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An Interview with Christine Mummery

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Biosketch: Christine Mummery studied Physics at the University of Nottingham, UK, and has a PhD in Biophysics from the University of London. In 1979, she received a postdoctoral fellowship from the Royal Society (UK) for research at the Hubrecht Institute where she studied ion channels in neuroblastoma cells during neuronal differentiation. This led to an interest in the control of differentiation and from 1982 onwards she studied firstly mouse embryonal carcinoma (EC) cells, then human EC cells (through collaboration with Chris Graham, John Heath and Martin Pera, then all in Oxford) and later mouse embryonic stem cells (through collaboration with Martin Evans and Colin Stewart). Christine recalls, ‘Once teratocarcinoma as a malignant disease became curable by chemotherapy after ~1988, it became very difficult to find funding for research on pluripotent stem cells as at that time they were considered neither “real” developmental biology nor an important cancer research model’, so for 10 years she studied the role of transforming growth factor β (TGFβ) in early mouse development, more specifically its effects on vasculogenesis, as mutant TGFβ mice have embryonic lethal defects in yolk sac vasculature. The first report of isolation of human embryonic stem cells (hESC) rekindled Christine’s interest in the control of pluripotency and differentiation and through collaboration with Martin Pera and Alan Trounson, she introduced hESC into the Netherlands in 2000. The use of surplus IVF embryos for derivation of hESC was not covered by law at that time, but the introduction of the cells from abroad precipitated the debate that resulted in the law becoming operational in 2002. During this period, she became involved in the ethical and scientific debates surrounding stem cell isolation from human embryos. In 2003, her lab derived the first hESC lines in the Netherlands. Her focus of research however, remained control of differentiation, specifically to cells of the cardiovascular lineage, for the serendipitous reason that this was the first differentiation experiment that had worked convincingly for her.

In 1990 Christine had become group leader at the Hubrecht Institute and in 2002, Professor of Developmental Biology. Her research continued to focus on mouse development and the differentiation of mouse and human ESC. She pioneered the studies of differentiating and characterizing cardiomyocytes from hESC and was among the first to inject these cells into the mouse heart and assess their effect on myocardial infarction. In 2008 she was appointed chair of the Department of Anatomy and Embryology, Leiden University Medical Centre. Here she continues research on heart development and the differentiation of pluripotent human cells into the cardiac and vascular lineages but in the context of a clinical environment with view to translating aspects of research to medically relevant questions. The immediate interest of her lab is the use of stem cell-derived cardiomyocytes and vascular cells as disease models, for drug discovery and future cardiac repair. In 2007, she spent sabbatical leave as a joint Harvard Stem Cell Institute/Radcliffe fellow where she studied cardiac tissue engineering with Kit Parker and Ken Chien. Upon return to the Netherlands, she initiated a programme to derive human induced pluripotent stem cells from patients with cardiac and vascular diseases.

She presently serves on Ethical Councils of the Netherlands Academy of Science and Ministry of Health, providing specialized advice on human embryos and stem cell research. She is an active member of several Scientific Advisory Boards and has written a popular book on stem cells entitled ‘Stem Cells, Scientific Facts and Fiction’. She is also an editorial board member of Stem Cell Research, Cell Stem Cells, Stem Cells and Differentiation, elected member of the board of ISSCR and president elect of the International Society of Differentiation. She was also recently elected as member of the Royal Netherlands Academy of Arts and Sciences.

 


A Interview with Christine Mummery, by Carla Mellough

Your training was initially in the field of physics and biophysics, so what was your original motivation for pursuing a career in stem cell research?

After a PhD in Biophysics, I became more interested in biology than physics but had to try and find a bridge, a way in. That was through the study of ion channels in an electrically active cell, neurons from neuroblastoma. This was a differentiating cell – which was fascinating – at a time before mouse ESCs had been isolated but EC cells were being worked on by a small group of developmental biologists. After a book was published on Teratocarcinoma Stem Cells (Cold Spring Harbor Conferences on Cell Proliferation Series), I became fascinated by this as a model system and had room on my Royal Society fellowship to do more research. So EC cells it became, with John Heath in Oxford and Barry Pierce in Denver helping me start out with mouse EC and Chris Graham and Martin Pera in Oxford with human EC.

How has this motivation evolved?

Around the same time, the first mouse ESC lines were derived and I met Martin Evans in Cambridge and Colin Stewart, then in Oxford but about to move to Heidelberg. I found ESCs even more exciting because even then we thought, what if we could get these one day from humans? Colin showed me the practicalities of derivation, passage and generating aggregation chimeras when I spent some time in his lab in Heidelberg.

How do you think your multidisciplinary knowledge affects your approach to your research?

I think being a physicist (long ago!) makes me think quantitatively. I like to measure things (or these days have them measured!). Being able to quantify the number of cardiomyocytes we get from our pluripotent cells rather than just say they beat, measuring their action potentials rather than just assuming they will be those of a heart cell; things like that. Taking the “witchcraft” out of it all.

Much of your work is focused on the study of cardiomyocyte development from hESCs as a disease model and the use of cell therapy for heart patients. In your experience, what appear to be the main differences between hESC-derived and endogenous cardiomyocytes?

Probably their maturity. This is a good thing for transplantation because adult cardiomyocytes die if they are transplanted to the heart and fetal or stem cell derived ones do not. Otherwise they are very similar, which is great for many of the things we want to do (which are much less focussed on cardiomyocytes directly as therapy).


What do you think are the main factors which mediate these differences?

It’s probably because stem cell derived cardiomyocytes do not have to do physical work, they just sit there in a dish, beating away for weeks on end. That makes them mature a little but if we stress them (by making them undergo cyclic stretch and strain for example) they mature more. Transplanted cells mature in the heart and they probably do this because the heart beats and makes them stretch cyclically.


How quickly do you think cell therapy for heart patients could be transferred to the clinic?

Difficult to say but cells which do not become cardiomyocytes like bone marrow or fat derivatives are already in clinical trials. They do not form cardiomyocytes (in contrast to earlier ideas that they transdifferentiate) and are thought to have some effects through paracrine mechanisms, but the outcome of most of these trials has been that they are safe but have little long term benefit. If you are talking about cardiomyocytes for stem cell therapy for the heart, that could have risks of creating arrhythmias (abnormal heart beats) in humans because they are immature and electrically active at transplantation and only couple to the hearts pacemaker cells properly when mature. There are many safety issues yet to be addressed aside for making sure that the transplanted cells line up properly in the heart.


What is your understanding of successful research?

Research in which a hypothesis is formulated, tested and proved; research that can be repeated robustly by others; research that discovers the unexpected. The frustrating thing about the EU for example is that they want a list of things you are going to discover in 4 years time (called deliverables and milestones). That would seem to be by definition pretty dull research although the EU would likely describe it as successful.


Can you reflect on what you feel was one of the most important experiences or defining moments in your education, career, or life that has contributed to your success as a researcher?

A couple of things: having an excellent mentor as a young postdoc who was generous in sharing ideas and opportunities (that got me into EC and ESCs in the first place). Having our first attempt to derive heart cells from hESC work (if it hadn’t, I might have gone on to do something else). Having a husband that created enough space for my work as well as his own (and who has really shared the parenting!). And as a negative: I had a PhD supervisor who had a very slow turnaround on anything I wrote; I said I would never do that to any PhD student or postdocs – they always want to know really quickly what you think of what they have written.


How do you think this has this affected your work and/or career?

It has allowed me the best of both worlds: a happy family life (good kids doing their own thing – I would probably have been much too intense to be a good full time mother; much better at it part time!) - and made me fairly efficient to be able to fit in a career as well. And on the quick turnaround: I’ve never had any complaints on slow feedback so that must be OK too.


How easy or difficult do you find it to keep abreast of the vast volume of new literature in the field?

I find it difficult to keep up with everything in depth. I review a fair number of grants and papers and you are always getting updated by the introductions/background literature of those and go to a fair number of meetings when you often here the latest news. I read a lot on planes and in the train to the lab (an hour each way), probably more than I did even a few years ago. And I often have a hard copy of Nature in my bag should there be a dull moment. I actually like hard copies of journals and am also always happy to receive Stem Cells.


What do you feel is the most challenging aspect of your job?

Making sure there is continuity by getting enough grants in. Trying to choose areas of research that we can have a little time and space to work things out thoroughly.

How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?

I like collaborating very much: it’s very enriching for the group and for me to collaborate, especially with those abroad or from different disciplines: interactions with proteomics and genomics groups, tissue engineers and the like have been great inspirers.

What would your words of advice be to young researchers trying to find their way in the stem cell field and obtain funding in this highly competitive field and under the current economic climate?

Publish in the best journal you can and join the best group possible; if you do those things right then usually funding follows. And it is always handy at the start of your career not to be seen as “difficult” for whatever reason.

It seems that the barrier is always being raised for the achievement of success in publishing manuscripts and obtaining funding. What effect do you think this has on the research that is being undertaken and the way in which it is conducted?

The bar does seem to have been raised and you need to have a great deal more data it seems to publish something well. It has to be a complete story, not just one episode of a soap. You seem to have to fight for every article these days – even top groups have to revise extensively sometimes or set their sights a little lower.

How do you think the current funding situation will affect the progression of stem cell research in the short and/or long term?

Funding is a major issue, very much influenced not only by results but also by ethical and IP considerations. Funding agencies often need to know how you are going to “valorise” results and want commercial company input from the outset. It is at the cost of funding for basic research. The whole hESC and hiPSC research field developed out of good basic research that was difficult to fund until its potential was realized.

There has been a huge shift in public thinking about the use of stem cells for research and to ameliorate human disease. In your opinion, what are the main barriers that still remain for the clinical translation of hESC? How do you foresee these being overcome?

The costs and regulatory issues are major obstacles aside from the obvious issues of safety and effectivity. It would seem unlikely for example that iPSCs would be a personalized treatment simply because of the costs of GMP production. Issues like animal reagents, scaling up production, even teratoma formation would seem to me to be something that could be solved.

A number of recent articles implicate that iPS cells may be more dissimilar to hESCs than was initially thought and thus cast some doubt over the applicability of iPS cells for the treatment of human disease. In your opinion, how important do you think these differences are?

The reasons and consequences of the differences are still being investigated so it is a little hard to tell at this point. There is much new work coming up that all seems to bring us a step nearer to having a true reprogrammed equivalent of hESC. That said, an interesting review in Stem Cells a little while showed that the majority of published data on hESC actually only uses two hESC lines, H1 and H7. So what is the golden standard actually and what are the differences?


In your opinion, what do you consider to be the most important advance in stem cell research over the past 5 years?

Unquestionably the discovery of human iPS cells. It has not got us any further yet in the biology but because of the difference in ethical issues, the have allowed many new groups, institutes and industries to enter the field. It has now become the new “race to the moon” it seems.

What are your hopes for the future stem cell research and clinical translation in your specialist area?

I think, hope and believe that macular degeneration, diabetes and spinal cord injury are likely to be the first clinical translational areas, as do many others; for the heart, I think direct cell therapy will remain difficult for many years to come but we will learn an incredible amount about human heart physiology and disease from the hESC and hiPSC (disease) models that it will be a platform for the discovery of new treatment strategies.

 

Mummery's Lab Featured on Stem Cells Portal