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RESEARCHER SPOTLIGHT: Dr. Marius Wernig, Stanford Institute of Stem Cell Biology and Regenerative Medicine, Stanford University

30th June 2015

Dr. Wernig was born in Innsbruck, Austria and received his medical degree from the Technical University of Munich. He and his wife, Dr. Gerlinde Wernig, have 2 children.

Interview with Dr. Paula Grisanti, Chair, National Stem Cell Foundation

PG: You have such an interesting background – I know you’re a gifted musician and composer and that orchestras in Germany and Austria have performed your compositions. What made you decide to become a researcher?

MW: Actually, when I was younger, I thought I should become a musician. I played violin and piano and started to compose. It was a great time – I wrote a little opera, pieces for chamber groups and even one orchestra. Dr. Wernig’s compositions were performed in Bonn and Cologne, Germany and in Vienna, Austria. He won 2nd place in Germany’s national composition competition in 1991. To hear your work performed, that is really exciting. The education system is a little different in Europe, though. There is no college, really – when you finish high school, you have to decide what graduate school you want to join. You have to decide at a very early age what direction you want to go. I thought my chances of becoming a composer would be very slim, but I had always been interested in life sciences, also. I very much liked physics – it seemed to me the ultimate discipline to understand how things happen around us. So at 18, I chose physics. Now music is my hobby. I don’t get to spend as much time as I’d like with it now, but it’s something you never lose.

PG: You have a joint grant from the National Stem Cell Foundation and the National MS Society for research in myelin regeneration. How would you explain that project to a layperson?

MW: We’ve found a way to turn skin cells directly into the cells that make myelin in the brain. They’re called oligodendrocyte precursor cells, or OPC’s. OPC’s will find naked axons (the nerve fibers that transmit electrical impulses) in a dish – or in people – and wrap myelin around them, a process called re-myelination or myelin regeneration.

Myelin is the fatty insulation around nerve fibers that allows messages to be transmitted from your brain to the rest of your body. There are many diseases that result from imperfect myelin production or myelin destruction. Cells called oligodendrocytes produce myelin in the central nervous system.

PG: How do you turn skin cells into OPC’s?

MW: There are two ways of getting skin cells to turn into OPC’s. You can convert skin cells directly into OPC’s, which is still difficult in human cells (one of the aims of the grant is to optimize that conversion), or you can take a detour and push these skin cells into iPSC’s (induced pluripotent stem cells), very flexible cells that give rise to all cell types and tissues of the body. Then you catch them before they’ve decided which kind of cells they want to become and coax them into becoming OPC’s. Other labs have found ways to convert skin cells into something similar to OPC’s using this detour; we have optimized that work so that we are in a position to convert these skin cells – directly and indirectly – into OPC’s. The challenge is getting them to convert only into OPC’s and not a mixture of cell types.

PG: That’s really exciting. A lot of people will benefit from that discovery when myelin regeneration becomes possible – where do you start?

MW: We’ve first taken a sample of skin cells from a child with PMD (Pelizaeus-Merzbacher disease) and coaxed them into becoming OPC’s. We started with PMD because we know exactly what the problem is – a gene mutation that interferes with myelin production – and no one had yet “modeled” it for study outside the body.  

Pelizaeus-Merzbacher Disease (PMD) is one of a class of neurological disorders called leukodystrophies that affect myelin formation. PMD is rare, caused by mutations affecting the gene for proteolipid protein (PLP), a necessary component of myelin. Nearly all affected individuals are boys who inherit the gene mutation from their mothers. There is currently no cure for PMD.

PG: Once you have these cells, how do you use them?

MW: There are two very interesting ways to approach the use of these cells when the patient’s own OPC’s are dysfunctional or exhausted. You can “fix” the gene mutation outside the body and transplant the cells back into the patient as a therapy, or you can use these cells to “model” the disease in a dish. You can’t study diseases inside the brain because you can’t look at what the cells are doing – or even harder, what the molecules are doing. Why are these cells getting sick, why does this mutation affect myelin production the way it does? If we can study these cells outside the body, in a petri dish, we can see what’s going on. We can directly compare the original cells to the cells we fixed to see how they behave. We can run all kinds of tests and assays, do molecular analysis, expose them to different drugs to see if there are any changes. This is typically done in mice, but now we have a way to model in human cells – even from a patient’s own cells. And after all, mice are different from humans. We have learned a lot from mouse models, but this this is an advantage – and much faster.

PG: How far away are we from having a therapy available for these children?

MW: It takes a long time to get a therapy approved by the FDA. If you had asked me two or three years ago, I would have said “I have no idea.” But now, we are a little more advanced. The ability to “model” and correct these cells in a dish makes it easy to move faster. We have also been working with a dermatologist at Stanford on another disease – also caused by a single gene mutation – called Epidermolysis Bullosa. We are trying something similar with this disease. We push iPSC ‘s into becoming keratocytes (skin cells) in a dish and make sheets of the patient’s own skin to graft back onto the body. We have already been in touch with the FDA for feedback. We know it works, we know that we can make these skin grafts. It works in a dish, it works in mice, and now we need to find a way to manufacture in a way that is approved by the FDA. But pivotal pre-clinical studies are very expensive and there is still a lot of work that will need to be done. With funds and a commercial partner to do the pre-clinical work? It could happen in 2 years or so. These are your own cells, so there is no rejection.

Epidermolysis Bullosa (EB) is a group of rare, inherited diseases that cause skin to blister. Depending on how fragile the skin is, symptoms may vary from mild (few but painful blisters) to severe (large areas of blistering inside and outside the body). EB is typically first diagnosed in babies or toddlers. There is currently no cure for EB.

PG: Have you had any “aha” moments with the PMD study?

MW: We may have stumbled upon a new, previously unappreciated pathway that seems to be off in the OPC’s of children with PMD that might lead to a new treatment option. So far, it look very promising, and if it’s true, it might benefit these patients a lot. It’s too early to know for sure yet, but we’re very excited.

PG: You’ve started with PMD – will you add MS and other demyelinating disorders as you begin seeing results?

MW: From a scientific viewpoint, it is much easier to start with simple things where the cause is known. There are many underlying factors that make MS more complicated to model. There is a myelin component, but there is also an immune response component. It may be that OPC’s in the MS brain don’t myelinate properly – they may have a differentiation block that keeps the OPC’s from turning into oligodendrocytes. Maybe that’s because of the immune response, or maybe it’s because the cells are exhausted from multiple immune attacks. There isn’t a single gene you can introduce into these cells to fix them and we don’t yet know exactly what a good control would be, so it’s much harder. Down the road, yes. But now, we have to prove concepts. There are researchers at Case Western Reserve, USCF and in Britain who have modeled MS in a dish and are screening thousands of small molecules (drugs) to see if they can improve or increase differentiation.

PG: Is there anything I haven’t asked that you’d like to tell me about?

MW: You might be interested to know my very first scientific meeting was in Louisville, Kentucky. The field of neural stem cells was just getting traction and my father (Dr. Anton Wernig, then a neurophysiologist at the University of Bonn, Germany) was invited to give a talk and brought me along. I was probably 16, and it was my first trip to America. Very exciting! I remember that Louisville was very warm and humid and I appreciated the air conditioning. I would go outside to warm up, go back inside to cool off. Louisville is someplace very special to me, even though I haven’t been back – you might say my stem cell career started in Louisville.

The following is a short list of the many national and international research awards given to Dr. Wernig:

Honors & Awards

  • The Outstanding Young Investigator Award, International Society for Stem Cell Research (2013)
  • ASCINA Award, Republic of Austria (2010)
  • New Scholar in Aging, Ellison Medical Foundation (2010)
  • Robertson Investigator Award, New York Stem Cell Foundation (2010)
  • Donald E. and Delia B. Baxter Faculty Scholarship, Stanford University (2009)
  • Cozzarelli Prize for outstanding scientific excellence, National Academy of Sciences USA (2009)
  • Longterm fellowship Human Frontiers Science Program Organisation, HFSP (2004-2006)
  • Margaret and Herman Sokol Award, Biomedical Research (2007)