A conversation with the Co-Director of Harvard Stem Cell Institute.

Question: What are stem cells? 

David Scadden: Well, stem cell is a very unique concept; actually it’s a wonderful very creative notion of a single cell that has the capacity when it divides to give a reproduction of itself as well as one cell going off to become all the other cells that can make up of tissue or organ of the whole body. So, it has this really unusual characteristic of these two outcomes from a single division.

Most cell types, they’re either moving their way progressively towards something that is more defined, more specialized, more restricted in what it can do. And they also have the capacity to; they don’t have the capacity to sexually renew. And so they’re basically moving down the road toward self destruction. They end up generally having fairly short half life, and some cells live a long time. But then they’re not actually dividing things like a heart cell or brain cell. Those are generally fairly stable; they don’t divide very much if ever. And they can live for a while, but a cell that has a capacity to generate new cells and yet restore itself. So it’s a self-replenishing resource. It’s a very unusual entity. It’s really quite a wonderful concept actually.

Question: What kinds of stem cells are there? 

David Scadden:          There are different kinds of stem cells. What has generated the most controversy is this so called embryonic stem cell that comes from a very early stage in development; it is after the first week to ten days following fertilization in human. Those cells have unique capability to become virtually any cell type, so they’re called Pluripotent. Most cells after that time are much more restricted on what they can become. But stem cells of this more restricted nature stay with us throughout life. So we all have stem cells. These are cells that are capable of forming for example all the cells of the blood. So a blood stem cell is a very important part of active therapy today. We have those in the skin, we have those in the skeleton, we have those in the intestine, we have many of those different adult stem cell types, but they are limited to what they can become. They can’t have the ability for let’s say, a blood stem cell to become a nerve cell where as these other pluripotent cells can. Now though that divide between the pluripotent stem cell or embryonic stem cell and the adult stem cell was something that was thought to be unbridgeable gap, but over the last three years, there’s been a revolution in that we now have the ability to take essentially any mature cell type and convert it back into one of these pluripotent cells. So there’s been a tremendous shift in thinking and capability in the stem cell arena. Because now it seems any cell can be made to become a stem cell. It’s a really phenomenal concept.

Topic: Stem cells and the healthcare industry. 

David Scadden:          This idea that you could regenerate tissue is one that could really potentially reverse some of the calculus of how any new medical intervention means, such an incremental additive cost. We’re hoping that if we really can accomplish even part of the promise of stem cells that we’ll be able to put back in place tissue that might otherwise have been damaged. If that tissue is capable of sustaining function, what that could do would be to reverse some of the disability. It could reverse some of the dependence on chronic care. If we could improve the heart function of individuals who have terrible heart failure. Well those individuals are entirely are bed-ridden and are highly dependent on health care providers and their family and on medicines. If we can provide some of that function. If we can restore some degree of independence, the impact of individual life would be enormous. If we think about multiplying that in terms of its impact on those care providers, those health care needs, the societal implications could be really, actually quite dramatic.

And so we’re hoping that the investment in this area is one that will in many ways generate a return that may have a potential of lowering our health care cost. If this is something that really offers a chance to reduce disability, we have to explore that. It’s really something that our health care system so needs now as a way to try to reduce some of the cost. So, I’m actually quite excited that this field, if it can be moved ahead in rapid pace, might actually come to play at a really a critical moment in our health care delivery system. We’re clearly getting to the point where we almost have an unsustainable level of cost. Maybe if we have something that intervenes, creates greater ability that people can gage, but gage in more healthy way, less disability. Well that has a great deal of impact on our national productivity, health care cost would be enormously invaluable resource. So, maybe a bit grandiose but I’d like to think that this science is one that could really have societal implications that would be very positive on many fronts.

Question: What are the therapeutic and diagnostic uses of stem cells?

David Scadden:          The use of stem cells in medicine is still actually very limited. So we know a lot about the cells, we know that they can be extraordinarily powerful as therapy. But the uses of them still are very limited.

So we learned about stem cells as a defined entity in humans about fifty years ago. And that was work that was done really in the Cold War era. And in an effort to try to understand how you might be able to survive a radiation injury. That work actually led to some early studies on animals, that first defined that there is such a thing as a stem cell in an adult animal. It was hypothesized the same as exist in humans because some people had survived radiation injury, places like Hiroshima and Nagasaki. And that actually led them very quickly turned into an effort to use those stem cells as a sort of a bone marrow transplant. That work has now been going on for over four decades and has been a very powerful tool to treat people with blood diseases and cancer.

So stem cell transplant is actually not a new concept. Stem cell therapy is not a new concept. What is new is that this was thought to be something that was rather a curiosity of the blood. And that clearly isn’t the case. We now know that the blood is one of many tissues that has stem cells, and so the idea that the success that’s been achieved in the blood system might apply to these other tissues. Now it’s something that has really opened a door on the idea of stem cells as a source of therapy of replenishment. We know the blood stem cell can completely restore the entire blood immune system. Well, if you could do that in other tissues that are injured, that would be of course tremendously powerful.

So, that has really spawned this great enthusiasm and interest in pursuing these other applications of stem cells. That concept has largely been one of trying to replace, damaged cells. The idea of using a stem cell as a replacement part, that’s a very easy concept for people to grasp. It’s of course very complicated in other tissue types and so that is actually very narrow way to use stem cells. I think one of the other interesting aspects of stem cells is that they have an opportunity to have an impact on Medicine. That’s very different than this idea of just the replacement part.

Topic: Activating stem cells. 

David Scadden:          So if we know stem cells exist in the body in other tissues besides the blood, what we know is that those cells have important roles in making the tissue-- first, forming and developing, also in maintaining tissue. But we don’t think of them as doing a tremendous amount in the setting of injuries so there are stem cells in places like the brain. They clearly don’t have much ability to restore functions, some of these are true. And one of the questions is, if  those cells can be identified, can be isolated, can be shown to grow and do lots of different things in the laboratory; why can’t we get them to turn on and be more effective, to regenerate tissue in somebody with an injury like stroke, or like Parkinson’s disease.

And one of the issues now is to them, think about not necessarily taking the cells out, because they live in a very deep spot in the brain in the place where no one really wants to go in and biopsy. That maybe what we can do is understand how to turn them on. So this idea that we might be able to develop medicines that now activate stem cells that we know exist in many of our tissues is an on-going, very active aspect of research. So you can imagine in that case, what we might be thinking about is not so much using a cell, infusing it, putting it in the place of a damaged tissue, but perhaps just taking medicines, something that we already know a lot about, and now asking these medicines to change the context, to change the signals the triggers for the stem cells that lives in the tissue and forcing it to start to become more active and regenerating, rather than just essentially maintaining, rather than allowing a scar to form. Actually getting engaged and started to regenerate the tissue. Now, it may not completely restore function but if it had a minor effect, it could have a big impact on people’s disability, level of activity.

Topic: Stem cells and the pharmaceutical industry

David Scadden: So, there are ways in which this technology could be viewed as something that would be potentially a threat to the pharmaceutical industry. I think most of the pharmaceutical industries are excited about this area. Their caution comes more from the concern as to know exactly how to utilize this new biology in a way that will result in products that can really make a difference for people. And developing products is a very long sequence of events when we’re dealing with entities that are trying to forestall for the deterioration or trying to target particular molecules that are known to be abnormal in a particular disorder. Those are paths that the pharmaceutical industry has worked out very well for a long period of time and are clearly outstanding at doing so.

How to use the idea of a regenerative process, that’s something that’s very complicated and it’s still very much in the days of early exploration. So, understandably a pharmaceutical company is generally the commercial side of health care has been in the wings trying to understand, to assess, to really think about how you might be able to lay-out a path to move forward to the clinic. I think now, there are a couple of developments in the field where the pharmaceutical industry has started to get engaged. One of them is this idea that we can make models of diseases in a Petri dish, that of course then becomes terrific, raw material for drug companies to be able to use it and try to develop new therapies. We’ve clearly seen that large pharmaceutical industry players are getting actively involved to that, and that I think that’s the real advantage for them for the field.

This idea of using drugs to regenerate tissue, activating what are the stem cells within, that’s an area that they’re just starting to pick up on and I think that still, it’s still complicated models and in general the pharmaceutical industry doesn’t have these complicated animal models in-house so they need to partner with academic teams that work on those things. And that starting to happen as well, so I think we’re starting to see that what used to be a purely academic endeavor and frankly one limited to the number of academic centers that could get around some of the limitations that government funding had on the field, it’s starting to break. And now we’re starting to connect both with other sources of funding in terms of the academic enterprise, but also bridging the gap into the commercial world. What we’re starting to really think about what are their applications that might turn stem cell biology to stem cell medicine. And that’s clearly a critically important component of the work in the next five to ten years.

Topic: Cancer cells and stem cells.  

David Scadden: Where is often been viewed as a disorder of genetic disruption of a particular cell type that goes on to have an unlimited growth and invasion capabilities and then metastasize. Now we’ve often focused on the cancer cell as something that is an entity that it is distinctive from the rest of biology. It has this disordered genetic information by virtue of mutations. And it develops some amount of heterogeneity, some cells are not, they start identically but then they start to change and it’s generally been thought that the cancer has a fairly equivalent composition. That is that all the cells, they may look a little different but they’re all pretty much the same nasty creature.

And one of the things that has happened by virtue of viewing cancer through the stem cell lens, is that there is some sense that maybe cancer, like normal tissue, is organized so that there’s a hierarchy of cells, if you will. And at the base of this hierarchy is a very primitive cell type, a stem cell or a stem cell like cell, and it gives rise to all the other cells of a normal tissue or of a malignant tissue. And that it’s among the number of cells that composes tissue relatively modest and negative.

So for example in our blood system, we have a very very tiny number of stem cells that gives yield to tens of millions, tens of billions, a thousand billion new blood cells a day. So that capacity to generate offspring is something that, maybe that’s what a cancer stem cell does. And yet all of those blood cells that are generated from a normal stem cell actually tend to die out. What happens if that’s true in cancer? Maybe there’s just a few cells that are really essentially the root of the cancer. The stem cell, they are capable of self renewing, capable of forming metastasis, and that those are the root cause of cancer.

And while we develop drugs generally by trying to target the bulk of the tumor, maybe what we’re doing is actually missing the opportunity to cure the tumor because we’re not focusing on those root causes of the stem cells. And that model has been around for a long time, it’s just recently been tested. And it was demonstrated to actually be true in human leukemias. Now, whether this is true in other cancer types in humans, is something that there’s evidence on both sides of this debate. But certainly I think for some tumors that model will be useful and it will change the way we do drug development. We’ll focus more on trying to eliminate the cancer stem cell, or the equivalent of, and maybe even try to not just target the suspect but follow them and see how we’re doing. If we’re just following the bulk of the tumor, what can happen is we can see remissions but perhaps not cures. Our hope is that if you focus on the root cause of the stem cell you’d be able to generate cures.

Topic: Recent discoveries in stem cell research. 

David Scadden:          Up until just a few years ago, the only source of pluripotent cells was from cells generally very early in development. Then it was found that there were cells that might actually exist in places like the testes that might have pluripotent capability. That broke the barrier down a bit. And then there was this revolution, the work of a fellow Shinya Yamanaka, aninvestigator in Japan. He showed that by introducing genes into a fully mature cell, you could essentially be hitting a rewind button so that its history would go all the way back to the point where it now functioned very similarly to a cell that was one of those cells that existed just seven to ten days after the fertilization of it.

So that concept of having flexibility to reprogram a cell from a mature adult changed our way of thinking about cells in general; changed their way of thinking about the accessibility of these broadly potent cells; changed our way of thinking about whether or not those cell types could now provide good models of disease that only adults tend to acquire. And also of course changed some of the nature of the ethical debate. That if we didn’t need to isolate a cell from this “day seven to day ten” following fertilization blastocyst, then maybe we didn’t need to disrupt that blastocyst, maybe we could get away from the whole ethical controversy, that is of course tremendously desirable for both scientists, the public at large and ethicists.

We are still in the process of validating that this rewinding process really gets us to an equivalent state. Now it does seem by most measures that these so called “induced pluripotent cells,” these reprogrammed cells, functioned in much the same way than an embryonic stem cell does. It may not be exactly identical, frankly we may not need it be exactly identical. But there are still issues; we don’t know exactly whether all that we were hoped to do with the pluripotent cell can be achieved by these reprogrammed cells.

I would have to say, I’m quite optimistic that we’ll get there. I’m also quite optimistic that we’ll get there without having to do some of the modifications in these reprogrammed cells that have made them susceptible to cancer, which has been a big concern. But I think we’ll get around that and we’ll end up being able to both have the ethical debate be one that’s essentially one of historic interests, and also have a great deal more flexibility in terms of generative cells. And it might be applicable to all of us. We can all have our own source of cell. That’s now technically possible. It we could be of great value of course as a potential personalized tool kit for developing new medicines. Really quite a wonderful concept that this technology now allows.

Recorded on: July 06, 2009