Core Principles and Challenges

David Williams is the current President of TERMIS. He is a Professor and Director of International Affairs at the Wake Forest Institute of Regenerative Medicine, Chairman of the South African medical technology company Strait Access Technologies Pty and a Master of the DeTao Academy in China.

The New Organ Initiative is hosted by the Methuselah Foundation.

Click here to read part 1 of this interview.

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New Organ: How would you express the core values or principles that guide your aspirations for regenerative medicine?

David Williams: I could talk about the importance of honesty and so on, but I think the critical piece is that we make sure that the products of science and technology are translated for the benefit of humankind. That is fundamental.

Of course, as I’m sure you’re aware, there are some dangers in overstating things, and perhaps in underestimating the difficulties. But my core principle is to address in an honest way—initially scientifically, but also from an infrastructure point of view—those issues which we can't ignore if we want to get to successful clinical translation.

You cannot translate bad science. You also cannot translate no science. If we honestly want to address unmet clinical needs, we have to have the appropriate science, whether that's stem cell, or biomaterials, or bioreactors, or immunology. We have to put all these areas together to give us the best chance of succeeding. So my core value is this: Let's take fundamental principles and work to develop them for the benefit of patients for whom there is no existing successful treatment.

NO: Absolutely. But here’s another question: Your values are probably shared by most of your colleagues, and yet people often operate within environments that make it difficult for their values to be expressed. If you agree with that view, what’s getting in the way?

Williams: Yes, I do. That's a hugely important point, and I have a lot of sympathy, especially for young scientists who share these core values. I mentor them. I teach them. And they’re seeing significant barriers to their own progress.

We know about the difficulties with the NIH in getting grant funding. There’s also the whole incentive structure with rewards based upon metrics and not necessarily on alignment with core values. By this, I mean building up CVs for the sake of CVs. This is something I’ve been very focused on. You see it time and time again if you’re the editor of a journal—the rationale motivating people who want to be published in your top journal, and who are being forced down this route because they’re putting in a grant and have to be able to quote three good papers in order to get to the next level, or need at least five papers of a certain impact factor on their CV to get promoted from assistant to associate professor.

The metrics are driving things, and we’re all to blame here. But the grant-giving bodies and the select panels at universities are far too driven by metrics and ticking boxes and far too little concerned with the core values of how good a person’s science is and how good his or her philosophy is. I think even at its best, it’s very tough for young scientists. It takes a brave man or woman to stand in the way of these rules.

NO: A related concern is that if tissue engineering and regenerative medicine are built upon the existing bedrock of healthcare economics without significant improvements to that bedrock itself, it’s going to leave a tremendous amount to be desired. We have the opportunity to influence the initial conditions by which the frontier-to-industry transition happens for this field. We want to be working to optimize that transition for maximum societal benefit.

Williams: I agree. Broadly speaking, I think there are two different levels to consider. First, as I said before, you can't translate bad science or no science, so we still need a big effort on the science side, especially in the handling of cells and their ability to express new tissue. We don't fully understand that yet, and everything has to flow from there.

Then from a higher vantage point, even if we get to the place where it looks like we are getting the science right, we still need to tackle all the problems of translation through manufacturing. I know a few big companies are making progress—like Mesoblast, as I mentioned—but there are still a number of confounding issues to deal with. One is the communication between regulators and the scientific commissions. I’ve got a lot of sympathy with the regulators, but at the moment, they are serving as more of a barrier rather than being of assistance. Secondly, as I also mentioned, it’s still unclear how regenerative medicine is going to be profitable. Is it a product? Is it a service? Who’s going to pay for it? Is the payer here in the U.S. the insurance companies? Private pockets? Who is it?

NO: All great questions.

Williams: One of the things that has struck me over the last couple years is that research funding in the U.S., especially through the NIH, is in a diabolical situation. I'm not sure I have an answer for that. The NIH has a big budget, and maybe we're just trying to spread it too thinly. I don't know. But when you have a success rate of 10% or less, that gives rise to circumstances that are very difficult and inefficient. For the amount of time that professors have to spend writing grants, a 10% chance of success is a pretty desperate situation.

At the same time, put that alongside the fact that for most of the large hospitals with medical schools, the last few years have not been kind to them in terms of their own economies. They’re making their academic doctors do more clinical work just to pay the bills, and so they have less and less time for research. I've known several senior clinicians who have recently decided to retire because they were, even at very high levels of seniority, being forced to go on call and spend all their time in the clinic with no time whatsoever to even think about research. So I think these things together are working against us.

The other issue is that if this area is eventually to become commercially successful, then you might reasonably expect to see investment from big companies, and right now, most companies in the medical technology sector are more or less closed to R&D. None of the big companies—Medtronic, Boston Scientific, Johnson & Johnson, St. Jude’s—do R&D any more, or hardly any.

They used to. Good medical technology discoveries were funded by the big companies, either in their own labs or extramurally, and that funding came out of revenue from their existing products. Now, companies have stopped doing that, and in the regenerative medicine area, of course, there are no revenues. What they’re doing these days is more or less sitting back and waiting till they see a discovery being developed in a small university startup, and then going in and buying it. But the startups in universities have their own set of problems. They have no revenues, and this area is expensive, and the investors putting money in want their rewards sooner rather than later. It's a huge trap.

NO: It’s definitely indicative of a general problem that's been going on for a while. We just don't have that many Bell Labs or Xerox PARCs around the U.S. anymore.

Williams: Exactly.

NO: And we've been seeing multiple valleys of death (i.e. funding gaps in translating research into the market) emerge over time, in different areas. How do you think we might get a handle on this funding conundrum?

Williams: Well, there’s been a lot of discussion about NIH funding, and there was a significant increase in NIH funding for research for a period of time, but it’s leveled out again. Personally, I think there is good funding here in the U.S., but it’s being spread too thin. When you have a hot topic like tissue engineering and regenerative medicine, a great many universities and medical schools wish to get into that space, and therefore the number of proposals coming in has increased. In turn, people are without a doubt having greater difficulty in finding funding.

Without naming names, I’ve talked to some really good people in this area over the last few weeks who are no longer getting support, and they used to be just two or three years ago. Once you get down to a 10% or 12% funding level in any study section in the NIH or NSF, then issues other than basic science or clinical outcomes become important, which means politics. That’s where regenerative medicine is right now. It's difficult, and probably will get more difficult, and I don’t think the national politics are going to help over the next few years.

NO: If you were master of the universe for a little while, how would you change funding allocations to better advance the field?

Williams: That’s a very good question. One important angle to mention is that the Department of Defense has been a major funder of research in the U.S., primarily aimed at servicemen and women and veterans who have been very seriously injured. That's been a huge issue. As you know, the Armed Forces Institute of Regenerative Medicine (AFIRM), which is now spread out across the whole country, is a coordinated effort to look at regeneration in areas of large-volume muscle loss and craniofacial issues and so on.

That program is still there, but there is a decrease in need now with the scaling down of wars in Iraq, Afghanistan, and elsewhere. And this does allow the U.S. to broaden its focus. I've made this point before: the areas of “unmet clinical need” are changing. Right now, I believe the U.S. has a good opportunity to say, "We still should invest heavily in regenerative medicine, but where are we going to get the best value in areas, such as Alzheimer's and Parkinson’s? How about macular degeneration and diabetes Type I?”

Those areas where we don’t really have good therapies are where I think we need to concentrate. In my view that means the whole of the nervous system. Interestingly, I just saw on the news a major breakthrough in the UK and Poland on stem cell therapy and spinal cord injury. I believe the U.S. should look at that and say, "We're pretty good at that. Maybe we should see if we could invest more here in the U.S. on those main areas where there is literally no treatment at the moment."

NO: How about the challenges on the science side? What would you say are the key technical hurdles that still need to be overcome in order to specifically create new solid organs, which many see as one of the holy grails of regenerative medicine?

Williams: That’s another good question. I'm not sure whether there is any one single scientific issue. Again, I go back to the need for a systems approach. Bear in mind that what we're trying to do is to take a group of cells and persuade them to do something they don't want to do. That is, to express new extracellular matrix that can then be organized into the structure and function of an organ.

I think many of the different scientific principles are in place. We’ve made big progress already, and to me, the key issue is in putting everything together such that we can develop the structures that function as organs do. We know how to do the little bits, but we still have to explore the complex functioning of the whole.

Another thing we haven’t talked about yet is imaging and diagnostics, and these are both hugely important for regenerative medicine. If you look at Parkinson’s, for example, by the time a patient knows they have Parkinson's, probably from the tremors somewhere, they've already lost 95% of their dopamine-producing function, and it’s too late. So treatment for Parkinson’s is going in the direction of personalized medicine, with better imaging and screening and biomarkers. This is a hugely important step, but like a lot of what we’ve been talking about, it’s also going to be a massive problem as far as the economics are concerned.

NO: One of the scientific rate limiters that we heard a lot about in our work developing the New Organ Liver Prize was vascularization. What are your thoughts on vascularization as a major clinical hurdle that still needs to be overcome, particularly in the context of the heart, liver, kidney, lung, and pancreas?

Williams: Yes, that is still one of the most important issues. There has been a fair bit of progress made in vascularization, especially in using some small molecules and certain growth factors to encourage newer vascularization. So there are encouraging signs in this area, but it does remain one of the bigger challenges.

NO: How would you define the major benchmarks or milestones in overcoming that particular hurdle?

Williams: I’m not sure, but it generally goes back to a point I made before about having a suitable animal model. I think we have to demonstrate sufficient vascularization within a suitable animal model first, and I've got a feeling that means we’re going to have to show significant vital vascularity over a period of time in one or more non-human primates. We’re going to have to do that before we get into humans, I think, and that’s going to be very difficult to do.

Overall, I think that scientific progress has been good. There are still some key scientific issues that have to be addressed. But again, more than solving any particular issue, I believe it’s the integration of individual projects that is the most important and most difficult challenge.

Take muscle tissue engineering, for example. It’s already possible to regenerate small amounts of muscle, but the integration of that into a functional muscle regenerative project is much, much harder. We need to address the integration issues more than anything, and we need to start doing it for the areas where our current therapies are weakest. We had to start somewhere, and so skin, cartilage, and bone were good starting points. In most all of these areas, we’ve now had some degree of clinical success in alternative treatment modalities. Where we don’t have good therapies at the moment is in areas like degenerative disease, especially neurodegeneration and musculo-skeletal regeneration, and I’d like to see more effort being addressed in those areas.