Towards a Diabetes Cure: Beta Cell Updates from the PDRC Symposium

By: Karmel Allison | February 7, 2012 
Categories: Featured, Research, Type 1

It was late January and the temperature was in the mid-seventies without a cloud in the sky – one reason to love being in San Diego. Another reason? The Pediatric Diabetes Research Center (PDRC) at the University of California, San Diego was holding its third-annual symposium. The PDRC aims to bring together the numerous research efforts around type 1 diabetes in the San Diego community in order to improve the lives of patients and push us towards a cure, and so their big event of the year, the annual symposium, draws a heterogeneous audience of academics, clinicians, nurses, biotech scientists, and community members like me with a vested interest in diabetes research.

This year’s theme was beta cells– how to make them, and how to put them where they belong– and the speakers throughout the day presented their recent results from the lab. In type 1 diabetes, the immune system attacks and kills off the insulin-producing beta cells in the pancreas, meaning the body can no longer produce the crucial hormone insulin. Finding a new and plentiful source of insulin production that works naturally within the body, then, is one half of a cure for diabetes. Further, as some speakers touched on throughout the day, as type 2 diabetes progresses, scientists have seen that beta cells begin to die off, probably a result of cellular stress and toxicity. So, beta cell replacement will be important for the treatment of diabetics at large, and a working replacement system would be a huge boon to global health.

 More details of some of the talks are below, but I want to begin with two of the major takeaways for me:

 1. The body knows so much more than we do.

For all that scientists have learned about beta cell biology– and they’ve learned a lot– we still understand only the basics of the concert of cells and hormones that goes into natural regulation of insulin production and secretion. We can trace the progress of a single beta cell from embryonic stem cell to a series of interim progenitors to the final state of beta cell, but we can only name a fraction of the proteins and genes that are involved in the process. And, if we try to explain how each protein or gene is involved, we find we know even less.

The body, however, induces a working system without having to understand or control each player along the way.  Dr. Maike Sander, one of the key researchers in beta cell differentiation from embryonic stem cells, described a set of experiments in which she and her team took pancreatic progenitor cells, capable of turning into many different cells of the pancreas, and tried to turn them into beta cells in a petri dish. They got insulin-producing cells, but they weren’t quite beta cells; they produced other hormones like glucagon, and didn’t produce insulin specifically in response to glucose. But, when they took the same pancreatic progenitors and stuck them inside mice, the cells naturally differentiated into happy little pancreases, with beta cells that produced only insulin, and only in response to glucose stimulation. Like magic.

So what does the body know that we don’t? A lot, it seems.  The good news is we don’t have to wait until we learn everything before we have a working system. The successful implantation of progenitor cells, rather than mature beta cells, that will then turn into beta cells within the body, is the basis of the current beta cell replacement strategy that the company ViaCyte  is executing (see below). The more we understand about the mechanisms behind the physiology, the better, but it’s nice to know we can also leverage the body’s existing systems to achieve our desired ends.

 2. It ain’t over till it works in the clinic.

Speaking of ViaCyte, every time I hear someone from ViaCyte speak about their progress, I think, “Wow, well, they’re almost there! They almost have a working system to replace beta cells!” And indeed, listening to Dr. Olivia Kelly from ViaCyte, speaking, full of optimism for an inevitable successful product, I couldn’t help but wonder why all these other academics– self-deprecating and skeptical in comparison to Dr. Kelly– were trying other methods with varying degrees of success. Why don’t we all just jump on the ViaCyte bandwagon?

The answer came from Maike Sander, during her closing remarks. She pointed out that until we have a replacement strategy that works in the clinic, we need to keep trying different methods, because we don’t know for sure what will work all the way through the end until it actually does. And I realized the truth of that sentiment, as it’s often the last mile that proves the most difficult. This is true to some degree already in beta cell biology, as getting from embryonic stem cell to pancreatic progenitor proved very possible, but taking that next step from progenitor to beta cell is still a work in progress. And getting from mature beta cell to working treatment is a very long last mile.

So, until we figure out what the right answer is, it is important not to limit our options to just one precocious strategy. The PDRC symposium was faithful to that end, giving voice to an array of beta cell replacement studies and strategies.

Here are some summaries from just a few of the many speakers:

Michael Brehm, Assistant Professor at the University of Massachusetts Medical School

Development of Humanized Mouse Models for Diabetes Research

Dr. Brehm presented research and recent results from his experiments with humanized mice. Humanized mice are just about as bizarre and Frankenstein as the name sounds—mice bred to lack crucial components of the immune system are then engrafted with human cells and tissues such that the cells and tissues survive in the mouse and can be studied. Such mice serve as a bridge between murine studies and human trials—they are mouse enough to allow us to ethically experiment, but human enough that we can get an accurate picture of how the processes we observe or drugs we test will act in actual humans. The system is by no means perfect, but it seems we will see more and more humanized mice as scientists try to more efficiently create treatments that will reliably work in the clinic, rather than just in the lab.

Humanized mice have the potential to greatly advance our understanding of many diseases, one of which is type 1 diabetes. Brehm’s lab has been working to create mouse lines that imitate as closely as possible the human disease. Starting with mice that lack essential cells of the immune system (T cells, B cells, and Natural Killer [NK] cells), the researchers then transplant in human hematopoietic stem cells (HSCs), which differentiate inside the mouse into a full suite of immune cells. Importantly, however, these cells are human in origin, rather than mouse, and therefore we can observe how human cells respond to certain stimuli or hyperglycemia or even human beta cells in islets that are transplanted.

Currently, Brehm’s lab is working on creating a mouse that takes this idea one step further—they are creating a humanized mouse that has human immune cells that carry the HLA haplotype that is highly associated with type 1 diabetes. In other words: there is a genetic region that we know is highly correlated with the development of type 1 diabetes in humans, and Brehm and his team are trying to put cells with that genetic region into the mice such that we can see how this particular region changes the way immune cells behave and leads to the development of an autoimmune reaction against the cells of the pancreas. This is no small task, but if they succeed, these mice could give researchers much insight into how exactly a genetic region leads to a particular autoimmune reaction, which could in turn give researcher hints as to how to stop the process.

Olivia Kelly,  Research Scientist at ViaCyte, Inc.

Developing an Encapsulated Stem Cell Therapy for Diabetes

ViaCyte has inspired much excitement and press in the scientific community over the past few years. Their aim is to develop an implantable source of insulin-producing cells from embryonic stem cells for use by diabetics who no longer produce insulin. Though a for-profit company, they are widely respected in the academic world, as they developed the now widely-used protocol that takes embryonic stem cells in a petri dish from pluripotency down to being pancreatic progenitors, cells much closer to being insulin-producing beta cells.

Dr. Kelly spoke at the symposium to give an update on the progress made by ViaCyte thus far towards its goal. She described the three key components of the end product that they are working on—a renewable cells source (a special line of human embryonic stem cells), a therapeutic cell product (the insulin-producing cells derived from the stem cells), and an encapsulation device to hold the cells when implanted into the patient.

In contrast to the academic speakers, who as a tribe are trained to be skeptical, Kelly was very optimistic about the progress so far and the prospect of a product for human use in the near future. Despite several years of effort, ViaCyte has not succeeded in making true insulin-producing cells entirely in the petri dish, but, Kelly reported, they’ve done something else that may prove just as good: they’ve designed a repeatable system for creating pancreatic progenitor cells in a petri dish, and once these cells, which ViaCyte calls pro-islets, are implanted into mice, they mature in vitro into different pancreatic cells, including glucose-responsive beta cells. ViaCyte researchers and associated academics are thus far unsure what exactly is happening after implantation to induce the pro-islet cells to become operational, but, luckily for us, that lack of insight will not stop progress toward a marketable product.

Indeed, Kelly described the ways in which progress was being made at ViaCyte. They are currently fine-tuning their processes such that the cells that worked in the lab with mice can be produced at scale in a reliable, FDA-approvable fashion. They are setting up a pipeline that starts with frozen human embryonic stem cells, differentiates the cells over a several weeks into pro-islet cells, freezes the pro-islets for storage for up to ten months, then thaws the pro-islets, transfers them into specially designed implantable envelopes, and ships them to the clinic for implantation.

Importantly, they are extensively testing the product at each stage to ensure expected quality, behavior, and safety. ViaCyte has completed a FDA-required Good Laboratory Practice (GLP) safety study, and has assessed a number of safety endpoints for the implanted device in mice and rat studies. They have even attached Dexcom continuous glucose monitors to rats to show that, after administering a toxin that kills beta cells, the implanted cells are able to maintain normoglycemia in the rats for extended periods of time.

Kelly preached the promise of the ViaCyte therapy, but some of the experts in the audience were so not easily convinced. Dr. Fred Levine , director of the Sanford Children’s  Health Research Center and Associate Professor at UCSD, asked Kelly why there were so many delta cells showing up in the images taken of pro-islet filled devices that were implanted into mice, then removed after the cells matured. Levine saw the beta cells, but also saw an abundance of other pancreatic cells that begged for an explanation. Kelly did not have a direct answer, but noted that researchers were investigating the various ways in which cell maturation in the device was governed. And when Levine asked where the implanted devices would go, and how big they would be, Kelly noted that there were no clear answers on dosing yet, but that they could estimate the number of cells needed from the size of the patient.

 In sum, it seemed, ViaCyte has an extremely promising product making good progress, but, as Dr. Sander said, we won’t know for sure what the answer is until it we’re done.

 Timothy Kieffer, Professor at the University of British Columbia

Reprogramming Intestinal Cells for Insulin Replacement Therapy

Dr. Kieffer presented recent research from his lab on an alternate way to develop an abundant source of beta cells—differentiating them not from stem cells, but from other mature cells. The particular mature cells that Kieffer and his team work with are the gut K cells in the interendocrine system. These are cells that make up about 1 – 2 % of the lining of the intestines. Other researchers are working with liver cells and even gall bladder cells, but Kieffer thinks the K cells of the interendocrine system are a particularly promising home for insulin production because they are close to the pancreas to begin with, and, crucially, they are already glucose-responsive. You see, interendocrine cells are the cells responsible for secreting the incretins like the hormone GLP-1 in response to ingested glucose—so, rather than take a stem cell or liver cell and teach it to respond to glucose and secrete insulin, Kieffer aims to hijack the existing secretion mechanisms of K cells and teach them to secrete both incretins and insulin.

 Though still in its infancy, the idea is intriguing and clever. Thus far, Kieffer’s lab has created an insulin transgene that they can deliver to mice such that many cells in the mouse harbor the gene, but only the K cells of the gut actually start to express the gene and make protein from it. They have shown that mice indeed start to make insulin in their K cells after the delivery of the transgene, and, further, that Non-Obese Diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, are able to produce insulin from the gut without inducing an immune attack on gut K cells.

 One of the initial hurdles that Kieffer’s team must overcome is figuring out how to safely and reliably get the insulin transgene into the K cells. The normal process for doing this in cells in the lab, using viral vectors, has been used clinically in a few cases, but this sort of gene therapy is considered risky and prone to causing immune reactions. The researchers are therefore investigating non-viral methods for introducing gene-carrying DNA into cells, including most recently chitosan-based nanoparticles that deliver the insulin transgene to cells throughout the body.

 Thus far, Kieffer and his lab have demonstrated the successful induction of glucose-responsive insulin production in mice and even pigs for up to 150 days, and are currently continuing to push this alternate means of beta cell replacement forward.

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 All in all, I was sincerely impressed by the creativity and excitement in the room for the PDRC’s Annual Symposium. We’re not there yet, but every day we get closer thanks to the concerted efforts of a great number of scientists who, for whatever reason, can’t help but try to solve this problem of missing beta cells. So, from one person waiting for a new set of beta cells—thanks!

 Full disclosure: The PDRC Annual Symposium was free to attend, and I have not been paid or asked to write about what I heard. However, I am very much a fan of the PDRC and the research they fund, so consider me biased.

Karmel Allison is science editor of ASweetLife.  She writes the blog Where is My Robot Pancreas?

Islet cell image courtesy of Wikipedia under Wikimedia Commons.

Massachusetts General researchers discover stem cell that makes eggs

E-mail| Print | Comments (3)02/26/2012 1:01 PM

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By Carolyn Y. Johnson, Globe Staff

Massachusetts General Hospital researchers reported today they have discovered a rare stem cell in women’s ovaries that they hope one day might be used to make eggs, a claim already generating vigorous debate among scientists familiar with the research.
For decades, it has been thought that women are born with a finite supply of eggs, limiting their reproductive years. Doctors have sought ways of extending the fertility of women, especially as many wait later in life to begin having children.
The research, led by Jonathan Tilly of Mass. General and appearing in the journal Nature Medicine, opens the door to the possibility of taking tissue from a woman’s ovaries, harvesting stem cells from that tissue, and then creating eggs.
But scientists not involved with the Mass. General research said such an approach -- if it is even possible -- sits far in the future and will require considerably more work. Several scientists said Tilly, who co-founded a company focused on developing novel infertility treatments, had not yet made a convincing case that the stem cells he discovered can yield viable eggs, a critical first step.
Tilly has been a lightning rod in the field of fertility medicine since 2004, when he challenged the orthodoxy that women do not produce new eggs. In a research paper published that year, Tilly laid the foundation for the findings reported yesterday.
“There was a lot of backlash. It wasn’t surprising, given the magnitude of the paradigm shift that was being proposed -- this was one of the fundamental beliefs in our field,” Tilly said. “The subsequent eight years have been a long haul.”
In his new study, Tilly extended research by Chinese scientists published in 2009. He developed a technique that allowed scientists to sift out rare stem cells within the ovaries of mice that were tagged and implanted into the ovaries of normal mice. In the mouse ovaries, the stem cells produced eggs, which were removed and fertilized in a laboratory dish. They developed into embryos, although scientists did not use the embryos to produce mice.
Tilly and his team then wanted to know if such cells existed in humans, too.
The research team obtained ovarian tissue removed from young women undergoing sex change operations in Japan and performed the same experiment they’d done with the mouse ovaries. Much to their excitement, they discovered the rare, egg-producing cells in humans.
In later experiments, the human stem cells were used to produce cells that appeared to be eggs. In part because of ethical limitations, researchers were not able to show that the eggs could be used to create human embryos.
Tilly said that he has patented the stem cells and licensed the technology to OvaScience, the startup he co-founded.
Outside researchers described the findings as intriguing and provocative but also raised many questions. Scientists said it was still far from certain that the eggs created in the experiments could be used to produce babies. And they expressed concern that the findings could falsely inflate the hopes of women struggling with infertility.
Dr. David Keefe, chairman of obstetrics and gynecology at New York University Langone Medical Center, said he and other clinicians who see patients would like more than anything to have greater options for women to overcome infertility. But he said the Mass. General researcher had a history of leaping ahead from basic research findings to suggest clinical possibilities.
“Those of us who take care of patients are extremely protective of their hopes,” Keefe said. He noted that a few years ago, he saw half-a-dozen patients who wanted to delay their fertility decisions because of earlier research at Mass. General.
Even if the new findings are immediately replicated in labs around the world, Keefe said, “it’s so far from being clinical that it’s predatory to not be circumspect about it. Humility is an absolute requirement in this field. You’re dealing with people’s hopes and dreams.”
A 2005 study led by Tilly and done in mice suggested bone marrow transplants might offer a way to restore fertility. A year later, a separate group of Harvard researchers showed that this was unlikely to be true. Tilly himself no longer believes this is a way to restore fertility.
“The big difference in that work, now in retrospect, is these non-ovarian sources [of stem cells] don’t appear to do the job,” he said.
Tilly’s work in the past has divided researchers and failed to persuade many in the field that his interpretations are correct.
Teresa Woodruff, a professor of obstetrics and gynecology at the Feinberg School of Medicine at Northwestern University said she had already drawn up a chart of the claims made in the paper, the evidence to support those claims, and the questions they raise. Still, she said, “I do think he’s pushing the envelope in a way that does push all of us to think more broadly.”
Evelyn Telfer, a cell biologist at the University of Edinburgh, who criticized some of Tilly’s earlier work, said she is excited about the new findings. Tilly said that next month, he will fly to Scotland to begin a collaboration with Telfer.
“What he’s saying is we can get these cells,” Telfer said, “and I think it’s pretty convincing.”
The new paper doesn’t offer evidence that such stem cells are active in the ovary, supplying eggs during a woman’s lifetime. But the powerful cells could provide new insights into the important and poorly understood process in biology of egg-formation and allow scientists to look for drugs that might increase the activities of these stem cells, in order to overcome fertility problems.
Skeptics and supporters agreed on one thing: much work lies ahead.
“That’s science,” said Hugh Clarke, a professor in the department of obstetrics and gynecology at McGill University. “Of course, dogma should be challenged, but we shouldn’t assume dogma has been overturned based on a single report.”
Carolyn Y. Johnson can be reached at cjohnson@globe.com. Follow her on Twitter @carolynyjohnson.

Dr. Bruce Hensel reports on a new study from Cedars Sinai, which found that heart attack patients who received stem cell injections were able to reverse some of the damage to their heart.

See the NBC report

Authors of a small study using cardiac-derived stem cells in “convalescent” MI patients say they’ve uncovered some of the first true evidence that the heart can regenerate, describing a new method that, they say, led to “unprecedented” improvements in viable heart muscle.

Results of the CADUCEUS study, published online February 13, 2012 in the Lancet, showed not only that scar size was reduced on MRI at six months—something also seen in previous research—but also that the amount of viable heart mass and regional contractility were also improved.

Dr Raj R Makkar (Cedars-Sinai Heart Institute, Los Angeles, CA) and colleagues used a proprietary technique to harvest autologous heart cells from endomyocardial biopsy specimens, then grow these cells—dubbed cardiosphere-derived-cells—to the therapeutic dose. The test population was made up of post-MI patients with left ventricular ejection fractions (LVEFs) ranging from 25% to 45%, with subjects randomized 2:1 to receive cardiosphere-derived cells (17 patients) or to standard care (eight patients).

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Researchers make breakthrough in stem cell research

February 13, 2012

(Medical Xpress) -- University of Queensland scientists have developed a world-first method for producing adult stem cells that will substantially impact patients who have a range of serious diseases.

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The research is a collaborative effort involving UQ's Australian Institute forBioengineering and Nanotechnology (AIBN) and is led by UQ Clinical Research Centre's (UQCCR) Professor Nicholas Fisk.

It revealed a new method to create mesenchymal stem cells (MSCs), which can be used to repair bone and potentially other organs.

“We used a small molecule to induce embryonic stem cells over a 10 day period, which is much faster than other studies reported in the literature,” Professor Fisk said.

“The technique also worked on their less contentious counterparts, induced pluripotent stem cells.

“To make the pluripotent mature stem cells useful in the clinic, they have to be told what type of cell they need to become (pre-differentiated), before being administered to an injured organ, or otherwise they could form tumours.

“Because only small numbers of MSCs exist in the bone marrow and harvesting bone marrow from a healthy donor is an invasive procedure, the ability to make our own MSCs in large number in the laboratory is an exciting step in the future widespread clinical use of MSCs.

“We were able to show these new forms of stem cells exhibited all the characteristics of bone marrow stem cells and we are currently examining their bone repair capability."

AIBN Associate Professor and Co-Investigator on the project, Ernst Wolvetang said the new protocol had overcome a significant barrier in the translation of stem cell-based therapy.

“We are very excited by this research, which has brought together stem cell researchers from two of the major UQ research hubs UQCCR and AIBN,” Associate Professor Wolvetang said.

The research is published in the February edition of the STEM CELLSTranslational Medicine journal. 

Provided by University of Queensland

Parkinson's disease brain cells created in lab

Scientists have successfully made genetic brain cells with Parkinson's disease in a lab, a huge breakthrough for curing the disease.

Talia RalphFebruary 8, 2012 19:42

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Scientists have created stem cell versions of brain cells with Parkinson's disease, a breakthrough for finding a cure. (Spencer Platt/AFP/Getty Images)

Exact replicas of human brain cells with Parkinson's disease have been created by scientists from the University of Buffalo, a huge step towards finding a cure, BBC News reported. 

The stem cells will allow researchers to find out how other forms of Parkinson’s develop, The Mirror reported. The cells also give scientists the unprecedented ability to run tests on live brain tissue; such neurons were formerly inaccessible, because they are located too deep in the brain. 

"This is the first time that human dopamine neurons have ever been generated from Parkinson's disease patients with parkin mutations," said Dr. Jian Feng, professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and the study's lead author, The Digital Journal reported. "Before this, we didn't even think about being able to study the disease in human neurons. The brain is so fully integrated, it's impossible to obtain live human neurons to study."

More from GlobalPost: EU stem cell patent ban is 'unbelieveable setback', say researchers

The study was published by Nature Communications. The scientists have called their discovery a "game-changer" in the fight against Parkinson's. 

To make the neurons, Dr. Feng and his team used a technique which turns donated skin cells into brain tissue, BBC reported. They used skin samples from two healthy people and two with Parkinson's disease, which allowed them to study the parkin gene that causes the disease. 

The research was inspired by a 2007 Japanese study in which researchers converted human cells to induced pluripotent stem cells (iPSCs) that could be subsequently morphed into nearly any cells in the body, The Daily Journal reported. 

“This study is particularly exciting because it describes for the first time how researchers have successfully generated nerve cells from people with a rare genetic form of Parkinson's, linked to the parkin gene," Dr. Michelle Gardner, a research development manager at Parkinson’s UK, told the Mirror. 

The research also found that inserting the correct form of the gene into the nerve cells could restore their proper functioning, which points towards possibilities for new treatments of Parkinson's. 

More from GlobalPost: China inserting human stem cells in goats