You are hereJune 12, 2012
An Interview with Ludovic Vallier
Some words from this month’s featured Investigator.
‘Embryonic Stem cells (ESCs) and endoderm differentiation have been the focus of my research since my PhD in the laboratory of Professor J. Samarut (1997-2001). The objective of my PhD was to define the mechanisms controlling cell cycle regulation of mouse ESCs (mESCs) and this work resulted in the development of new tools to conditionally express genes in ESCs and in transgenic mice. After a year in the private sector, I eagerly joined Professor Roger Pedersen’s group who just moved from UCSF to Britain. I actively participated in the organization of his new team in Cambridge, and my first achievement was to set up human ESC (hESC) cultures when only a few laboratories in the world were capable of growing these cell lines. In 2005 I was awarded a stem cells career development fellowship jointly funded by the MRC and Diabetes UK to continue my work on pluripotency and differentiation. I was then awarded a competitive MRC senior-non clinical fellowship in 2008 to further develop my interest in the mechanisms controlling the transition between pluripotency and endodermal fate using hESCs as an in vitro model of development. In the mean time, I was offered to join the newly opened Anne McLaren Laboratory for Regenerative Medicine (LRM, Cambridge) as a junior independent investigator. More recently, I became interested in human induced pluripotent stem cells (hiPSCs) and created the Cambridge Biomedical Research Centre hiPSC Core Facility, the main objective of which is to develop in vitro models of disease “on demand”. To date, this platform has derived 400 hiPSC lines from 70 patients. I am now leading a group of 12 including 5 PhD students. My group remains committed to understanding the basic mechanisms controlling early cell fate decisions, but also the development of innovative therapies against metabolic disorders.’
- Ludovic Vallier
An Interview with Ludovic Vallier, by Carla Mellough
What was your original motivation for becoming a researcher in the field of stem cells?
I started to be interested in mouse embryonic stem cells during my undergraduate studies at the ENS Lyon and then during my PhD more than 10 years ago. I was immediately fascinated by the capacity of these cells to grow indefinitely in vitro and also to differentiate into almost every tissue. My initial interest was to use this in vitro system as a model of development. So, I was purely focusing on basic research questions.
How has this motivation evolved?
hESCs came later on and I became progressively aware of the therapeutic potential of these amazing cells. hiPSCs have amplified this aspect. Basic research remains the main drive of my group but the clinical translation of our results represents an aspect which is now extremely exciting.
Much of your work is focused on the study of endoderm development and its derivates, particularly pancreatic and hepatic cell types. How did your specific interest for working in this area originate?
I was already interested in the mechanisms controlling germ layer specification during my PhD. My main objective was to investigate mechanisms controlling the cell cycle and differentiation of mouse ESCs. However, the specific focus on endoderm started during my post doc with Roger Pedersen. My project was to generate endoderm cells and then pancreatic cells from hESCs. To stimulate endoderm differentiation, I decided to overexpress Nodal in hESCs and, by doing so, discovered that these cells were unable to differentiate. This was one of the first steps in uncovering the importance of the Activin/Nodal signalling in pluripotency. I have never stopped being fascinated by the endoderm germ layer and its derivatives. We are now able to generate liver, pancreatic, lung and gut cells. This is amazing progress in less than 15 years since the derivation of the first hESC line. Nevertheless, there are still a vast number of basic questions to address while the clinical need for organs such as pancreas and liver is constantly growing.
Your work has reported on many aspects of the biology and capacity of pluripotent cell types, ranging from their transcriptional requirements for directed cell differentiation and specification to the use of iPSCs as disease models. In your opinion, what has been your favourite experiment and which experiment has caused the greatest impact?
There are many experiments which have been really exciting, from the observation that Nodal/Activin signalling maintains hESC pluripotency to the modelling of liver disease in vitro using hiPSCs. But the most important was probably the derivation of mouse Epiblast Stem Cells. It took us several months to set up the necessary experiments, but it immediately worked. This was amazing to confirm our hypothesis concerning the embryonic origin of hESCs in a single experiment. This study has opened a new area of research and enabled the identification of different pluripotent states. More importantly for us, this work has also confirmed that hESCs represent a step before the gastrulation stage and are thus a better system to model early cell specification in vitro.
What is your understanding of successful research?
Successful research means creative work with an impact beyond the impact factor. Research that leads to new discovery, which feeds back to society not only in terms of clinical development but also basic knowledge.
What do you wish to achieve as a scientist? What are your main goals (personal and/or academic)?
My goals are to increase our understanding of basic mechanisms and to translate this knowledge into something useful. Only the combination of these two aspects is entirely satisfying.
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? How do you think this has this affected your work and/or career?
The most important choice/opportunity in my career was to join Roger Pedersen’s lab when he moved from USCF in 2001. To be honest, I did not know him, his research or even Cambridge. However, I knew that he was one of the rare scientists working on hESCs at this time. This type of research was not authorised in France and I was desperate to work on a model more relevant to the human situation than mouse ESCs. Thus I had a choice between moving to the US or to the UK. Joining Roger’s group was by far the best opportunity of my career. Roger is a fantastic mentor who gave me all the support and freedom necessary for me to grow and develop my own interests. He really gave me the best conditions possible to develop my research and thus my career.
How easy or difficult do you find it to keep abreast of the vast volume of new literature in the field?
I read the usual high impact journals and the specialised journals such as Stem Cells. International conferences are also helping but the quantity of publications in the stem cell field is far too vast. Thus, I have to be selective for my area of interest.
What do you feel is the most challenging aspect of your job?
I will say two things. first one is the combination of jobs. As a Principal Investigator, you have to be a manager, supervisor, accountant, negotiator, writer, reviewer etc… Ultimately all these activities (which are necessary) distract your attention from your original goal which was to be creative and to develop new exciting ideas. The second aspect is publication. The peer review system is not working very well. It often takes more than a year between submission and publication. Furthermore, the system is unfair at the best of times for small labs without pedigree. This situation systematically delays and even blocks the publication of important results. In parallel, the amount of publications is becoming so large that only papers published in high impact journals are being read. So a vast amount of knowledge is currently lost or undermined. Overall, the reviewers are not doing a very good job but the journals are also refusing to address this major problem. Solutions are available including anonymous submission, publication of reviewer’s comments, etc…but there is a clear reticence to change a system which is several decades old. It could be fun to explore new media systems including social networks to publish scientific results.
How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?
Collaborative work is essential. Only the combination of expertise can generate important studies, especially with hiPSC which often requires not only basic knowledge in stem cells but also clinical knowledge of specific diseases. In addition, one of my main interests in my job is to work with a broad diversity of people and collaborations are great for that. EU consortia are especially great for this aspect since they often mix a broad diversity of culture.
What would your words of advice be to young researchers trying to establish themselves in the stem cell field today?
Don’t get discouraged, focus on your research and choose a good mentor.
How do you think the current funding situation will affect the progression of stem cell research in the short and/or long term?
These are hard times for everybody including stem cell research. Nevertheless, the UK has been a very supportive environment and we have been able to maintain important research. Nevertheless, this will not last - especially if we don’t deliver at least some of the clinical promises associated with stem cells.
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/hiPSC-derived pancreatic or hepatic cells?
Safety is the main issue and will remain the main problem for a long time.
How do you foresee this being overcome?
The only approach to overcome this challenge is to perform systematic studies in animal models. The main challenge is demonstrating the safety of hESCs for pancreatic and hepatic cell transplantation. This work is essential since a lot of concerns are irrational and not based on scientific observations.
Do you think that stem cell transplantation therapy will be transferred to the clinic in the foreseeable future?
I am convinced that this major challenge can be addressed and that cell therapy remains on the map. However, it will take time and much more funding. Furthermore, these studies do not exclude the need for further basic research. Indeed, generating fully mature cells from hESCs remains a challenge and the variability between lines could be a major issue for future personalised cellular therapy. Thus understanding the basic mechanisms controlling pluripotency and differentiation is essential.
A number of recent articles implicate that induced pluripotent stem cells (iPSC) may be more dissimilar to hESCs than was initially thought and thus cast some doubt over the applicability of iPSC for the treatment of human disease. In your opinion, how important do you think these differences are, both for their use as models of development and disease, or for transplantation therapy?
First, hiPSC will not be used in vivo for a long time due to the reason cited above. Second, hESCs and hiPSCs are not phenotypically different - at least in our hands. Systematic studies are required to validate the safety of hiPSCs and their potential differences with hESCs. These studies will have to use hundreds of hiPSC lines to be relevant. Nevertheless, hESCs and hiPSCs are very similar and thus, hiPSCs represent an amazing tool to study disease in vitro and to develop new drugs. This message is very important. hiPSC are already an essential tool which can be used intelligently to generate very exciting results.
In your opinion, what do you consider to be the most important advance in stem cell research over the past 5 years?
hiPSC are by far the most important discovery in the stem cell field.
What are your hopes for future stem cell research and clinical translation in your specialist area?
I would like to see more clinical applications specifically for liver disease and diabetes. The possibility to transplant hepatic/pancreatic cells in patients would be fantastic progress. The possibility to use hiPSC to model metabolic disorders in vitro is also an important step.
- Teo AK, Arnold SJ, Trotter MWB, Brown S, Ang LT, Chng ZZ, Robertson EJ, Dunn NR* and Vallier L*. (2011). Pluripotency Factors Regulate Definitive Endoderm Specification through Eomesodermin. Genes and Development. 3(25):238-250. 40575. * joint authorship.
- Brown S, Teo A, Hannan N, Cho C, Lim B, Vardy L, Dunn NR, Trotter M, Pedersen R, Vallier L. (2011). Activin/Nodal signalling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells. 29(8):1176-85.
- Yusa K*, Rashid ST*, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan N, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA*, Bradley A* and Vallier L*. (2011). Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 478(7369):391-4.
- Chng ZZ, Teo A, Pedersen R*, Vallier L*. (2010). SIP1 mediates cell fate decisions between neuroectoderm and mesendoderm in human embryonic pluripotent stem cells. Cell Stem Cell. 6(1). 59-70
- Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A, Vallier L. (2010). Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology. 51(5):1754-65.
- Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang – Doran I, Ahrlund- Richter L, Skepper J, Griffin J, Semple R, Weber A, Lomas DA, Vallier L. (2010). Modelling inherited metabolic disorders of the liver with human induced pluripotent stem cells. Journal of Clinical Investigations. J Clin Invest. 120(9):3127-36.
- Vallier L, Touboul T, Brown, Cho C, Bilican B, Alexander M, Cedervall J, Chandran S, Ährlund-Richter L, Weber A, Pedersen RA. (2009). Signalling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells. Stem Cells. 27(11):2655-2666.
- Brons IGM, Smithers LE, Trotter M, Rugg-Gunn P, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L. (2007). Derivation of pluripotent Epiblast Stem Cells from mammalian embryos. Nature. 12;448(7150):191-5.
- Vallier L, Reynolds D, Pedersen RA. (2004). Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol. 275(2):403-21.