You may have read recent media stories stating that a cure for Type I Diabetes is “imminent” and wondered what the buzz was about—is a cure indeed imminent and, if so, what does this mean for modern medicine?

Yes, scientists at Harvard University have recently made a huge breakthrough in the treatment possibilities for Type I Diabetes, an inherited condition affecting over three million Americans that causes the body’s immune system to malfunction. Type I Diabetes destroys the pancreatic beta cells in the body that manufacture insulin, a hormone critical for processing sugars. Under current medical practice, people with Type I Diabetes must regularly check their blood sugar levels and inject themselves with insulin to keep levels in check, an imperfect process disruptive to routine life. For decades, researchers have tried to generate pancreatic beta cells that could be used to provide insulin for Type I patients.

Now, thanks to a research group led by Doug Melton, a stem-cell researcher at Harvard Medical School, they may in fact be closer to that goal: Melton’s talented team of scientists have generated functional human pancreatic beta cells from stem cells in large quantities (the paper reporting these findings was published in Cell on October 9, 2014). Hippo Reads’s Science Correspondent Wudan Yan spoke with Felicia Pagliuca, a postdoc in Melton’s lab, about the work that went into this landmark study, the importance of collaboration, and where diabetes research will go from here.

WY: Thanks for chatting with Hippo Reads! We’re interested to know: how did you first get involved in this research?

Felicia Pagliuca: I had been doing my PhD at Cambridge University in the UK at the Gurdon Institute. I was conducting research in cancer biology at the time but [Doug] Melton came to Cambridge to give a seminar. By the end of that seminar, I was just blown away—completely inspired by his vision and what you could do with stem cells in the field of regenerative biology and the impact that could have on patients. I reached out to Doug and told him about my interest and background. We hit it off and I was fortunate enough to be offered an opportunity to work in his laboratory.

WY: What did Doug talk about that was so captivating?

FP: He posed a very simple question: How could we use a stem cell to cure a disease? I think one of the most straightforward diseases that could be treated with stem cells is Type I Diabetes because only one cell type (the pancreatic beta cell) is missing. He thought that if we could make that happen, it would be a watershed moment for stem cell biology and prove that stem cells can actually be used to treat diseases.

I realized the question Doug posed was one I really wanted to solve, so I joined his lab with the specific purpose of what we reported doing in the Cell paper.

WY: Who else contributed to the Cell paper?

FP: There were approximately 30 people in the lab, and it fluctuates because we have undergraduates who work with us. My team had other postdocs and graduate students, but one of the interesting things is that we also had an extraordinarily talented undergrad named Michael Segal who made some of the seminal discoveries that enabled us to achieve this breakthrough. Michael was the first person to find a combination of chemicals to get pancreatic cells to secrete insulin in varying levels of glucose. That provided the first hint we had gotten to the right point, or taken the right path.

The neat thing about the Melton lab is that we have multiple postdocs and students working in projects in parallel for a long time. What really pushed this project forward was bringing all these parallel projects and protocols together and optimizing them. That led us to something more effective than any stream of research on its own. It’s fantastic that we work this way, and I think it’s often hard to have a really effective and exciting collaboration.

WY: That sounds like quite the process. What was it like? What did you learn along the way?

FP: We have been trying lots of chemicals in the lab that were thought to have an effect, so we had been trying them in different combinations. Together, Michael and I brainstormed ideas of combination of chemicals to try. Just finding the right compounds took over two years, and all the work we did was built upon ten to fifteen years of work in Doug’s lab and other labs around the country.

It turned out that in addition to having the correct chemicals, we needed the right context. That is, how we grew the cells. These cells didn’t attach to the bottom of plastic petri dishes, but grew better in a 3D-suspension culture and, as a result, secreted insulin.

It’s interesting because when you take islet cells from the pancreas, which is a technique currently used for diabetic patients, you purify a lot of little spheres. That insight was the inspiration for trying the suspension culture. Since the normal context is for these beta cells to grow in spheres, we tried to mimic that in our culture systems.

Altogether, this paper brought together hundreds of protocols that required a high degree of collaboration.

WY: What was the status quo in this field before your work was published?

FP: Scientists couldn’t make functional pancreatic progenitors to beta cells. The cells they tried to make could make insulin, but the insulin they made wasn’t dependent on the presence of glucose. They would just indiscriminately dump insulin into culture, which is not what we want.

WY: In the paper you say that, in addition to making functional pancreatic beta cells, you were able to make a lot of them. In what way was that challenging?

FP: In both the body and in the petri dish, beta cells don’t divide rapidly. Stem cells can, but beta cells cannot. At any given time in humans, less than 1% of beta cells are replicating at any given time. That’s challenging because we have to make a large number of them and we can’t rely on proliferation to expand the cells that we do make.

WY: How did you react when you saw so many functional beta cells being generated?

FP: I had taken one of the clusters out from culture and sliced it to stain the cells for insulin, a marker of functional pancreatic beta cells. Where there used to be a cluster with very few cells that stained positive for insulin, nearly every other cell was insulin positive. We were just blown away. I brought Doug down into the basement of our building to have a look at the picture as soon as we saw it. You can get a lot of cells, but if doesn’t matter if they’re not expressing the things we want. Getting the cells to express insulin was the tricky part.

WY: You wanted to see if these cells you’d generated could also work in mice. Did you go immediately into working with mice, or was there a time lag before that happened?

FP: There was definitely a lag in time—experiments in mice are very difficult. Some of the early procedures we used worked in culture, but not in mice, so we first went through this iterative process of improving things and testing them, improving and testing. After we got these cells into immunocompromised mice, we injected them with sugar and measured if their insulin levels went up. We use this technology called ELISA, which we add to our samples.

WY: Do you remember the day when you first saw that these cells were making insulin in mice? What was that like?

FP: It was a very late day in the lab and nobody else was around. The technician brought the samples up from the mouse room. I remember very vividly sitting by the shaker with one of the other co-authors, watching the ELISA plate, in real time, turn blue, which indicated there was all this insulin in the blood of the mice.

It was amazing! I got my cell phone out to take a picture of this plastic plate with all this color coming out of it to email to my husband (who doesn’t work in science, and doesn’t necessarily understand how exciting this was), and I explained more when I got home.

The cells have been growing in mice for several months now, and have continued to produce insulin over the course of six months. We don’t know how long they’ll be around for, so we’ll just have to wait and see!

WY: You mentioned that the mice you used were immunocompromised. What does that mean in the context of, say, clinical trials?

FP: Because the mice are immunocompromised they wouldn’t reject the human beta cells that we are transplanting into them. To put these same cells into a patient would require for us to disguise them from the immune system. We have a number of ways of doing this and looking into these methods is a great next step for us.

WY: What other next steps is the team looking at?

FP: We want to see if we can apply the same procedure we used in the Cell paper to stem cells found in diabetic patients to model the actual disease. We want to study how beta cells really work in diabetics, and we currently don’t have access to diabetics’ cells. The other one, which we talked about, is to generate more preclinical data for the FDA to get these cells into patients. If all goes smoothly, we hope to get this into patients and Phase I trials (to assess the safety) in about 3-5 years.


Image credit:  Oskar Annermarken via flickr

  • Claire

    I used to work in diabetes and clinical trials. It’s quite possible this might work although it sounds like there’s still a long way to go. Without reading the actual Cell publication, it sounds like they’ve generated beta cells that can produce insulin both in the Petri dish environment and in mice. But as she said the limitation is that the mouse is immunocompromised. A real patient’s immune system will likely reject foreign cells unless its their own stem cell. And making them immunosuppressed just isn’t worth it (faster to just inject insulin). But it’s definitely a beacon of hope I would say.:)

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