David Green: We want to bring regenerated organs for transplant to patients who need them. HART has been around for about five years, but it’s only really been visible since November of last year when we were spun off as a separate public company from our parent company, Harvard Bioscience.
I founded Harvard Bioscience, which sells laboratory equipment, 17 years ago. And in the course of developing products, we became interested first in stem cells, and then in regenerative medicine. We signed our first sponsored research agreement with Massachusetts General Hospital in 2008, and later that year, Paolo Macchiarini published a paper in The Lancet on the world’s first regenerated tracheal transplant.
I’d never heard of Dr. Macchiarini before, but in that paper he described a bioreactor similar to what we were interested in. So I sent him an email congratulating him on the achievement and asking if he wanted to license his technology. Thirty minutes later, he wrote back and said “yes.” That began our collaboration, as well as our interest in the trachea as an organ for regeneration and transplant.
Green: Well, the bioreactor for the trachea is basically a cell culture vessel inside of which the tracheal scaffold is rotated a bit like a chicken is rotated on a rotisserie in order to distribute the cells into the pores of the scaffold. You can’t just pour the cells over the top, because most of them will just wash away. You need to continuously feed the cells into the scaffold in order for them to become embedded within the fibers of the scaffold and start to grow. So that’s the purpose of the bioreactor: to feed the cells onto the scaffold, keep them at body temperature, and keep them sterile for two days prior to the transplant.
If you go back to that first paper in The Lancet in 2008, that was using a decellularized natural donor trachea. In other words, a trachea was taken from the donor, someone who had died in a road accident, and then all the cells were stripped off of it, leaving behind a collagen tube in the shape of the trachea. They then took bone marrow cells from the patient and seeded them onto the scaffold in the bioreactor.
That patient is still alive more than five years after the surgery, so it’s been a great medical success. However, she did have complications, one of which was that the scaffold became floppy after the surgery. It eventually stiffened up, and she’s fine now, but she went through a period where she had to be stented in order to maintain the open airway. Because of this, Dr. Macchiarini was very interested in finding synthetic approaches to scaffold fabrication that could be made much stronger and avoid this risk of tracheal-collapse. We partnered with him to do that.
The first synthetic scaffold was used in 2011 on another patient, who had trachea cancer. Prior to the surgery, he was given two weeks to live, and he ended up surviving two and a half years after that. So it was another great medical success story. That was the first use of a synthetic scaffold. Eventually, we developed a new scaffold using a nanofiber approach, and that technology has been implanted in the most recent five patients, starting in 2013.
Green: We are focused on the trachea primarily because we need to get it through clinical trials and onto the market. We expect to start clinical trials next year and then get the product approved by the regulatory agencies by the end of 2017.
Of course, scientific research still goes on, both our own research and that of our collaborators. Our collaborators have also succeeded in regenerating and transplanting both the esophagus and the lungs. So far, those organs have only been done in animals, but one day we expect to be able to do them in humans as well.
Green: Harald Ott at Mass General, our original collaborator, did that work on lung regeneration and transplant that was published in Nature in 2010. And just a couple of months ago, Paolo Macchiarini published “The Regeneration and Transplant of an Esophagus in Rats,” also in Nature. We’re also working with the Texas Heart Institute on heart regeneration, the Mayo Clinic on heart valve regeneration, and several other collaborators whose names are confidential.
Green: Usually both. The scaffold technology we have today is only usable with hollow organs—things like the trachea and the esophagus. It’s not really amenable to solid organs like the heart and the lung, so most of the research work being done in heart and lung regeneration is being done with decellularized donor material. Just like I described for the first trachea in 2008, a donor lung or a donor heart is decellularized—all the cells are stripped off it, leaving a collagen shape behind—and then that scaffold is recellularized with cells from the patient.
Green: I think there are two main challenges to the more complex solid organs. One is revascularization. So far, we’ve succeeded in generating a scaffold and then cellularizing it so that it’s covered in cells at the time it’s implanted. But it does not have a vasculature. In cases such as the trachea, that’s okay, because the trachea doesn’t have any real metabolic load. It’s not like the heart that’s beating or the kidney that’s processing and filtering the blood, so it can survive with a very limited amount of vascularization. Vasculature still does have to be provided by the body, but that can occur after the scaffold is implanted. But that strategy probably won’t work for a heart or a lung. There’s just too much need for oxygen in the cells.
The other main issue is simply fabrication of the scaffolds. At this point, 3D printing is not capable of producing scaffolds with the kind of resolution necessary to make them friendly for cellularization, let alone vascularization. The fibers we make, for example, are about one micron in diameter, which is about one one-hundredth the width of a human hair. But the best resolution you can get from a 3D printer today is about 20 to 30 microns.
The other big issue with 3D printing is the materials that are available are typically things like steel or rigid hard plastics that engineers like to use to make things like telephones and other industrial products. They’re not biological materials. Obviously, to print a scaffold through cellularization, you would need a biological material, or at least a biologically compatible material like we use for the tracheal scaffolds. So there are major issues with 3D printing for regenerative medicine.
Green: At least for a whole heart or a whole lung, I think the issue really isn’t the bioreactor technology at all. The bioreactor technologies we have today are good enough to do what is needed for decellularization and recellularization of hearts and lungs. The challenges lie much more in the vascularization of those scaffolds, and that’s more a biological issue than it is a bioreactor issue. If someone can crack that problem, they will almost certainly win the Nobel Prize.
Solving this challenge would be incredibly beneficial to patients, as well, because it could make organs viable that currently aren’t good enough for transplant. There are about 2,000 heart transplants per year in the US, but there are many more donor hearts than that. There’s just a very narrow window during which a heart can be harvested from someone who’s died before it needs to get implanted in the recipient, and some of them don’t make it in time. However, even if an organ didn’t make that four or five hour window for direct transplant, it could still conceivably be used for decellularization.
There is a limited amount of starting material for making decellularized organ scaffolds, both for heart and for lungs. And once this vascularization problem is cracked, I think it will be possible to commercialize a decell-recell (that’s what we term a decellularized-recellularized organ scaffold) for heart and lung transplants. Ultimately, I think we’re going to have to figure out how to build synthetic scaffolds, both for hearts and for lungs, because the number of patients you can treat through decell-recell is always going to be limited. There just isn’t yet any technology available that can fabricate those types of scaffolds.
Green: Well, you don’t need to go faster than the speed of light to manufacture a synthetic lung scaffold or a synthetic heart scaffold, so it’s not like we’re talking about breaking the laws of physics here. I think these are much more engineering challenges than they are scientific challenges. It’s certainly not impossible to imagine a 3D printer with a one-micron resolution. I think it’s mostly a matter of money, to be honest.
The big 3D printing companies are not that interested in developing 3D printing for biological scaffolds, I don’t think. 3D Systems and Stratasys, for example, want to bring manufacturing back to the US from China. Compared to that enormous trillion-dollar opportunity, I think they view medical stuff as being kind of a sideline.
I’m not aware of anyone yet who has made the commitment of money, people, and resources to seriously try to overcome these challenges for the fabrication of synthetic organ scaffolds. I know Organovo isn’t trying to do it. As far as I know, they’re focused on building organ-type structures directly from cells rather than trying to fabricate scaffolds for further cellularization and vascularization. I’m not aware of any academic groups who are focused on it, either.
Green: I suppose everyone would say funding, right? I’m perhaps not quite as paranoid about that as a lot of people are, because HART is very lean, and my criticism of a lot of biotech companies is that they typically waste a lot of money. Clearly, everyone thinks they could do more if they had more money. But putting that aside, I think the biggest challenge for biotech companies in the regenerative medicine space is that this is all so new for the FDA.
If you’re developing a new small molecule drug for pain therapy or something like that, you can just pull the existing user manual off the shelf and follow the regs. There’s so much precedent, and it’s all pretty clearly laid out. You can take everybody else’s clinical trial designs. You know what the end points are going to be. You know how you’re going to evaluate it. You know how many trial sites and how many patients you need. It’s still a lot of work, but there’s not a lot of mystery about it.
When it comes to cell therapies, however, so few have been approved. Even the FDA admits that there is no playbook or user manual that you can follow, and as a result, it’s a lot more challenging. To its credit, I think the FDA has done a very good job of separating itself into the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), precisely because they recognize they need a different, more flexible approach for working with these new companies. But the lack of a playbook here is a serious challenge. We’re blazing the trail.
MF: In terms of that, what would you say makes HART unique relative to other regenerative medicine companies?
Green: We’re focused on life-threatening conditions, which is really my big criticism of most of the rest of the cell therapy and regenerative medicine industry. If you look at where this industry got started, with skin, the two companies that got FDA approval for skin both went bankrupt. It’s expensive to develop cell therapies, and you have to be able to charge a high price for them or you’re never going to be able to make a return on your investment.
You can only charge a high price for something if you’re delivering a high medical value to the patient, and the highest medical value you can deliver is to save a patient’s life. I’ll exaggerate to make a point here, but when you deliver a patch of skin to a patient for a diabetic foot ulcer, which is the only application that those two skin companies—Advanced BioHealing and Organogenesis—ever got FDA approval for, you’re not dealing with a death sentence. And unless you are dealing with death sentences, I just don’t think you’re creating enough medical value to be able to charge the prices you need to charge to recover and justify the huge R&D investment necessary to bring these products to market.
I used the skin companies as a case in point, but you could raise similar issues about the knee cartilage repair products that Genzyme has commercialized. Again, knee cartilage repair is not life threatening. It’s very painful, and I’d hate to have that condition myself, but there are many other, more affordable ways of treating defective knee cartilage.
To me, the industry so far has been characterized by too much science and not enough business. At the end of the day, the economics of the product you develop and the price you can charge for it have a huge bearing on which products actually get developed and commercialized.
I mean, it’s not all gloom and doom. We’re doing life-saving stuff with the trachea, but we’re not the only ones. There’s a company called Neuralstem, for example, that is using cell therapy to treat ALS, and ALS is 100% fatal. But there aren’t many of us.
Green: I think a successful commercial product would go a long way. If you’ve got a successful commercial product, you will have lots of investors who will want to invest, and once you have lots of investors, a lot of new products are going to get developed. I think that would probably be the single biggest catalyst.
Everyone would like more funding for basic research, but I’m not convinced that spending a lot more government money on basic research is really warranted anyway. I think any government funding would be much better spent on translational research, on getting products developed and commercialized that address significant unmet medical needs.
This is actually one of the reasons I’m pretty hopeful about this field in the long term. At this point, I think we’ve reached a kind of critical mass of knowledge about cells, scaffold environments, and patient conditions that whole organ regeneration is within reach. If you asked me this question 20 years ago, when Vacanti and Langer were publishing their papers about tissue engineering, we just didn’t have enough collective knowledge to be able to make confident predictions. But it’s a much clearer path for us now to go from cells to scaffolds to an organ.
With our particular effort, we’ve shown it can be done on the trachea, on three different scaffolds. One was a decellularized donor scaffold in 2008. Another was a synthetic scaffold using a plastic polymer called POSS-PCU in 2011. Then in 2012, we began these fibrous-type scaffold implants in humans. None of them are perfect, but they’ve all given significantly extended lifespans to patients who had very little lifespan ahead of them. So it’s coming. The proof-of-concept is there that organs really can be regenerated for transplant.
Green: Well, I think it’s very important, but the most important aspect of it is patient advocacy. I think we need an organization like the Juvenile Diabetes Research Foundation (JDRF), which does a fantastic job of pushing research towards the clinic. Unfortunately, there is no equivalent organization for organ transplantation. I mean, I know there are organizations like the United Network for Organ Sharing (UNOS), for example, but they’re not patient advocacy groups. They organize the donation of the organs and the logistics for implant.
Green: I’d be hard-pressed to find a better model to clone than the JDRF. I think there’s one for chronic myeloid leukemia (CML), as well. Several of these groups have been very successful, and often they are organized initially around a patient.
There’s a woman named Kathy Giusti, for example, who suffered from multiple myeloma, and who also happened to be a graduate of Harvard Business School and a successful executive somewhere. Following her diagnosis, she quit her job and co-founded the Multiple Myeloma Research Foundation with her twin sister Karen Andrews. She started going around to all the academics who were doing multiple myeloma research and said, “Guys, you have to start working together. This is ridiculous. You’re all competing with each other, and you need to start working together.”
The second thing she said is, “You need standards. You guys are operating as though this is all about academic research, but the FDA has requirements, and the work you’re doing is not up to the standards required by the FDA.” She kinda beat heads together and said, “Stop. Stop being academics. Start thinking about treating patients, patients like me.” And it worked.
I think some sort of patient advocacy organization like that would make a huge difference. A group that is capable of mustering large amounts of resources and playing a coordinating role for bringing therapies from basic science to a particular set of patients. But it’s not like this needs to be invented from scratch. There are plenty of role models.