In View: People in Transplantation
You grew up in North-East London and joined the Department of Pathology at the University in Cambridge in 1973. What motivated you to enter a career in Pathology?
My father was a General Practitioner—the “plan” was that I would take over his practice when I qualified in medicine. However, my father’s “iatrogenic” death in hospital changed my plans and I reevaluated my career, and what Clinical Medicine was able to offer at the time. I had always felt (from my Cambridge undergraduate training) that Immunology contributed a lot in understanding the pathogenesis of diseases and in providing the basis for new treatments. Thus, I “interrupted” my medical career (after qualifying) to undertake an Immunology PhD in the department of Pathology, Cambridge, UK
You were a visiting scientist with the Nobel Laureate Cesar Milstein at the Laboratory of Molecular Biology in 1978. How formative was this time been for your future career?
I gained much from seeing how Caesar approached science. Moreover, the hybridoma technology described by Cesar opened up huge opportunities to probe the immune system with precise antibody reagents, and to target disease-related molecules in therapy. Being there at the beginning was a fantastic opportunity and privilege.
You have achieved the dream of many clinicians/scientists in bringing a therapeutic from bench-to-bedside. Can you share a few critical steps in developing Campath-1?
Hard to speak of “dreams”—certainly offering treatments for unmet medical needs fulfilled one of my hopes when I entered research. Perhaps more surprising to me was the additional fulfillment to unravel mechanisms in immunity and immunological tolerance—all rendered possible through monoclonal antibody reagents. Throughout my career I found research a humbling process, and could only evaluate my performance on the basis of what we might uncover next, rather than what we might have already discovered.
You mentioned critical steps:
- I had hypothesized on how the immune system made decisions, whether to attack and destroy, or become tolerant. Monoclonal antibodies provided tools to test these hypotheses with the view to providing short-term therapeutic interventions in immunological diseases to gain long-term benefit.
- We generated antibodies to both, mouse and human lymphoid cells, so that we could always run basic and clinical studies in parallel.
- I was able to attract a fantastic team of enthusiastic young scientists who bought into this ambitious project.
- Early on we focused on finding antibodies with appropriate effector functions, and “operational” rather than “precise” specificities. CAMPATH-1 emerged as one of the few antibodies that could utilize the human complement system to kill lymphocytes while sparing stem cells.
- In the early period, there was some pessimism about whether antibodies would be useful drugs, as they were produced in rodents, and would be rejected by humans. All that changed in the late 1980s when, in collaboration with Greg Winter, we were able to convert the rat form of CAMPATH-1 into a humanized form. This was the first humanized antibody to be injected into patients, and we believe, was a catalyst for the antibody revolution which followed.
- We created our own GMP manufacturing facility which allowed us to perform clinical studies based on our best academic information, rather than commercial and institutional considerations that drive the pharmaceutical industry.
- We were able to identify many gifted medical collaborators who were able to undertake clinical studies that guided further basic science as well as future clinical application.
- All this can be summarized by saying that I do not think CAMPATH-1 could have emerged through the conventional drug discovery route in Pharma, nor through professional opinion-leaders who advise them.
What would you consider the ideal transplant population benefiting from the treatment with Campath-1?
My experience tells me that it is too early to answer that question, as the outcome depends on how it is used. In general terms I could, at least, say “to encourage drug minimization”.
While being a very effective lymphocyte depleting agent, homeostatic proliferation subsequent to Campath-1 treatment requires the ‘right’ drug combination to reboot the immune system in an optimal way. Can you speculate on an optimal immunosuppressive maintenance therapy applied with Campath-1?
We are working hard on that ourselves in what we call Physician Aided Reconstitution of the Immune System (PARIS). Thus far, we know that some degree of favorable reconstitution can be achieved in rodent models; however, this needs to be a treatment that is as simple as possible based on licensed drugs with known safety profiles. Perhaps a more promising avenue is to ensure that the lymphocyte depletion is “staggered’ during the induction phase so as to be less prone to a chaotic rebound. In regard to an optimal maintenance treatment, all I can say at this stage is that we need a regimen that gives an advantage to the reconstitution of cells with strong regulatory properties over conventional immune cells.
The commercialization of Campath-1 had been an exciting ‘adventure’ by itself. What have been critical steps?
This has indeed been a special and very educational experience. Some key experiences included:
- Dealing with unfounded perceptions of opinion leaders, and heads of Pharma with evangelical opinions of what is needed.
- Persuading Pharma that profits can be made from short-term therapy rather than prolonged immunosuppression.
- Trying to maintain contact with the pharmaceutical companies to be able to express opinions and advise. CAMPATH-1H has been through numerous biotech/pharmaceutical company owners, only one of which (early on) encouraged good 2-way communications. For example, our laboratory demonstrated early on that Lemtrada could be given subcutaneously with less immediate side effects, and much more convenience to the patient. Unfortunately this patient-friendly approach has not been taken up.
Understanding how Tregs Cells contribute to health disease has been another research interest. How can we best use the knowledge on Tregs Cells to induce tolerance?
To early again, I think, for me to give a wise comment—but my intuition is that we need to understand the privileged microenvironments that Treg cells can establish in tissues, and investigate ways to encourage these. Perhaps we can learn a lot from studying subsets of tumors that resist immune attack.
Looking back to a most productive career in immunological research what do you consider the most relevant ‘soft skills’ for a successful career in transplantation research?
Indeed a good repertoire of soft skills is critical. Just to name a few:
- Choose the right partner in your domestic life
- Do not let the b…s… grind you down
- Run a good team and keep your colleagues fulfilled in their career/life aspirations
- Do not believe everything you read, but believe in scientific rigor.
- Keep hoping that grant-awarding bodies and journals create a milieu where scientists can adequately pursue and convey their work, without being at the mercy of a few oligarch-transients.
How do you enjoy spending time away from work? What is intellectually inspiring outside of the laboratory?
Not an easy question—and things change as I get older…a few key observations:
- As perhaps predicted—spending time with my family and admiring the way they forge their own lives keeps me intellectually stimulated; I hope that our society will find routes to support that ultimate satisfaction in as many as possible.
- Listening and playing music by Chopin and Liszt (although nonimmunological neurological issues are a current challenge!)
- Reading different views on historical events-which constantly teach me that one should always leave an element of doubt in one’s mind on any matter.
- Finally—a great enthusiast for DIY around the house (Do not Involve Yourself)!