SEARCH

SEARCH BY CITATION

About Dr. Mummery

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

Christine Mummery received an undergraduate degree in Physics from the University of Nottingham, U.K., followed by a Ph.D. in Biophysics from Guy's Hospital Medical School, University of London, U.K., on the topic “Ultrasound in Wound Healing.” She then moved to the Hubrecht Institute in The Netherlands, a research institute of the Royal Netherlands Academy of Arts and Sciences, affiliated with the University Medical Center Utrecht and Utrecht University, where researchers specialize in the field of developmental biology and stem cells. Here she undertook postdoctoral studies, examining the differentiation of neuroblastoma cells and regulation of the cell cycle. In 1981, in collaboration with Chris Graham, John Heath, and Martin Pera in Oxford, she introduced mouse embryonal carcinoma (EC) cells into the laboratory, followed in 1984 by human EC cells. As a tenured staff scientist at the Hubrecht Institute in 1985, she worked with Colin Stewart at the European Molecular Biology Laboratory (EMBL) in Heidelberg to derive mouse embryonic stem cells (ESCs) and bring them to the Hubrecht laboratory, and in 2000 she collaborated again with Martin Pera and Alan Trounson in Australia to introduce their newly derived human (h)ESCs to The Netherlands. She earned an appointment as an Interuniversity Cardiology Institute of the Netherlands Professor of Developmental Biology at the University of Utrecht Medical Centre, and her lab began focusing on cardiomyocyte and vascular differentiation of hESCs. In 2007–2008 she took a sabbatical at Harvard University Stem Cell Institute as a Radcliffe Institute Fellow, and since April 2008 she has held an appointment as Professor of Developmental Biology and Head of the Department of Anatomy and Embryology, Leiden University Medical Centre, where her lab continues their groundbreaking work in cardiomyocyte and vascular development and differentiation. Stem Cells recently talked with Dr. Mummery, as part of our series celebrating 10 years since the derivation of the first hESC lines.

From Physics to Stem Cells

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

Early in her career, Dr. Mummery made the interesting transition from physicist to developmental biologist. “The origin of my interest in hESCs actually dates from the first papers of Martin Evans and Gail Martin on the derivation of mouse ESCs” explains Mummery. “I was a physicist, and then did my Ph.D. in Biophysics. Complete organisms seemed to me to be very complicated, so it was fantastic when mouse ESCs (mESCs) seemed to offer the opportunity to study development, or at least differentiation, in a culture dish. So I visited Martin Evans, then in Cambridge, and Colin Stewart, then at the EMBL, and learned how to derive and culture mESCs, and basically used them to learn cell biology. At the same, I found the work on their tumor counterpart, EC cells, intriguing and so I visited Chris Graham, Martin Pera, and John Heath in Oxford where I really became interested in human ECs and P19 mouse ECs. P19s make cardiomyocytes and nerve cells pretty easily, so that's how the fascination with these electrically active cells against my biophysics background got started.” Even in 1985, Chris Graham was trying to derive hESCs from the few embryos left over from in vitro fertilization (IVF) and was a true pioneer. “It was just a question of time before someone succeeded. So I decided to move over to real developmental biology, and through studying transforming growth factor β (TGF-β) signaling in differentiating mouse ES cells, got into vascular development in the mouse embryo.” Then in 1998, Jamie Thomson's lab derived the first hESC lines, followed shortly by the Australian group, where Martin Pera was working with Alan Trounson. “I knew both Alan and Martin well and they were kind enough to train me and two technicians in hESC culture and give them to us (no strings attached!) as soon as their Nature Biotechnology article was published.”1

thumbnail image

Figure 1. Dr. Christine Mummery, Ph.D., Leiden University Medical Centre, The Netherlands.

Download figure to PowerPoint

"There was no law covering import of hESC lines into The Netherlands, as I intended to do."

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

“At that time there was no law governing research on embryos, but the development of these laws was in progress, especially since people were anticipating the hESC line derivation. So when these first papers were published, it really hastened the whole procedure, particularly the public debates, and especially when it appeared that there was no law covering import of hESC lines into The Netherlands as I intended to do. I was therefore invited to many discussions involving politicians, ethicists, patient groups, and the like to explain what hESCs were and what the potential impact might be in the future. There was a fair amount of media exposure as the debate heated. Even though my lab has had other research lines running during this whole period, it was and still is our stem cell research that gets most attention. But as soon as the law allowing the derivation of hESC lines was in place in The Netherlands, we derived four hESC lines. Now there are so many around for research (and we have 12 lines, more than enough to cope with), that the actual derivation of hESCs is no longer a major activity in our lab.”

"It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

“In The Netherlands, IVF is accepted and as such most people realize embryos get left over and do not have an issue with using some for stem cell derivation. Creation of embryos for research is legally prohibited and the coalition government formed last year with two Christian parties agreed to keep it like that. That is more of a problem for IVF research than stem cell research though. In general, hESC lines are no longer an issue here, as in the U.K. I was a little culture shocked last year on sabbatical at the Radcliffe and Harvard Stem Cell Institutes to realize that this is still a major issue in the U.S. This is certainly slowing down the use of hESC derivatives for drug and compound screens there.” This could be a real disadvantage for U.S. researchers, since many people, including Mummery, believe that hESCs are still the gold standard of pluripotent stem cells, despite the huge and rapid advances with human induced pluripotent stem (iPS) cells. “iPS cells are certainly potentially very exciting for personalized medicine screens but there are issues on epigenetic and phenotypic stability of differentiated derivatives and their methods of derivation that need sorting out before they are suitable for drug screens, let alone therapy. In addition, they potentially only circumvent the immunological issues, but not the transplantation and functional integration challenges. In addition, we still have to see robust evidence of disease phenotypes in the differentiated derivatives, and there are many more questions still to be answered. hESCs and the antipathy to them have been a huge driving force behind adult stem cell research and the generation of iPS cells themselves; I wonder if human iPS cells would have been identifiable as such without the hESC platform.”

Differentiation of Functional Cardiomyocytes

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

Ten years after the derivation of the first hESC lines, we are still searching for the “magic formula” for how to keep hESCs in culture undifferentiated using chemically defined medium. In terms of growing and differentiating functional cardiomyocytes in culture, “The field has advanced enormously from the original technologies used, but hESCs still sometimes ‘go off’; they start growing very fast and spontaneously transform or completely differentiate. However, some lines are very well adapted to culture and even from first derivation appear to be easier to handle than others. It would be really interesting to know whether this is something clonal from the beginning at the inner cell mass (ICM) isolation or something stochastic later in culture. We may find out if we could derive multiple lines clonally from one ICM. Also, the serum-free based protocols for differentiation seem to be much better than the original ones although there is still clearly variation. I think things will continue to improve in the coming years though, especially with huge interest in human iPS cells. Everyone wants to know how to control their differentiation effectively, so the impetus to work things out is enormous. But I doubt whether there will ever be 100% conversion of hESCs into the cell type of interest—some kind of selection will be needed.”

"Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

“Cardiomyocytes from hESCs are very immature in terms of their electrophysiology (they have small action potentials and high resting potentials) and morphology (with disorganized sarcomeres; irregular and not the rectangular shape of adult cardiomyocytes). This could ultimately be an advantage for transplantation to the heart in cardiac repair, because they need to mature and align after transplantation. Cyclic contraction of the heart could make this happen and we are trying to mimic that in culture to see.” “It also might make them more useful for screening cardiac drugs, although when we actually look at drug responses, they are rather more like mature cardiomyocytes than those derived from mouse ESCs.” However Mummery also believes that “Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart.” Searching for solutions to this problem was one of the things that led to her recent sabbatical at the Radcliffe Institute. She worked with Kit Parker's laboratory, in the Disease Biophysics Group in the School of Engineering, to learn the basics of engineering two-dimensional cardiac tissue, and to study cardiomyocyte shape in relation to force of contraction. Then, in the laboratory of Kenneth Chien, Director of the Cardiovascular Research Center at the Massachusetts General Hospital, they shared their work on the identity and properties of cardiac progenitors cells. In terms of the future availability of hESC cell therapy for patients, Mummery says, “I think the regulatory requirements may not be the major issue for the heart. Even if all of the current regulatory requirements were met (i.e., xenofree conditions, no teratoma formation, pure cell populations, stable karyotypes, etc.), we still have the challenging issue of the effectiveness of the transplanted cells. Most animal experiments to date, including our own, have been done in acute myocardial infarction models. But at the time of transplantation, there is no scar tissue making the heart wall noncontractile, no ensuing heart failure has taken place, and these are the really common cardiac conditions.” In addition, “putting in beating cells could disrupt normal heart beating (i.e., cause arrhythmias) and potentially be very high risk. We need to know how to integrate cardiac cells probably, and get them to electrically couple properly to respond to normal pacing signals in the heart, so that they all align and “pull” in the same direction. Maybe in the end engineering cardiac tissue in culture and using it as a kind of elastoplast or rubber band may be the answer. There are several groups who are now trying this approach.”

The Importance of Teamwork

  1. Top of page
  2. About Dr. Mummery
  3. From Physics to Stem Cells
  4. "There was no law covering import of hESC lines into The Netherlands, as I intended to do."
  5. "It has been interesting to see how ethical viewpoints in society change quite rapidly, particularly when information is provided correctly and openly."
  6. Differentiation of Functional Cardiomyocytes
  7. "Even if we have a large number of cardiomyocytes, it's going to be difficult to get them to behave properly in an injured or diseased heart."
  8. The Importance of Teamwork

“I'm really for teamwork whenever necessary, as I believe it gets things done better (even though the “divide and rule” approach is often faster). I'm very much for setting the stage for young talent to be creative in research and do my best to facilitate that in my lab. I try to be fair and give credit where it is due and try to encourage people to realize they may underestimate the input of others to research or solving issues and often overestimate their own. Authorship I guess is a case in point. I'm very much a team player and try to recruit those of like mind. I take it as a great compliment if people move on and said they enjoyed working in our group—science should above all be exciting and fun. I would also say be open about your science, with all its risks, and maybe we will be able to return to times when people reported unpublished results (warts and all!) at meetings. It doesn't help us to make real progress if people gloss over the problems just to score in top journals.” And, as Mummery explains, as a scientist, teamwork is important not only in the lab and your professional life, but in your personal life also. “It's good to start early to get your family involved in the adventures in your life.” On her recent sabbatical, her husband and three children went with her to Boston. “You need to educate your partner and kids early on about the peculiar life of a scientist, and take them to the best meeting spots with you so they share the benefits. Also, don't be afraid to decline invitations that encroach on your precious family weekends.” “You also have to work hard and efficiently when you can (such as during your postdoc), then reduce your workload selectively when you need to (for example, for pregnancy leave, caring for young or sick children, or elderly parents) by becoming a highly focused 'super specialist' for a while and get your priorities right. Getting papers finished and out is the number one survival factor!“