Connecting the Lab and the Clinic

Dr. Jennifer Elisseeff is Director of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine. She focuses primarily on tissue regeneration, and is working to develop an artificial cornea.

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Methuselah Foundation: Let’s start by talking about the Translational Tissue Engineering Center at John Hopkins. What kind of work are you doing there in your lab?

Jennifer Elisseeff: Well, we named it the Translational Tissue Engineering Center because we’re focused not just on the development of new technologies in regenerative medicine, but on addressing clinical challenges and developing new therapeutic outcomes for patients. In my lab, we’re looking at a number of different applications in orthopedic surgery, rheumatology, and musculoskeletal repair. We're working on the regeneration of cartilage tissue, which lines the surfaces of joints. We’re also looking at bone repair, which is important for joints and in craniofacial reconstruction, and exploring what can be done with muscle disease to repair tissues and treat the underlying disease.

Then there are the plastic surgery applications—reconstruction of tissues and wound healing in the craniofacial region and soft tissue throughout the body. We’re also in an ophthalmology building, so we're surrounded by a lot of clinicians focused on the eye, and we’ve begun projects looking at both corneal repair and retinal repair.

MF: What work are you most proud of so far?

Elisseeff: That’s tricky. I'm often most excited about the newest things that we're doing, but those are still in the early stages, and so their impact is still unclear. Right now, for example, I'm excited for what's going on in immunomodulation, and how we can use that to promote tissue regeneration.

If I look back at impact, however, I would say that where we've been able to translate things clinically, we’ve also gained important knowledge to help us develop things in the laboratory more efficiently. In other words, the translational applications also help us target the right problems in the research. Without that feedback loop, we might be in the lab playing around with what we think are important variables, only later to find out that they actually aren’t that important when you get into working with people.

MF: Is there anything about the center at Johns Hopkins that you think makes it special or unique, compared to other research centers in US?

Elisseeff: One of the big advantages we have is that we are right in the middle of a fantastic clinical environment. There are surgeries happening on the bottom floor of our building. If you walk out of our building and hit anything close by, there's patient care happening. We’re surrounded by physicians who are keenly interested in seeing the next therapy get out, and can give us real guidance on what is needed to make that happen and how best to design true therapeutic improvements. In addition, we have a great stem cell center, the Institute for Cell Engineering, that gives us capabilities across the whole spectrum from the basic, fundamental science to the everyday needs and challenges of physicians and patients.

MF: More broadly speaking, how would you describe the potential of tissue engineering and regenerative medicine to impact patient care?

Elisseeff: The impact of regenerative medicine in the clinic ranges all the way from the everyday aspects of wound healing—closure, scar tissue reduction, etc.—to the most complex challenges of composite tissue transplantation, reducing rejection, avoiding immunosuppressives, and rebuilding tissues from the ground up. There are so many challenges along that spectrum from the most simple to the most complicated, including treatments for myocardial infarction or heart attacks, minimization of injections that reduce scars and promote solid tissue growth, whole-systems approaches to treating osteoporosis, and addressing multiple factors that influence disease.

MF: What are your overall thoughts about the state of tissue engineering and regenerative medicine today, both in terms of key opportunities and key roadblocks?

Elisseeff: What's interesting right now is that there seems to be a renewed excitement for cell therapies and gene therapies, both among students and in the commercial sector. These types of industrial investment and commercial excitement tend to go through ups and downs, and I think there's a lot of excitement right now that we definitely want to get more and more connected with.

One of the biggest gaps in my mind is what happens at the university versus what's feasible in commercial settings, and there are a number of these so-called valleys of death between the two. There’s a valley of death in the laboratory of moving to proof of concept and actual efficacy in the most relevant pre-clinical models that the FDA will approve. Then there's another valley of death when you come out of the laboratory regarding how to manufacture and deliver whatever technology you’re working with, and how to make it commercially viable.

MF: Are there particular reasons why there is a lot of excitement right now around cell and gene therapy?

Elisseeff: For one thing, we’ve moved past some critical barriers in the manufacturing of cells. It's not at all easy to develop reproducible manufacturing and delivery mechanisms for getting cells into patients. And then finding the right diseases where that even makes sense. It might not make sense in orthopedics or for arthritis, for example, but it might be the perfect solution for a disease like ALS. So it’s been challenging to understand which disease targets are most relevant for cell therapies, and there have recently been some exciting successes in cellular immunotherapies that have given us all great hope for the field.

MF: What stands out to you right now as the most promising work in the field?

Elisseeff: Right now, I'm most encouraged by the interface between regenerative medicine and transplantation. There have been some exciting advances in transplantation and microsurgery, for example, with very complex grafts on the face, hands, and arms. And in order to take it beyond that, and make it less of a rare, boutique occurrence into something more widespread and accessible to a larger number of people, I think it could be very interesting to combine the latest work in cell therapy with the latest in both materials and immunomodulation.

Also, I think some of the recent advancements in cancer immunology, which is really a type of regenerative medicine engineering—in other words, engineering the immune system to treat a disease—involve principles that are very promising and can be applied to many other things.

MF: How would you characterize the overall funding climate right now, especially in the US?

Elisseeff: It's terrible. Many people running laboratories are spending much more of their time trying to fundraise and write grants than they're spending doing science, education, or mentorship. And I think that’s a huge problem.

The peer review process is a great thing in the US. As much as I complain about it, whether it be for manuscripts or grants, we do get a lot of great input from our peers to help us do better science. But right now, it's gotten to the point that it’s untenable. I’m on a panel, so I’ve seen how they run, and it’s really impossible to choose between the top X percentage of grants. They’re all great. So you end up just nitpicking, and you lose a lot of good science in the process. Then those researchers have to write up another X number of grants because they didn’t receive money for that very good grant to start with.

Overall, it’s just a very destructive environment for science and future innovation. It’s particularly challenging for junior faculty members, but it’s not a walk in the park for anybody. I often wonder how many hours and how much science we lose because of this. At the moment, at least, there's actually a much better climate right now in Europe for funding scientific research.

MF: We’ve been hearing this a lot as well. With NIH budgets continuing to drop, how about the social or charitable sectors? Do you see much funding coming towards stem cell science, regenerative medicine, and tissue engineering from the philanthropic side?

Elisseeff: Did you see the article in the New York Times this year about philanthropists and donors taking a far more significant role in the directions of science? There are many interesting ways to perceive whether that's a good thing or if we're moving too far away from peer review.

MF: Yeah, we saw that. But either way, there are 1,300 billionaires in the world. Do you see many of them making regenerative medicine a priority right now? If not, why?

Elisseeff: I suspect that it’s a marketing battle more than anything else. Regenerative medicine is such a young field compared to fields like cancer research. It doesn't have as many celebrity spokespeople yet, but it has the potential to capture interest, particularly with respect to battling aging.

MF: How about the state of patient advocacy around these things? It often seems like people are more inclined to orient promotional efforts around specific diseases as opposed to an entire field like regenerative medicine.

Elisseeff: I think it's still at a very early stage. For example, if you look at arthritis, you see a lot of interest emerging now in a genetic perspective on treatment via various drugs coming out of regenerative medicine. I think those approaches are just relatively new, and probably not yet fully appreciated as alternative therapies.

Regenerative medicine is somewhat hard to define. It's tissue engineering—regenerative medicine—immunoengineering—gene therapy—cell therapy—and so on. Because the field is so broad, it’s perhaps a little bit harder to clearly express to people.

MF: Do you think that there are dramatic changes needed in the way clinical trials and regulation currently works in the U.S.?

Elisseeff: Yes. In our first two translation experiences at Hopkins, all of the clinical testing was done outside of the U.S. Right now, we’re trying to work in the U.S., and even for something relatively simple, it's still very difficult to do. When you are dealing with cutting edge therapies, there just isn’t any clear guidance on regulatory matters. Everybody is trying to figure out the safest way to go about it, and we have such low risk tolerance here. I think something needs to be done about that if we want to improve the chances for regenerative medicine to make an impact in this country.

I heard a great description of the medical translation challenge once from a Congressmen who is also a medical doctor. He said simply that there is no one in Washington whose job it is to promote and stimulate innovation in health technologies, to shepherd things through and promote the innovation process. There are people responsible for regulating products and making sure that people are safe, but nobody with the real objective of stimulating innovation and translation. How can we promote as much innovation as we can, but in as safe and efficient a manner as possible? Particularly with new therapies for which, despite all the pre-clinical testing, we don’t know much about what’s going to happen in a clinical environment? We need to be actively asking these questions.

MF: If you were master of the universe for a little while, what would you do to greatly accelerate research in regenerative medicine, in order to save and improve lives as rapidly as possible?

Elisseeff: If we can enhance our methods and strategies for translation, it will create a positive feedback cycle in which more and more translatable technologies lead to better and better research, and ultimately, greater and greater impact. To me, a big part of that has to do with better education of academic faculty in how this process works. On the other side, it also depends on demonstrating the potential to those who are in a position to translate, either from the investor end or the commercial end.

We also need to cultivate more of an appreciation for the unique challenges, and unique value, of multi-disciplinary research. One of the major hurdles today for regenerative medicine strategies, including research proposals, is that there’s not enough appreciation for the fact that no single investigator is ever going to be an expert in everything at once—in stem cell biology, in the particular disease under consideration, and in all the other relevant fields.

This sort of universal domain expertise is not only impossible, but unnecessary. In our peer review panels, for example, what we’ll often see is that a proposal will come in that might be able to satisfy one particular domain expert, but there will inevitably be three others, all in different fields, who are each unhappy with some aspect of the proposal. It’s really hard to make all the experts in all the relevant fields happy, and I think more of us need to learn that the complexities of multi-disciplinary research require different considerations.