Peter Andrews (Arthur Jackson Professor of Biomedical Science, University of Sheffield) is chairing Abcam's upcoming stem cell conference 'Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells' in Cardiff, October 2011. The event will bring together a group of researchers who contributed to the establishment of the embryonic stem cell field. Recently, we had the chance to chat with him about his plans and expectations for this meeting.
"...ideas in science come and go – partly because a field is distracted by new and exciting developments, partly because the technology is not available or other concepts are not available for exploring such ideas that are 'before their time'!"
— Peter Andrews
Q: What sparked your passion for science?
It is always difficult to say what starts you on a path. I always found science subjects at a school more fascinating and something I could do, compared for example to languages for which I never had a good affinity. In some part it probably came from my parents who were interested, though not educated as scientists, and from being intrigued by trying to see how things work. But in truth possibly the biggest draw as a small boy was the fascination with the dramatic – making bangs and bright flashes – something perhaps that is lost these days with our culture being rather more focused on health and safety!
Q: What exciting research projects have been occurring in your lab?
Excitement is always in the eye of the beholder, so what excites me may not being so exciting to others, and many things have attracted me over the years. Right now two areas have my attention. The first is the notion that stem cells exist in multiple states which are interconvertible but may have different properties, such as differentiation potential and lineage bias. Understanding how to recognise this heterogeneity, how to identify cells in different states and how transitions from one state to another is controlled will, we think, be essential to being able to efficiently manipulate stem cells for specific applications. The other area is what we have termed culture adaptation, the notion that ES cells in particular are subject to strong selection for variants that have a higher propensity for self-renewal and less propensity for differentiation. Understanding the genetic and epigenetic drivers of this inevitable phenomenon is essential for the successful application of stem cells, for example, in regenerative medicine. It can also provide us insights into some of the mechanisms underlying cancer development and progression.
Q: How did you first connect with Abcam and come to chair this conference?
I have known Abcam for a number of years as a supplier of antibodies, and my first direct connection probably came when they licensed from the institute where I worked previous, a number of the hybridomas that we developed many years ago for the study of human embryonal carcinoma (EC) cells, the malignant counterparts of embryonic stem (ES) cells. These same antibodies have since found a use in the study of human ES cells. I was also aware of the conferences that Abcam have sponsored and organised, and attended one on stem cell biology in Dublin a couple of years ago.
"...how a field develops is dependent upon imaginative, curiosity driven research – and not by ideas of eventual application"
— Peter Andrews
Q: What were your motivations to organize a conference on Rediscovering Pluripotency?
I presume as a result of my connections over the years, Abcam approached me after the Dublin meeting to ask if I would chair another stem cell meeting. At first I was reluctant since there are any number of meetings on this subject given its widespread interest. However, one of my side interests is history and the history of science, and it has intrigued me how ideas develop over time. In particular, it strikes me as interesting that ideas in science come and go – partly because a field is distracted by new and exciting developments, partly because the technology is not available or other concepts are not available for exploring such ideas that are 'before their time'! For example, as a PhD student in the early 1970's I worked on chromatin: at the time there was a controversy as to whether there was RNA to be found in chromatin and whether it had a function in controlling gene activity, or whether it was an artefact. I think, probably, the consensus at the time was that RNA did not have a role in controlling gene activity – a view that contrasts markedly with the results and huge interest in regulatory, non-coding RNA today. The idea of cancer stem cells is another example – an idea that is old but now going through a renaissance. It was with these thoughts that it occurred to me that it would be interesting to bring together people who had made major contributions to the embryonic stem cell field as far back into its history as possible, and see if they could recall ideas and concepts that were prevalent early on and had been put aside, but that might now be new avenues to address with new technologies available today.
Q: What makes this meeting different from other stem cell meetings?
I think that the historical nature of this meeting and its attempt to see what lessons the history of the field has for its future should make it fun and interesting, with a different feel to other stem cell meetings.
Q: The meeting is about the past and future of stem cell research. What has changed in the field over the last 30 – 40 years?
I think one aspect of the ES cell field is that its history spans two major paradigm shifts in the technology available to biologists. One was the development of monoclonal antibodies. The other, obviously much more wide-reaching, was the development of DNA technology with gene cloning and genome sequencing. In the 1960's and early 1970's, experimental mammalian embryology was particularly difficult because of the problems in accessing the developing embryo. In that time, teratocarcinomas, strange tumours that appeared to recapitulate embryogenesis, albeit in a haphazard and uncontrolled way, offered an opening to many people. That led to the characterisation of embryonal carcinoma (EC) cells as the stem cells of these tumours, and the recognition that they closely resembled the pluripotent cells of the early embryo. In turn this led to the isolation of mouse ES cells, by which time the revolution in molecular genetic was well under way. Eventually that resulted in the use of genetic manipulation of ES cells to produce mutant mice that could be used to explore in detail the genetic control of development. Consequently, the study of teratocarcinomas and ES and EC cells for their own sake went out of fashion and they became tools that facilitated developmental genetics. With some very notable exceptions there was subsequently and for many years little focus on the molecular mechanisms that regulated the stem cells themselves. It strikes me that the irony of this is that whereas the field started with the notion that teratocarcinomas and EC cells would tell us something about the embryo, today with the great interest in applications for human ES cells, it is our knowledge of embryogenesis that in large measure informs research to drive ES cells into particular lineages for regenerative medicine or other uses.
Q: Where do you see things going? What do you think will be the next big breakthrough in stem cell research?
Crystal ball gazing is a difficult and dangerous occupation. I think many would agree that the most recent major breakthrough was the unexpected discovery of the means to make iPS cells. At the moment, following that, it seems to me we are in a phase of 'incremental' science as we piece together the different parts of the jigsaw that will give us a detailed understanding of how to regulate ES cell proliferation and differentiation. There are many challenges to be overcome for the eventual effective use of these cells, whether in regenerative medicine or elsewhere: how to grow large numbers of these cells while retaining their genetic and phenotypic fidelity; how to promote differentiation to particular lineages while preventing differentiation into others; how can we ensure that the differentiated cells express mature functional characteristics; can we generate functional differentiated cells in large numbers directly, for example by transdifferentiation? I think it would be unwise to suggest now how such challenges will be overcome. What is important though is to emphasise to the public that these things will not happen overnight; it is important for the scientific community to be able to tell the public of the excitement and opportunities but not to oversell the work and mislead people into believing that there will be applications readily available tomorrow.
Q: What new and exciting developments may we hear more of at the meeting?
This is impossible to say. Almost by definition, new and exciting developments are not planned – they appear when we least expect them – like the announcement by Shinya Yamanaka in 2006 at the ISSCR meeting that he and his colleagues had discovered that it was possible in a relatively simple way to revert a fully differentiated somatic cell back to a pluripotent state corresponding to such cells in the early embryo.
Q: We have a great line up of international speakers for the conference. Is there a particular topic or speaker you are looking forward to hearing?
These are people who have contributed in a variety of different ways to the field as it has developed, and they are still active today. I hope that they will be able to shed light on how this field has evolved and perhaps identify old ideas and concepts that are worth revisiting, as well as telling us about their own current work. But another aspect of this is to show policy makers, politicians and funders of science how a field develops and is dependent upon imaginative, curiosity driven research – and not by ideas of eventual application. This is true in many areas of science and it seems to me that many of the advances and developments that underpin human healthcare today have their origins in peer-reviewed, investigator-led research. For all the excitement about the potential applications that are now expected from human ES and iPS cells, we would not have got here without the interests of earlier researchers, spread over decades, in the biology of the very strange and rare cancer we know as a teratocarcinoma. That work was certainly not driven by even any thought that one day we might be able to cure diseases by transplantation of functional cells differentiated in culture from stem cells related to those in this cancer.
Q: Who do you think would be most interested in this meeting?
Hopefully the meeting will be of interest to a wide range of people. I am bringing a number of my new PhD students as I feel it will provide them with an important historical context of the field they are now entering. It should also be of interest and instructive to more senior researchers who may be able to gain insights into 'forgotten' ideas that might have relevance to their current work. Then it should also have interest to historians of science, and also to policy makers and funders who might gain, from this particular example, a better understanding of how science works and develops.
Q: Why did you choose that special location for the meeting?
There are obviously many places in the UK and abroad with particular links to the history of ES cell biology. In a sense, though, Cardiff provides a link between the past and the future. Sir Martin Evans was one of the pioneers in the field, recognised by his Nobel Prize a few years ago. At the same time Cardiff is actively building a new presence in stem cell biology, particularly in cancer stem cell biology with their new Institute headed by Alan Clarke, and also in neuroscience where researchers like Steve Dunnett, Anne Rosser and Nick Allen are closely involved research that could lead to applications for treating neurological disease such as Parkinson's and Huntington's diseases.
Q: What are the highlights of your career so far?
I think for me the highlight has really been the opportunity to work with many outstanding scientists over the years, and to see a field in which I have been working, in my case starting with human EC cells and teratocarcinomas, grow from a small niche area into one of widespread interest.