Harvard group publishes Cell paper on a new process for generating human beta cells from stem cells – October 9, 2014

An article on a remarkable new procedure for producing large quantities of human insulin-producing beta cells from stem cells was published today in the journal Cell. JDRF and Helmsley Charitable Trust provided vital support for the project, which was conducted in the lab of Dr. Doug Melton (Harvard Stem Cell Institute, Boston, MA). Dr. Melton and JDRF Director of Discovery Research Dr. Albert Hwa have also provided valuable insights on the project in a press conference call and an individual interview with us, for which we are most grateful. Islet transplants have shown promise in helping type 1 diabetes patients achieve glycemic control and insulin-independence, but the lack a sufficient supply of islets has limited scalability. The new procedure can generate hundreds of millions of beta cells in a single flask, enough for a transplant, in a matter of four to five weeks. The cells produced through the new method are notable for their quality in addition to their quantity. The Cell report presented extensive evidence that the stem cell-derived beta cells are similar to beta cells from human islets in terms of their gene expression and structure. Additionally, the cells were able to secrete insulin in a glucose-responsive manner and rescue rodent models of type 1 diabetes from hyperglycemia.

Assuming Melton et al.’s process proves reproducible and scalable, it could one day revolutionize the care of type 1 diabetes patients, including the most vulnerable (so-called “brittle”) patients – this group will likely pioneer the therapy when it hits the clinic. However, new-onset type 1 diabetes patients and also insulin-dependent type 2 diabetes patients could also see enormous benefit from beta cell transplantation. Such a therapy is years away at the nearest, with at least one year of preclinical work left to go. Additionally, our optimism is tempered very slightly by the occasionally discouraging history of beta cell regeneration or replacement therapies for type 1 diabetes until now. In particular, the autoimmunity of people with type 1 diabetes will need to be addressed for this approach to reach its potential - ViaCyte is attempting this by encasing beta cells in a protective device. However, if and when the products of the Melton et al. procedure are available to patients, it could be an absolute game-changer and majorly disruptive to the insulin market. Although major insulin manufacturers might see this as a challenge, as ViaCyte and BetaLogics (which are also working on cell-based diabetes therapies) might as well, both groups of companies can view Dr. Melton’s team’s work as an opportunity. The project will need a pharmaceutical industry partner at some point before late-stage clinical development, and companies with existing beta cell encapsulation technologies could conceivably gain from such a large-scale source of beta cells. For an extensive review of projects to cure type 1 diabetes, we encourage you to read our team’s book, Targeting a Cure for Type 1 Diabetes: How Long Will We Have to Wait?

Read on below for more background on cell-based therapies for type 1 diabetes, an overview of the procedure and results outlined in the Cell report, the potential for this work beyond type 1 diabetes, and the steps ahead for Dr. Melton, his team, and his collaborators.

Background on Cell-Based Therapies for Type 1 Diabetes

• The lack of sufficient quantities of suitable beta cells has been a major factor limiting the potential of islet transplantation and other cell-based therapies for type 1 diabetes. Transplantation with human islet cells from deceased donors has been shown to effectively restore insulin production in patients with type 1 diabetes, but the large-scale usefulness of the procedure has been severely hampered by the limited availability of high-quality donor cells. A number of researchers have explored various means of converting pluripotent cells or other differentiated cell types into beta cells (see our coverage of some of these approaches at ADA 2014), but so far none of these methods has been able to consistently produce a sufficient number of functional beta cells for widespread therapeutic use.
  
  • During the GNF-JDRF Diabetes Research Symposium earlier this year,  JDRF’s Dr. Richard Insel foreshadowed that beta cells from human embryonic stem cells might be available to researchers in the near future – see item #1 of our report. We have to imagine that he might have been hinting at the progress being made in Dr. Melton’s lab, although there are plenty of other groups working on projects similar to this.
  • ViaCyte and BetaLogics are also working on encapsulated beta cell transplant therapies for type 1 diabetes. ViaCyte’s product, VC-01, consists of stem cell-derived pancreatic progenitor cells encapsulated in an immune protective device that can be implanted under the skin. In the past several months, ViaCyte has signed a rights agreement with Janssen and received a $16.6 million grant from the California Institute for Regenerative Medicine (CIRM) to support the ongoing phase 1/2 trial (ClinicalTrials.gov Identifier: NCT02239354) of VC-01. J&J venture BetaLogics is pursuing a similar strategy: as of April, the company had developed a protocol to differentiate human stem cells into pancreatic progenitor cells and was working on an encapsulation device. One notable issue with using pancreatic progenitor cells is that the cells can take a few months post-transplant to mature to the point where they can produce insulin in sufficient quantities.

Overview of the Melton et al. Protocol and Resultant Beta Cells

• The protocol developed by Dr. Melton’s group successfully generated hundreds of millions of insulin-producing beta cells from human pluripotent stem cells within four to five weeks. The development of the protocol did not rely on a single stroke of inspiration, but rather a lengthy and deliberate process of refining a multi-step process through trial and error (and some success). Embryonic stem cells were initially used as the cell source, although induced pluripotent stem cells were also tried later.
• Functionally and structurally, the resulting cells appear to very closely resemble endogenous beta cells. The cells consistently secreted high levels of insulin in response to repeated glucose challenges in vitro; the response was comparable to that seen with beta cells from human cadavers and significantly better than that of “polyhormonal” cells derived from stem cells using older protocols. A five million-cell transplant restored insulin secretion within two weeks in immune-compromised mice (in contrast to the three to four month maturation period required for pancreatic progenitor or polyhormonal cells to begin secreting insulin) and successfully ameliorated hyperglycemia in rodent models of type 1 diabetes.
• At the May 2013 Joslin Diabetes Symposium, Dr. Melton stated that his lab would produce glucose-sensitive beta cells from stem cells in vitro by the end of the year. Given that peer-reviewed publication can be a lengthy process, it seems like his lab was on or near this target

Applications Beyond Type 1 Diabetes

• Although the current focus for the project is type 1 diabetes, this cell-based therapy also has enormous potential for type 2 diabetes patients, especially patients with longstanding diabetes that are dependent on insulin injections. The type 2 diabetes application has the additional advantage that there is less of a need to protect the transplanted cells from autoimmune attack. In the shorter term, this area of opportunity might help sweeten the deal for potential partners, given that adding insulin-dependent type 2 diabetes patients to the pool of type 1 diabetes patients in the US roughly doubles the size of the potential market. In the short term, we would expect the focus to remain on type 1 diabetes due to the high unmet need in that disease area as well as the priorities of the project’s current funders (JDRF, HCT). However, if and when a larger pharmaceutical partner comes onboard, we would not be surprised to see parallel pursuit of stem cell-based therapies for type 2 diabetes and possibly other applications.
• The authors also emphasize the potential to use the new supply of human beta cells in areas beyond direct cell therapy, such as high-throughput drug screening or disease modeling. The Cell report notes that a single flask of cells could provide enough cells to screen 30,000 compounds (in a 384-well format with 10,000 cells per well. The cells could also be used to identify and test novel biomarkers for beta cell health and function. Such a development is particularly noteworthy given the poor translatability of findings from rodent models to humans. Further down the road, the beta cells could also be used to develop more fully formed islets and pancreatic organs through integration with mesenchymal and/or endothelial cells. This set of enticing possibilities, which seems almost too good to be true, attests to the value of being able to efficiently produce what was once an incredibly scarce resource.

Future Steps

• One major step on the medium-term horizon is a partnership with industry, or more specifically with a pharmaceutical company. The support of JDRF and Helmsley Charitable Trust have been critical in getting the project to this point, but the shared belief is that industry is likely best suited to help the project make the final (and most resource-intensive) steps of clinical steps before regulatory submission. JDRF Director of Discovery Research Dr. Albert Hwa noted that multiple pharma companies have already expressed interest in cell-based therapies in general, even though cell therapy is generally a new area for most companies in the field. For context, beta cell regenerative small molecules and biologics (including betatrophin) discovered by Dr. Melton's laboratory have previously been licensed by Janssen.
  
  • Given that resource limitations have been rate limiting for Dr. Melton and his team’s work, a strong financial backbone will be a key criterion for any potential partner. As was shared during a press call held before the paper was published, the work could move four times as quickly if the team had four times the financial resources. In addition to finances, we imagine that a commitment to type 1 diabetes would be a possible criterion for a partner given the motivations of the Harvard team and its current supporters. This would not need to be an either-or proposition, as many partners might also be willing to invest in a parallel program for type 2 diabetes while keeping the ball moving forward for type 1 diabetes.
• One key challenge that lies ahead is finding a way to encapsulate the beta cells to protect them from autoimmune attack in type 1 diabetes patients, or induce tolerance. Failure to find an acceptable solution would be a major setback for the overall project. At this point, the other primary alternative would be immunosuppressant therapy, which is very difficult for patients from a safety and tolerability perspective. Given the high stakes, the JDRF and Helmsley Charitable Trust are supporting multiple encapsulation projects, some of which are working directly with Dr. Melton’s group. Dr. Daniel Anderson (MIT, Cambridge, MA), supported by both Helmsley and JDRF, is working on a “microencapsulation” strategy involving modified alginate (from algae) that would form micro-bubbles around sets of cells. Dr. Jeffrey Karp (Brigham and Women’s Hospital, Boston, MA), supported by JDRF, is leading a team that is working on a more structural “macroencapsulation” strategy - the route used by ViaCyte.
  
  • Encapsulation will likely be the rate limiting step to the clinic: JDRF’s Dr. Hwa speculated that encapsulation research might take at least a year or two more before it (combined with the beta cells) can enter the clinic.
  • The choice between microencapsulation and macroencapsulation has regulatory implications: microencapsulation could add to the volume of the final cell transplant, to the point that it would necessitate placement within the central (peritoneal) cavity. Such placement would involve a surgical procedure that would carry higher risk than a subcutaneous application. Macroencapsulation would have its own unique set of regulatory questions, perhaps including the implantation and removal procedure.
  • Additionally, the specific encapsulation strategy used could adversely impact the lag time in the equilibration of glucose concentrations in the body vs. near the transplanted cells. The design of the device could slow the equilibration of glucose levels inside and outside the device, or could hamper the release of insulin from the cells into the bloodstream. Worst case, too much lag time could lead to over-secretion of insulin, and perhaps hypoglycemia. We imagine that this is an area in which regulatory authorities might request specific studies.
  • Similarly, encapsulation needs to strike a challenging balance between preventing immune cells from reaching the beta cells, while allowing oxygen, nutrients, and of course glucose and insulin to easily travel between the beta cells and surrounding tissues. Given the fragility of beta cells, poor oxygen or nutrient supply could lead to their failure.
  • On the other side of the safety equation, (macro)encapsulation also has the potential to serve as a failsafe, perhaps in the unlikely event that implanted cells have tumor-causing potential. If a tumor begins to develop it would be contained within the encapsulation device and could be removed expeditiously. However, teratogenicity will certainly be examined in preclinical testing to a great degree, and should not be a major risk if and when this therapy moves into the clinic. The ability to quickly remove all transplanted cells could also be useful in other circumstances. This is a characteristic of macroencapsulation that ViaCyte has frequently highlighted.

Close Concerns Questions

• What is the timeline for initiating clinical trials?
• How reproducible will the Melton et al. procedure be, and to what extent can it be standardized?
• What would be the ideal point for an industry partner to enter the picture?
• Is there any chance of collaboration with ViaCyte or another company pursuing cell-based type 1 therapies?
• How far along in development are the encapsulation devices under consideration? Are there any other options to protect the cells from immune attack?
• Will the Melton et al. group exclusively pursue development for type 1 diabetes or broaden the focus to type 2 diabetes as well? How might that decision impact the search for a partner?
• How will the public perceive stem cell-based therapies? Will the political issues that once surrounded embryonic stem cells have any impact?

Press Conference Call

Mr. B.D. Colen (Harvard Stem Cell Institute, Cambridge, MA): Hi. This is B.D. Colen of the Harvard Stem Cell Institute. I want to thank everybody for joining us today to hear about this very important paper from Doug Melton’s lab. On the call today we have Doug Melton, who will speak for a few minutes about the work, Eliot Brenner of the Helmsley Charitable Trust, who will talk about why the Trust is supporting this work and Dr. Albert Hwa of the JDRF, who is in charge of their Beta Cell Therapies Program.

Dr. Doug Melton (Harvard Stem Cell Institute, Cambridge, MA): Yes, good morning everyone. This is Doug Melton and thank you all for taking the time this morning to hear about this finding and your interest in this work. In a paper that will come out in Cell, we are reporting the ability to do two things. One is to make hundreds of millions of cells – enough for patients. We can make, in about a coffee cup size, enough beta cells to treat one patient and these cells accurately respond to multiple glucose challenges. You could think of it like breakfast, lunch and dinner. Each time we gave them a sugar challenge they secreted the right amount of insulin. They packaged the insulin in granules as is found in normal human beta cells and when we provide these cells to an immunocompromised mouse, a mouse without a functioning immune system or a mouse with a mutation in their insulin gene, in both cases the mice being diabetic, we can cure their diabetes right away in less than ten days.

So we’re very excited about this because as I indicated earlier, it provides for type 1 diabetics in my view, sort of half of the solution to the problem, namely type 1 diabetics are missing beta cells and they have an immune attack which kills them, so problem one is replacing those cells and these cells are suitable for that kind of replacement. Problem two is something we can talk about later, which will be some kind of encapsulation or some other form of immune protection.

For type 2 diabetics, this would replace their inability to make insulin. Using iPS technology, a patient’s own cells could go back into them or it could be put in before the patients become insulin-dependent and then forestall the progression of the disease.

So I will in a moment be happy to answer questions about this, but to just summarize why we think this is important: this finding provides a kind of unprecedented cell source that could be used both for drug discovery and cell transplantation therapy in diabetes. I don’t claim that this was an original idea. It’s a sort of obvious application in regenerative medicine and stem cell biology. People, including us, have been talking about it for more than a decade. And our solution to the problem came as an applied developmental biology solution, which involved many years of work, more than 15 years of work and certainly more than 50 students and postdocs here in my lab over this period working by trial and error to find the right mix of chemicals and growth factors that would tell a stem cell to become a beta cell.

There’s more work to be done on improving the method, the protocol. It’s a 30 to 40 day protocol and at the moment it’s not 100% efficient. But I think we’ve shown that the problem can be solved. We’re essentially at the finish line here showing how to make beta cells.

Before I end then I just wanted to say one more thing, which is not only am I forever grateful to the students and postdocs here at Harvard who worked so hard with me on this, but this work would not have been possible without philanthropy. Many of you will remember the years when the government thought that this kind of research either shouldn’t be done or should be done with so many restrictions that it made it nearly impossible and I am forever grateful to organizations like the Helmsley Trust, the JDRF and the generous philanthropists that have given money to the Harvard Stem Cell Institute. This event wouldn’t have happened without that kind of support.

Dr. Albert Hwa (JDRF, New York, NY): This is Albert Hwa, from the JDRF. I think Doug has provided a very nice summary of his really nice work. I wanted to speak about cell therapy for type 1 diabetes. We actually have clinical proof of concept that by transplanting human islets that we harvest from cadaver donors back into type 1 patients, a lot of these patients can then restore their ability to regulate glucose and they will become insulin-independent. However, there are two major limitations. One is that we’re never going to get enough cadaver donors to provide these islets and then number two, these people are just like any other transplantation patients, they have to take immunosuppression drugs that have a lot of risks.

These are the two limitations that we are trying to eliminate in order to make this kind of therapy more widespread. Doug’s research really has addressed that the first limitation that I mentioned, which is providing an unlimited amount of beta cells or islet cells, that you can transplant. This is sort of the Holy Grail of regenerative medicine or tissue engineering, where you’re trying to make an unlimited cell source or a tissue or organ source that you can replace in a patient in order to correct the disease.

Like Doug said, we have had a very longtime interest in this work in the early days of the early 2000s when there was the federal ban on this type of research. We continued to fund the early work of human embryonic stem cell research and Doug was one of the researchers that we funded at the time. So we are very, very happy and excited for the fruition of that research to this day, where we can have this amount of functional beta cells that potentially can be used for cell therapy, but also for further research to understand the disease better and also for drug discovery and drug screening purposes.

Dr. Eliot Brenner (Helmsley Charitable Trust, New York, NY): Hi. This is Dr. Eliot Brenner from the Helmsley Charitable Trust. I’m going to echo some of what Doug and Albert have already said. But I will say that Helmsley Charitable Trust is very pleased to have supported Doug and his team in this breakthrough. The ability to create mature insulin-producing beta cells not only has significant clinical potential for people with type 1 diabetes as a source of islet transplantation but it opens up a new path for researchers to understand and develop novel treatments for this disease, as Albert and Doug have said.

We’re very pleased to also be supporting Doug’s collaboration with Dr. Dan Anderson at MIT, to create an implantation device for stem cell generated beta cells. This has been outlined as a critical next step in the development of a potentially game changing therapy for type 1 diabetes.

Since the Trust began making grants in 2009 we’ve funded a range of beta cell related projects to advance the type 1 diabetes field and Doug is unquestionably a leader in this field and we have been and continue to be a very strong supporter of his work.

Q: I wanted to see if you could talk for a minute about the importance of embryonic stem cells for this work. You referred a few times to how controversial research was in this area going back to, I guess around 2000 and I wanted to see if you could just talk for a minute about why it was sort of indispensable for this type of work.

Dr. Melton: First, we’ve demonstrated that this method of making beta cells will work with human embryonic stem cells and the other type of pluripotent stem cell called an iPS or induced pluripotent stem cell, so it’s a general method for producing beta cells. Nonetheless, the iPS cells didn’t really exist at the time we began this work and if it weren’t for the availability of the human embryonic stem cells the most we could have done would have been try to find ways of using mouse cells to cure mouse diabetes, which is kind of scientifically interesting but not interesting to me personally. We really wanted to focus on human cells so it was absolutely essential that we had access to large numbers of embryonic stem cell lines created here at the Harvard Stem Cell Institute.

So a good question now is: are the embryonic stem cells better or worse than the iPS cells? And we don’t know enough yet to answer that question. We’ve been able to make beta cells from both but we haven’t been able to do really detailed, deep dive comparisons on the two.

Q: Could you do that quick dive into the technical aspect that you alluded to earlier? Was it literally just a trial and error process?

Dr. Melton: We started by studying all of the genes that come on and go off during the normal development of a beta cell in mice and in frogs and then the human material we could get access to. Once we knew which genes come on and go off we then had to find a way to manipulate their activity using something that we added to the outside of the cell because we did not want to genetically modify the cells.

Those things we added, which you could think of as kind of perturbing agents or inducing agents, were small chemicals, cell permeable chemicals and growth factors. And we tested literally hundreds of combinations and discovered that in a six-step procedure where we added two or three factors at each step, and the name of the factor and its concentration and the duration of its application all mattered, we developed a combinatorial complex protocol that after 30 days leads to beta cell production.

I would not contend that we had any intellectual insight. It was hard work, an empirical approach. I’m sorry that it’s taken us nearly 15 years. I wish it didn’t take that long. But there are different kinds of science. One is discovery science, where you immediately discover a solution to a problem. This is an empirical approach where you’re committed to finding the solution and you try all kinds of things.

Q: Could you talk more about the timing for getting these into humans and moving this perhaps at an accelerated pace? And is there anything that patient communities could do to support this and to perhaps help move this even faster?

Dr. Melton: I’ve been of course, thinking about that for a while and I don’t have a really strong answer, except to say that we need the best devices or device to put in the patients. Secondly, we’re always limited, not completely limited, but limited by resources. And then thirdly, we of course have to begin our discussions with the FDA, see what sorts of safety and toxicity tests would they like to see performed, because obviously we’re not going to just try something without being certain first that it’s safe.

I’m encouraged by the fact that two biotech companies, one called ViaCyte and one called BetaLogics, have made major investments in this area. Both of those companies are going forward with an encapsulation device, which I think we have access to, and the cells that they’re going to use are an immature version. With the cells I reported we could say you've gone through six or seven steps of differentiation. They’re using a cell population that’s gone through three steps and they know that some of the cells in their preparation will mature after three to four months inside an animal. I believe they’re hoping that the same will be true in a human.

And so that will be a nice proof of principle that this approach can lead to cells that produce insulin. We’d like to think our cells are better. They’re ready to go now. They’re secreting the right amounts of insulin on day one and so we can follow in their path and in some way learn from what they’ve done to try to speed the process in the patients.

Back to your question, what you're really asking me is why should it take three years? The best estimate I could give is that it’s going to take us probably a year to confirm and standardize this protocol, let’s say industrialize it, in a way that we can make it under standard conditions and then figure out which device to use. And then of course, get permission from the various required regulatory agencies to go through this.

And here again, we get enormous help and advice from organizations like the JDRF and the Helmsley, both of which have tried to help our government realize how important this problem is and how we should be careful not to just continually create hurdles that make it impossible to bring new technologies to patients.

Q: Thank you so much. We are so grateful to them as well as patients and parents and partners and people with diabetes.

Dr. Melton: I also might remind you that I’m not a medical doctor. I’m a basic stem cell biologist so we also need to coordinate and collaborate with surgeons who would be putting this in. And we have some ongoing collaborations already, one very nice one with José Oberholzer in Chicago, who’s doing the monkey trials with us. And so I’m confident that this work will attract enough attention to get more people to help us get it to patients faster.

Q: Can you speak a bit more as to how this would help type 2 diabetes?

Dr. Melton: About half of the insulin sold each year is injected into type 1 patients and the other half into type 2 patients. However, the type 2 patient population is enormous and about 10 or 15% of type 2 diabetics are insulin dependent.

In my view, the best way to think about this would be to make a patient-specific beta cell for each patient and then provide them with their own beta cells to relieve them of insulin injections or eventually to provide more beta cells before all their beta cells are killed off and prevent them from ever becoming insulin dependent.

Now that might sound like a dreamy proposition but I can tell you that in these preliminary discussions with pharmaceutical companies, they’re very interested in this because we can now make and induce beta cells from the patient’s blood. So a type 2 diabetic would come to the clinic, have a blood sample drawn and then by our calculations, within eight to ten months we can produce billions of their own beta cells. Then within a year, they could come back and begin to get a package of beta cells which would prevent them from having to inject insulin.

That’s a new business model for the pharmaceutical industry, but given the size of the patient population, it’s one that has their attention, particularly because as many of you know, the growth of type 2 diabetes in China and India is going to crush healthcare budgets.

The main point is that in type 2 diabetes one does not have to worry about an immune attack because there’s no autoimmunity. One merely has to worry about putting the patient’s own cells back.

Q: Can anyone tell me how many beta cell transplants have been done and what the success rate is?

Dr. Hwa: The total number of transplants done worldwide so far is on the order of about a thousand patients. In terms of annual rate, I think in the US, we’re talking about fewer than 40-50 patients and around the world around 100 per year.

So this is a procedure that’s not done that frequently and also you have to choose the patients selectively because these patients have to undergo immunosuppression, so not every type 1 diabetic can receive this procedure.

Q: Who normally gets it? Is it typically patients who let their diabetes become uncontrolled? What sort of patient would end up getting these cells or getting a transplant as opposed to just using injected insulin?

Dr. Hwa: People with really out of control diabetes, usually with life-threatening hypoglycemic unawareness would qualify. It’s really the compilation between benefit and risk, if the risk of giving these patients immunosuppression is outweighed by the benefit of relieving the life-threatening complication. So these patients, some of them actually will be more qualified for a full pancreas transplantation. With the full pancreas transplantation there’s even a higher risk from the surgery and all that. So if you don’t qualify for that, then islet transplantation is slightly safer in terms of the surgical procedure.

Q: Could you talk a little bit more about encapsulation? I’m having trouble envisioning what that looks like, what a patient has to go through to have that process done.

Dr. Melton: The way to think about encapsulation is you want to allow the cells to survive and function, which means read the amount of sugar and squirt out the right amount of insulin, but we want to protect the cells from an attack, a physical attack, by the T cells of the immune system,

It’s sort of like a tea bag where the tea stays inside, the water goes in and then the dissolved tea comes out. And so using that tea bag analogy, we would put our cells into this tea bag and then after the first phase of clinical trials you could retrieve the cells and study what's happened to them, how many have survived, how they’re still functioning.

But to get a little more serious about it, type 1 is not using the tea bag because the membrane on the tea bag has holes that are too large. So you’re using bioengineered materials where the holes are big enough for insulin and glucose to cross but small enough so that cells can’t get across.

There are a number of such devices that have been made and I’m most excited about, as I said before, the work of Dan Anderson at MIT. He’s made a microencapsulation device that surrounds the islets or the beta cells with alginate, which comes from algae, and he has chemically modified it so that fibroblasts don’t glom it up.

And so with this iteration one would make hundreds of thousands of these little tiny drops, each of which contains a cluster of beta cells and put that inside the equivalent of a tea bag into the patient. There is still the open question of where in the patient should be these cells be put? At the moment, most people are thinking of two locations. One is subcutaneous for testing and the other is in the body cavity or the peritoneum for larger devices and functions.

And lastly I’ll just add, how big of a device are we talking about? We don’t know the answer to that but by our calculations the device we would need would be on the order of the size of a credit card and it will require more experiments to determine really what is—it’s a dosing problem because we don’t yet know how long the cells will survive in the human. We know that they survived for more than six months in animals and we still have those animals going.

Dr. Hwa: I just want to mention that JDRF is also really happy to cosponsor the Dan Anderson research with the Helmsley Charitable Trust and we’re really happy that Dan Anderson has established a close collaboration with Doug.

And so like Doug said, there are a lot of design issues with encapsulation systems. He described what we typically call microencapsulation, which is he described a micro capsule, kind of a spherical round little device, and there are obviously other types of encapsulation systems. Macroencapsulation is more like a tea bag.

And there are obviously other design issues around compatibility. That can really refer to whether the body will form a fibrotic response again. We don’t want the body to wall off the cell from the host and we want to be able to have really good blood supply near the transplant itself.

We also want the insulin and glucose to have access to those blood vessels in the islet so we don’t have to wait six months. So we are happy to be sponsoring many different encapsulation projects.

Dr. Melton: It’s my own view that that the reason the biomaterials and devices as a project hasn’t proceeded as quickly as it might, is that there has been a lack of a cell source to test them. Up until now, people had to depend on human cadaveric material and these would have been cadavers whose beta cells were judged to be sick or too poor in quality for transplantation.

Now that we can provide unlimited amounts of beta cells with that group of bioengineers, I’m hopeful that it will really stimulate that activity now that they have an unlimited source of cells and we can say to them, “Can you figure out a way to protect these cells and allow them to survive and function in patients?”

Q: Could you speak to your personal motivation? What did you and your group do that others didn’t do and what do you think makes a difference? And then what additional animal testing would you be doing?

Dr. Melton: As a personal motivation it’s something I’m not all that comfortable talking about, but my 6-month old son, Sam, died of diabetes some 20 years ago and since that time, I did what any parent would do and said that I’m not going to put up with this and I want to find a better way. I’m not the only parent who feels that way and that’s tried to do something about a disease like this.

In our case, my wife and I were then doubly sorry when some years later my 14-year-old daughter, Emma, also came down with type 1 diabetes. So my motivation is very personal. I’d like to think it doesn’t cloud my scientific judgment, but it is a personal quest for me, which in part is why I’m so gratified to have all these people helping us to get to where we are now.

Why did we succeed and others failed? That’s a little bit harder to describe. I think it would be hard for anyone to explain that, except to say that this project isn’t an ideal project for an academic lab because it’s so time consuming. As I said, it took more than 15 years, and a typical graduate student or postdoc is thinking about a two to three year project, not a 15 year project and so that poses the challenge of dividing it up into chunks that would be interesting and appropriate for student work.

Two companies have been trying to do this, ViaCyte and BetaLogics, and I don’t know why they haven’t gotten as far, except to say that I suspect it has to do with their limits on funding and the pressure on them as companies to get something into the clinic. That’s why they have both decided to stop at an early stage and begin with a cell that I think will be good for proof of principle but is unlikely to ever be a final product. But they may have a different answer and a different opinion on that.

It wasn’t any great intellectual insight. I didn’t get an idea in the shower that helped to solve this. It was really just strategic, systematic hard work over a long period of time.

On animal models, we’ve now "cured" diabetes in many mouse models and are now trying to do that with José Oberholzer around monkeys. These mouse models are in some ways contrived but they’re the best models we have.

And I wasn’t satisfied with curing diabetes in a mouse. That’s been done by a number of methods many times. We’re really focused on getting these cells into human patients as quickly as possible and I believe the huge advantage we have is that we’ve made human beta cells. We haven’t made monkey or pig or mouse beta cells, we’ve made human beta cells and we can make them from the patients themselves. So I’m willing to bet a Coke that these are going to work very well when they’re put into a human.

Q: Could you say a little more about what the optimal pathway would be on the funding front? I think many are listening closely and would love to be more involved with your quest along with JDRF and the Helmsley Charitable Trust, who have been so very, very constructive and helpful to patients on this path.

And a follow-up on the type 2 front, as many type 2 patients are living much longer today, the number who will require insulin and particularly mealtime insulin will grow.  Do you have any comments about the prospects for helping that much larger community that is adding so many costs to the healthcare system? What possibilities are there for bending that curve?

Dr. Melton: It won’t surprise you to know that I think all the time about funding and resources. That is what limits our research. I’m not suggesting that we need a hundred times or ten times the amount of funding we have but it is certainly true that if we had four times as much funding we could go four times as fast. This is not unique to my case. You read this all the time in newspapers, that on the whole the funding cuts to the NIH and all other granting agencies have been really quite drastic in the last decade. And it’s just unfortunate in my view that that arrived at a time when stem cell biology was showing a new way to treat and even prevent some diseases from occurring.

So how will funding happen? I’m certain that my lab will continue to depend on philanthropic funding. We are very fortunate to have a group of supporters that can donate to the Harvard Stem Cell Institute and the grants, which you might be tired of hearing about now, from Helmsley and the JDRF are great examples and really essential to our work. Those are really substantial grants and we’re very grateful to them.

I think that is going to be essential for the next couple of years and then as we prove that this will work, to your point, it would be surprising if the pharmaceutical industry then didn’t take up the baton and say, “How do we make a business out of this?” Ultimately, we all want this to be commercialized so that it’s available to all patients. We’re not interested in just treating a handful of people, and that will require a business model and commercialization.

Pharmaceutical companies are already interested in this. You would have to ask them how do they make a calculation? Sanofi, Novo Nordisk and Lilly combined have somewhere between $15 and $20 billion a year of insulin sales. The question for them would be do they wait until this is clearly a disruptive technology that threatens their market or do they invest in that quickly and early on and move it forward faster?

Q: I would imagine that many of them also share the excitement about these prospects. You’re right, it is $20 billion plus. I think that also there are many more people who should be taking insulin and there are many more people who don’t have access to insulin, so it’s exciting for these populations as well.

Dr. Brenner: One of our goals as a philanthropic institution is to fund that early stage research and de-risk these kinds of things so that at some point business can step in and take over and bring this to the clinic for the benefit of patients. That’s what we’re all about. We want to see treatments make it to people to change their lives.

Dr. Melton: I want to thank you all for your interest in this. I do think it’s an important step. It’s halfway to my goal of getting a treatment for type 1. And if we’re lucky I hope we all can meet again in a few years and have a big party because these cells will be in patients and curing their diabetes.

Q: One more question and that is where you would see this device being implanted or how it would be implanted in the body?

Dr. Melton: The sites that I have heard the most about would be for trials, under the skin and a number of places in the belly region. For longer term supply, into the peritoneum, into the body cavity. Another potential site would be the left lobe of the liver, which I think has some other problems with it. And finally in between the shoulder blades in the back, the interscapular region, is another popular idea. But none of these have been tested yet, so those are the kinds of things we’ll be testing in animals and then in people in years ahead.

-- by Manu Venkat, Emily Regier, and Kelly Close