Brock Reeve is Executive Director of the Harvard Stem Cell Institute, whose mission is to use stem cells, both as tools and as therapies, to understand and treat the root causes of leading degenerative diseases.
For part 1 of the interview, click here.
Brock Reeve: I think the most interesting change has been that 10 years ago, people were basically thinking about stem cells as replacement parts. For example, how do we grow up enough heart cells to give to someone, or enough blood cells? Now, we’ve realized that cells are really little programmable units. Inserting just four genes out of the 25,000 or so you have per cell will totally reprogram an adult skin cell to an embryonic-like stem cell. That’s amazing. Cells are much more flexible than we used to think they were, and that opens up incredible new windows of opportunity.
It’s not only relevant to the whole drug discovery paradigm we talked about before. People are also looking at in vivo transdifferentiation. What I mean by that is, say you’re short a particular neuronal type in the heart or in the pancreas. Or say you’re diabetic and you have fewer and fewer beta cells. Is it possible to deliver either small or large molecules in vivo into a person and turn a related cell type into the type of cell that you want?
The first test of this kind was conducted several years ago in diabetic mice, and it succeeded in turning a certain type of pancreatic cell into a beta cell, restoring normoglycemia. People have also tried this in the heart. If someone has a heart attack, can you turn the related cells into heart muscle so the heart can rebuild itself? It’s already been done in embryonic mouse brains, turning one type of neuron into another. So, using our understanding of cell plasticity and cell programmability, how can we impact the body’s inherent ability to repair and regenerate, abilities that have either been lost with age or damaged by injury?
There are overlaps with bioengineering, as well. Several years ago, there were a whole bunch of trials about giving people either mesenchymal stem cells or heart cells for heart therapy. One of the things that they showed is that simply putting cardiac cells into people won’t solve the heart problem, because the MSCs don’t transdifferentiate into cardiac cells and the cardiomyocytes don’t electrically couple in the right way. In fact, you can raise the risk of heart attacks. A study done recently in monkeys, for example, showed that after a heart attack, you could give the monkeys more heart cells, but they all had arrhythmia (an irregular heartbeat), and you definitely don’t want to give someone arrhythmia.
It’s a difficult technical challenge to address. Some people are asking, “How do we combine these cells with different biomaterials? How do we put them on thin films or on a patch?” Another approach is looking at how to decellularize organs from a cadaver, and use the extracellular matrix that is left over as a scaffold rather than having to create new biomaterials. Because of what we know about iPS cells and reprogramming, can we repopulate the decellularized organ with a patient’s own cells and grow back a fully-functioning organ?
In some cases, it won’t be giving people new organs at all, but using degradable biomaterials and giving them growth factors that will stimulate internal growth and regeneration. So there are multiple strategies being explored, and I’m not sure how it’s all going to play out.
Reeve: Yes, I do think it’s true. When I was talking about genes being able to reprogram cells, that really is an information processing question. From the stem cell perspective, a lot of the information that we see is at the intersection with genomics. And at HSCI, we’ve set up a bioinformatics core facility for people to share bioinformatics data across experiments.
There’s a lot of work to be done to understand what genes get turned off, and when, and where, in the course of development of a particular cell type. How are cells comparable to one another? How do we manipulate their genetic backgrounds and capabilities? People used to say, “If we understand the gene, we understand the disease.” Now, we know that isn’t true, even in monogenic diseases.
Understanding the environment in which genes are expressed, as well as all the different feedback loops, is crucial. Which genes are upstream? How are cells signaling to each other? How do cells affect their neighbors? How does the substrate in which they’re laying affect things? How does physical stress in the body, such as blood flow or mechanical stress, impact cells, or in some case turn genes on and off?
Even simple things like exercise can be understood as information flow systems. There are all sorts of beneficial effects of exercise, but in many cases we don’t know why that is the case. There have been genes that have been identified that get turned on and off, but the complexity of information is everywhere, from the systemic level all the way down to the level of single cells.
I was just talking about cystic fibrosis with someone the other day, which is a gene that was identified back in the ‘80s. It’s a single gene, but it has hundreds of mutations, and those mutations manifest in very different ways. Some of them are misfolded proteins, some of them have to do with calcium signaling, etc. And that means you can’t have just one drug for cystic fibrosis. Even though it’s a monogenic disease, any particular drug will only help a certain subset of the population.
Reeve: Well, one of them is simply funding for basic science, because there is always pressure from the NIH just in terms of budgets. Most early-stage research in this country is funded by the NIH, and it’s getting harder and harder to get that money. As people try to commercialize these technologies, windows like the IPO market open and shut periodically. The pharmaceutical industry is getting more engaged, but as it comes under increasing pressure in terms of its own R&D pipeline and productivity, it’s getting pickier and pickier about deals with academics. So funding for early-stage research is a big bottleneck in the U.S.
To cite one example, California passed a bond act in 2004 that funded theCalifornia Institute of Regenerative Medicine (CIRM), which was driven at first by changes in federal funding of embryonic stem cell research. So there you have a state putting in $3 billion over 10 years to advance work in this field. But will that get renewed? I don’t know. It’s not looking good, right?
Countries like the U.K. have funded central facilities such as stem cell banks. Just last year, they funded several catapult centers, one of which was a cell therapy catapult. Other countries in Europe have various funding projects as well, including IPS cell banks. Years ago, Singapore put a bunch of money into the stem cell space. So as you look around the world, you see various pockets of funding emerging, where governments are trying to drive behavior and investment in particular directions.
One positive change is that the political bottleneck about the ethics of embryonic stem cells has really gone away. These days, I think the politics have more to do with questions of funding than questions of ethics. Of course, there are also technical bottlenecks. I was talking with someone recently who’s struggling with how to create biomaterials that won’t induce a fibrotic response, so that you can put them inside people without creating scar tissue that gets in the way of the cell signaling.
The fundamental science questions will always be there, in one form or another, and we’ll tackle them. But it always comes back to the money. One researcher here had an ambitious project recently to try to create custom humanized mouse models for diabetes—to basically take human beta cells, and blood cells, and thymus cells, and put them into mice in order to turn them into living test tubes for people. But the NIH doesn’t want to fund “blue sky” projects. They more or less told him that it was too innovative, and too risky. So he had to turn to private philanthropy.
Reeve: Well, in this country, the disease foundations have been very important in funding research in their fields of interest, where either the government or the companies were taking a “wait and see” attitude. And one of the things that I think would be highly useful for our field would be to figure out how to get disease foundations and companies and academic institutions all working together in what I call a “pre-competitive space.”
As an example, we’ve been talking with some people about this idea of creating neurons of interest for particular diseases, and how to get it done. We can make mostly mature dopaminergic neurons for Parkinson’s, for example, but not yet for schizophrenia or autism or Alzheimer’s. There’s still a lot of research necessary to get to the point where we can really model human disease in a dish. And you want to do it at scale. But that’s not something that a typical academic lab would do. It also extends beyond the boundaries of what any disease foundation is interested in. Nor is it proprietary to what a pharma company would want to do, because the real intellectual property would be the drugs you could build using those tools, rather than the tools themselves.
So we need to develop some kind of pre-competitive consortia that will allow us to take common problems, share them across groups that are interested in them—companies, foundations, academics, hospitals, etc.—and band together behind the notion that a rising tide is going to lift all boats. I think that’s still a stumbling block for the field, and you could really accelerate some interesting research efforts by picking chunks of that off.
MF: Is there a role for increased patient/public advocacy in all of this? There are historical examples—Parkinson’s, cancer, HIV/AIDS—that demonstrate how public involvement has played a key role in stimulating change. What’s your take on the temperature of public engagement right now?
Reeve: There’s an association called the Alliance for Regenerative Medicine, and they introduced a bill in Congress called the Regenerative Medicine Promotion Act in April. In general, though, people are motivated by tackling a particular disease, as opposed to regenerative medicine as a whole. If we go back to CIRM in California, they obviously had to do a lot of public awareness campaigning in its early days. But I think they may have oversold the benefits that were going to come from cell therapies and regenerative medicine. Part of how they sold it to the state was by saying, “You’ll save on your healthcare bills.” And the science was too early to promise that.
One of the big things I don’t know is what degree of backlash there might be. Last month, someone sent me an op-ed from the San Francisco Chroniclethat basically said, “Look, we backed CIRM when it first started, but we’re not going to do it again because we think taxpayer money shouldn’t go for this any more.”
MF: Do you think that’s more of an education challenge? Working to advance a frontier is such a tremendously complex endeavor. It seems we lack broad understanding about the challenges, and that our expectations are not properly calibrated. Isn’t it one of those cases where the journey is worth it even if you don’t arrive precisely at the expected destination?
On the other hand, what’s also increasing is a general understanding, whether it’s for Parkinson’s or organ transplantation or simply healthy aging, of just how far reaching the impacts of regenerative medicine are on different disease areas. This whole issue of repair and regeneration is a broad one, and as people understand that, then I think it plays out well.
Reeve: Not really, no. In terms of public policy, we just need more funding. When Mahendra Rao stepped down from the NIH Center for Regenerative Medicine about a month ago, he said: “Look, I had been promised funding to do five clinical trials. I got funding to do one. If we’re really going to do this, we need to do this at scale.” So I think the real public policy issue is the funding.
This is where groups like the NIH play into it. And then, how do state and local groups support that? CIRM is only for California. New York has something roughly equivalent called NYSTEM, and they’ve funded some large projects. They are funding a Parkinson’s study right now. I think they promised up to $1 billion over 10 years. Massachusetts set up a life sciences center, but it was more broadly focused on life sciences jobs in the state rather than just regenerative medicine. Also, in 2006, Maryland established the Maryland Stem Cell Research Fund, with over $110 million committed to date. It would be incredible to see a lot more of these state-level efforts.