St Mary's Branch: An Interview with Paul Farrell
The London St Mary’s Branch of Molecular Virology was established at Imperial College in 1986 under the leadership of Dr. Paul J. Farrell. On July 31st 2005, the Branch will close to consolidate LICR resources in London, and Dr. Farrell will become an LICR Affiliate based in the Department of Virology at Imperial College. Here he reminisces about the Branch history and talks about some of his future plans with Dr. Sarah White (Director, Office of Communications).
SW: The predominant focus of study at the St Mary’s Branch has been viruses and the cell cycle, how did that come about originally?
PF: In the 1980s tumour virology was still dominated by the study of SV40, polyoma and adenovirus – viruses that do not actually cause cancer in humans. The objective at the London St Mary’s Branch was to develop a research program on human cancer viruses and relevant cancer cell biology. Epstein-Barr virus (EBV) and human papillomaviruses (HPV) were the viruses I chose to study. It was already apparent that interference with cell cycle control and cell survival would be part of the mechanism by which these viruses contributed to cancer so it was natural to focus the rest of the program around those topics and relevant tumour suppressor genes or proto-oncogenes. This clear view of what the lab was about was important.
SW: The p53 aspect of this research plan in particular has certainly yielded some terrific research findings from the Branch.
PF: Oh, absolutely. That all started from Karen Vousden joining me as an Assistant Member to set up the second group. I didn’t know her beforehand; she was a post-doc in Doug Lowy’s lab and just applied to the advert I put out. It was very fortunate that she happened to want to return from the US at just the right time and we got on well. I remember interviewing her in the temporary windowless office I was given in the Psychiatric wing of the Hospital (the Ludwig labs were under construction), hoping she wasn’t put off by the groans of the inmates! The way the lab program developed became a combination of our overlapping interests. Although she worked on HPV E6 and E7, Karen soon began to focus more on the biology of the p53 and Rb pathways and she has made some really important research contributions. She was an excellent appointment as Director of the Beatson Institute, near Glasgow, one of the main cancer research institutes in the UK.
Then when Karen left I hadn’t expected to recruit somebody in such a closely related research area as Xin Lu but it was obvious that she would be successful in our Branch and she fitted perfectly with the research strategy. She had great success in identifying the ASPP gene family proteins that can modify p53 function and now look to be clinically important proteins in cancer. It is a great distinction that she was promoted to run the UCL Branch, I think only the second instance of an internal Ludwig promotion to Branch Director [Ed: Paul, himself, was the first, having been promoted from the ranks of the LICR Cambridge Branch, upon its closure, to head St Mary’s.].
SW: So back at the start of the Branch, there were two groups and your temporary headquarters were in the Psychiatric Wing?
PF: (Laughing) We weren’t in the Psychiatric wing for long, don’t worry. We soon included a clinical research group within the Branch, which was the normal Ludwig Branch structure at that time. We employed a new consultant oncologist, David Cunningham and some clinical research staff. He did some nice work on monitoring minimal residual disease in lymphoma by PCR and antisense strategies in lymphoma; also important early studies on the 5HT antagonist anti-emetics that became widely used in chemotherapy patients. David is now head of the Gastro-intestinal cancer unit at the Royal Marsden Hospital. We also had a series of clinical research fellows doing their PhDs in the lab, several gynaecological oncology ones to help with the papillomavirus project and some clinical oncologists. They are all hospital consultants now, and a few have continued with active research programs, for example Nicholas James, who is an Oncology Professor in Birmingham.
SW: So Paul, what has been your philosophy in creating and running the Branch?
PF: It always seemed to me that creating a very interactive environment where people feel encouraged to show initiative and get on with original research is the most important aspect of running the unit. In some ways that is contrary to the idea of a Ludwig Branch directed on a single research topic but I think the synergy you hope for is the real reason for bringing people together. Our Branch was always fairly productive but there were certain good periods when really innovative and creative work was done. That sense that things are really moving forward is one of the most rewarding things in science. Because our Branch was small, running the unit was never very difficult. I was also fortunate to have an excellent Branch Administrator in Julie Curtis. Julie joined us as assistant to Campbell Robertson, and when he retired she took over as Administrator. In addition to the usual administrator duties, Julie developed an important pastoral role for herself with the staff, helping them with all sorts of problems. It was a key part of the sense that the lab was a very supportive place to work, in some respects like a family.
SW: Speaking of family, one thing that really stands out from the Branch’s history is that so many of the Branch’s ‘youngsters’, so to speak, have gone on to key positions in the UK scientific community. Why is this?
PF: As I began to recruit staff, it didn’t take long to discover that young people like to come to London but the high cost of living in the capital can make it difficult to attract older scientists who have other commitments and costs to consider. Focussing on attracting good Assistant Member grade people for career development was the obvious strategy. This fitted well with the Ludwig philosophy of only a small proportion of staff remaining long term to achieve full Member or Investigator appointments.
SW: We all know about Xin Lu and Karen Vousden, but who else from the ‘alumni’ comes to mind as achieving big things in the scientific community?
PF: Well we trained over 50 research students, mostly PhD students and some of these have gone on to very successful research careers, with quite a few of them now group leaders at good Universities or Institutes, for example Graham Packham and Gareth Inman from my group at Southampton and the Beatson Institute, respectively. Some of the other Assistant Members who have gone on to good positions would be David Rowe, an Associate Professor in Pittsburgh and Fritz Propst, who returned to Austria. Of course, Eric Lam, who joined us originally as a post-doc with Roger Watson, and then became Assistant Member with his own group, is now at Imperial College Oncology Department and Eric is one of the leading scientific members of staff there now.
But Sarah, it’s not just the scientific community; we have contributed just as many clinical researchers by the opposite route, scientific PhDs deciding to train into medicine after their time with us. Tim Crook was the first of these and he has just completed his MRCP part 2 but there are four others at various stages of the training and I hope they will all be active clinical researchers. Tim is now a group leader at Breakthrough labs at the Institute for Cancer Research in London: he has done such good work on genetic and epigenetic markers that influence the outcome of chemotherapy, I am sure it will be the basis of future clinical application. His motivation and enthusiasm for research was also an inspiration for many in our Branch. The other basic scientist who has made a big contribution with clinical application is Cliona Rooney, who was in my EBV group as Assistant member at one stage. She is working now at Baylor (College of Medicine, Texas, USA), and has been instrumental in the successful immunotherapy of EBV associated lymphoma in transplant patients using specific cytotoxic T cells. It is by far the most successful and reliable cancer immunotherapy achieved to date.
SW: A lot of the LICR staff today know you as the Director of the Microarray Program, and that’s how I first met you in fact. So, how would you describe the Microarray Program and its impact? Some see it as a very useful technology for LICR, others that the technology never quite delivered on its promise.
PF: Personally, I had a lot of fun setting up the microarray program with you and Parmjit (Jat, formerly UCL Branch Associate Member, now an Affiliate at the Medical Research Council’s Prion Unit, Institute of Neurology in London); our outings to visit other labs and companies to see what they were doing stick in the mind. Although, remember the complexities of our interaction with the Sanger group, and our ‘rescue’ with the assistance of Brian and Victor (Stevenson and Jongeneel, respectively, from the LICR Office of Information Technology)? [SLW: Complexities indeed! It’s a little known fact that the tripartite consortium came very close to imploding at one stage from pressures and delays caused by technological and bioinformatics issues that arose as the entire microarray technology developed so rapidly. Paul, single-handedly and with a lot of ‘behind the scenes’ time and effort, kept all the representatives at the table, while managing the inclusion of the LICR Office of IT to assist in sorting out some of the issues.]
There is no doubt the program benefited labs in many of the Ludwig Branches and produced some good publications. Some locations had superior local array services and some people just couldn’t get the technology to work but almost every Branch received some arrays and some did a lot of work with them. I liked the way the program involved many Ludwig locations interacting on their own initiative, part of the philosophy that has become diluted in recent times. In the last few years, the commercial arrays have become more effective for expression profiling but that was not the case when the program was implemented.
SW: So now you and your group are becoming part of the Department of Virology at Imperial College. The St Mary’s Branch relationship has always had a very close relationship with the Department, right?
PF: Well at first, the Ludwig Branch ran almost completely independently of the University, but the change of Ludwig strategy (when Lloyd Old became Director) to favour interaction and integration came at the right time for us. We needed to get more space for our expanding research program and the only way we could achieve that was by taking over the adjacent labs, which belonged to Virology. Fortunately there was some relationship to our tumour virology work; I sometimes wonder how things would have developed differently if another Department had been located next door to us! The former Virology Department was quite run down and we were able to renovate and really get it going again as part of the infectious diseases initiative at St Mary’s (the Wright-Fleming Institute), which was part of the Imperial College rationalisation of what the different sites in the new Medical School would specialise in. My long-term colleagues Martin Allday and Roger Watson were both appointed into the Virology Department and it has become our home as the St Mary’s Branch closes. We were fortunate to have attracted Geoffrey Smith to head the Department and make it a lot more substantial.
SW: And where do you see your future research heading?
PF: The virus associated cancers have traditionally been seen by some as a bit of a side issue in cancer biology, but if you analyse what molecular biology has done for cancer treatment or prevention in the last 30 years, I think the vaccines against hepatitis B and human papillomaviruses will prove to be some of the most important achievements of the scientific community. The basic therapeutic problem of distinguishing cancer cells from normal cells must be helped by having a virus marking the cancer cells, as is the case in the EBV associated cancers. Recent clinical trials from both GSK and Merck have already proved the success of HPV vaccination, and, by the way, great credit has to go to Luisa (Villa, Sao Paulo Branch) for her basic research and epidemiological studies to get industry to the stage of clinical trials. As for EBV, recent GSK experiments suggest a vaccine may prevent infectious mononucleosis, but it doesn’t prevent infection, so I don’t think we shall see prevention of the high frequency EBV-associated cancers like nasopharyngeal carcinoma in South East Asia by vaccination.
We have spent many years working out the basic biology of the virus, trying
to understand how EBV makes B cells proliferate and how the virus replicates
but it is now more important to study the viral functions that are expressed
in cancers with the hope that they might be used to target a therapy, perhaps
analogous to the way acyclovir is so effective at treating herpes infections
because it is only activated by a gene expressed by the herpesvirus in infected
cells. And that is going to keep us busy for quite a while!