphothreonine on the thin layer plate, I had to come up with an alternative explanation, and this led me to propose that this compound was phosphotyrosine. This led to the discovery of a whole new family of protein kinases.
What is the most exciting thing about your work?
The most exciting thing is to make an unexpected discovery – this has only happened to me a few times: the discoveries of the TMV coat protein subgenomic mRNA, tyrosine phosphorylation, and that RING fingers are E3 ubiquitin ligases are three of the most important.
What is the greatest joy in your life?
Professionally, my greatest joy is learning about an exciting and unexpected finding in my field, but of course my family is very important, and particularly the outdoor activities that we do together. This year we spent 16 days white water rafting through the Grand Canyon, and had an exciting and challenging time negotiating the major rapids and hiking in the side canyons.
What is the funniest or weirdest thing, which happened to you at work?
Perhaps the weirdest thing that happened to me was on my 35th birthday, when several of my friends organized a surprise birthday party. When I was taken to the room I found a massive rock-like chocolate cake in which a wooden sword was embedded, and I had to pull “Excalibur” out of the cake. Then the sword was used for a mock knighting ceremony, where I was dubbed Sir Tony the Inflatable, in reference to my passion for river running, by one of my friends dressed up as Queen Elizabeth I!
