The Most Important Gift of All

Photo courtesy American Hospital Association

There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.

Organ and tissue donation saves lives, increases knowledge of diseases, and allow for the development of novel medications to treat them. When individuals or their families authorize donation for transplant or medical research, they allow their loved ones to build a long-lasting legacy of hope that could not be accomplished in any other way.

Four of CIRM’s clinical trials involve organ donations – three kidney transplant programs (you can read about those here, here and here) and one targeting type 1 diabetes.

Dr. Nikole Neidlinger, the Chief Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for Northern California and Nevada – says it is important to recognize the critical contribution made in a time of grief and crisis by the families of deceased donors. 

“For many families who donate, a loved one has died, and they are in shock. Even so, they are willing to say yes to giving others a second chance at life and to help others to advance science. Without them, none of this would be possible. It’s the ultimate act of generosity and compassion.”

The latest CIRM-funded clinical trial involving donated tissue is with Dr. Peter Stock and his team at UCSF. They are working on a treatment for type 1 diabetes (T1D), where the body’s immune system destroys its own pancreatic beta cells. These cells are necessary to produce insulin, which regulates blood sugar levels in the body.

In the past people have tried transplanting beta cells, from donated pancreatic islets, into patients with type 1 diabetes to try and reverse the course of the disease. However, this requires islets from multiple donors and the shortage of organ and tissue donors makes this difficult to do.

Dr. Stock’s clinical trial at UCSF aims to address these limitations.  He is going to transplant both pancreatic islets and parathyroid glands, from the same donor, into T1 patients. It’s hoped this combination approach will increase beta cell survival, potentially boosting long-term insulin production and removing the need for multiple donors.  And because the transplant is placed in the patient’s forearm, it makes it easier to monitor the effectiveness and accessibility of the islet transplants. Of equal importance, the development of this site will facilitate the transplantation of stem cell derived beta cells, which are very close to clinical application.

“As a transplant surgeon, it is an absolute privilege to be able to witness the life-saving organ transplants made possible by the selfless generosity of the donor families. It is hard to imagine how families have the will to think about helping others at a time of their greatest grief. It is this willingness to help others that restores my faith in humanity”

Donor Network West plays a vital role in this process. In 2018 alone, the organization recovered 702 donor samples for research. Thanks to the generosity of the donors/donor families, the donor network has been able to provide parathyroid and pancreas tissue essential to make this clinical trial a success”

“One organ donor can save the lives of up to eight people and a tissue donor can heal more than 75 others,” says Dr. Neidlinger. “For families, the knowledge that they are transforming someone’s life, and possibly preventing another family from experiencing this same loss, can serve as a silver lining during their time of sorrow. .”

Organs that can be donated

Kidney (x2), Heart, Lungs (x2), Liver, Pancreas, Intestine

Tissue that can be donated

Corneas, Heart valves, Skin, Bone, Tendons, Cartilage, Veins

Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys.  Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.

Rare Disease, Type 1 Diabetes, and Heart Function: Breakthroughs for Three CIRM-Funded Studies

This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.

Rare Disease

Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2. 

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.

However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.

Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains. 

In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,

“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”

Type 1 Diabetes

Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.

The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.

“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”

Heart Function

Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.

In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,

“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”

The full results of this study were published in Nature Genetics.

Breakthrough for type 1 diabetes: scientist discovers how to grow insulin-producing cells

Matthias Hebrok, PhD, senior author of new study that transformed human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

More often than not, people don’t really think about their blood sugar levels before sitting down to enjoy a delicious meal, partake in a tasty dessert, or go out for a bicycle ride. But for type 1 diabetes (T1D) patients, every minute and every action revolves around the readout from a glucose meter, a device used to measure blood sugar levels.

Normally, the pancreas contains beta cells that produce insulin in order to maintain blood sugar levels in the normal range. Unfortunately, those with T1D have an immune system that destroys their own beta cells, thereby decreasing or preventing the production of insulin and in turn the regulation of blood sugar levels. Chronic spikes in blood sugar levels can lead to blindness, nerve damage, kidney failure, heart disease, stroke, and even death.

Those with T1D manage their condition by injecting themselves with insulin anywhere from two to four times a day. A light workout, slight change in diet, or even an exciting event can have a serious impact that requires a glucose meter check and an insulin injection.

There are clinical trials involving transplants of pancreatic “islets”, clusters of cells containing healthy beta cells, but these rely on pancreases from deceased donors and taking immune suppressing drugs for life.

But what if there was a way to produce healthy beta cells in a lab without the need of a transplant?

Dr. Matthias Hebrok, director of the UCSF diabetes center, and Dr. Gopika Nair, postdoctoral fellow, have discovered how to transform human stem cells into healthy, insulin producing beta cells.

In a news release written by Dr. Nicholas Weiler of UCSF, Dr. Hebrok is quoted as saying “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

For the longest time, scientists could only produce cells at an immature stage that were unable to respond to blood sugar levels and secrete insulin properly. Dr. Hebrok and Dr. Nair discovered that mimicking the “islet” formation of cells in the pancreas helped the cells mature. These cells were then transplanted into mice and found that they were fully functional, producing insulin and responding to changes blood sugar levels.

Dr. Hebrok’s team is already in collaboration with various colleagues to make these cells transplantable into patients.

Gopika Nair, PhD, postdoctoral fellow that led the study for transforming human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

Dr. Nair in the article is also quoted as saying “Current therapeutics like insulin injections only treat the symptoms of the disease. Our work points to several exciting avenues to finally finding a cure.”

“We’re finally able to move forward on a number of different fronts that were previously closed to us,” Hebrok added. “The possibilities seem endless.” 

Dr. Hebrok, who is also a member of the CIRM funded UCSF Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was senior author of the new study, which was published February 1, 2019 in Nature Cell Biology.

CIRM has funded three separate human clinical trials for T1D that total approximately $37.8 million in awards. Two of these trials are being conducted by ViaCyte, Inc. and the third trial is being conducted by Caladrius Biosciences.

Friday Roundup: A better kind of blood stem cell transplant; Encouraging news from spinal cord injury trial; Finding an “elusive” cell that could help diabetics

Cool Instagram image of the week:

Pancreatic Progenitors

Diabetes Research Institute scientists have confirmed that the unique stem cells reside within large ducts of the human pancreas. Two such ducts (green) surrounded by three islets (white) are shown. [Diabetes Research Institute Foundation]

Chemo- and radiation-free blood stem cell transplant showing promise

Bubble baby disease, also known as severe combined immunodeficiency (SCID), is an inherited disorder that leaves newborns without an effective immune system. Currently, the only approved treatment for SCID is a blood stem cell transplant, in which the patient’s defective immune system cells are eliminated by chemotherapy or radiation to clear out space for cells from a healthy, matched donor. Even though the disease can be fatal, physicians loathe to perform a stem cell transplant on bubble baby patients:

Shizuru“Physicians often choose not to give chemotherapy or radiation to young children with SCID because there are lifelong effects: neurological impairment, growth delays, infertility, risk of cancer, etc.,” says Judith Shizuru, MD, PhD, professor of medicine at Stanford University.

To avoid these complications, Dr. Shizuru is currently running a CIRM-funded clinical trial testing a gentler approach to prepare patients for blood stem cell transplants. She presented promising, preliminary results of the trial on Tuesday at the annual meeting of Stanford’s Center for Definitive and Curative Medicine.

Trial participants are receiving a protein antibody called CD117 before their stem cell transplant. Previous studies in animals showed that this antibody binds to the surface of blood stem cells and blocks the action of a factor which is required for stem cell survival. This property of CD117 provides a means to get rid of blood stem cells without radiation or chemotherapy.

Early results in two participants indicate that, 6 and 9 months after receiving the CD117 blood stem cell transplants, the donor cells have successfully established themselves in the patients and begun making immune cells.

Spinal cord injury trial reports more promising results:

AsteriasRegular readers of our blog will already know about our funding for the clinical trial being run by Asterias Biotherapeutics to treat spinal cord injuries. The latest news from the company is very encouraging, in terms of both the safety and effectiveness of the treatment.

Asterias is transplanting stem cells into patients who have suffered recent injuries that have left them paralyzed from the neck down. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling in their hands and arms.

This week the company announced that of the 25 patients they have treated there have been no serious side effects. In addition:

  • Magnetic Resonance Imaging (MRI) scans show that in more than 90 percent of the patients the cells appear to show signs of engraftment
  • At least 75 percent of those treated have recovered at least one motor level, and almost 20 percent have recovered two levels

In a news release, Michael Mulroy, Asterias’ President and CEO, said:

“The positive safety profile to date, the evidence supporting engraftment of the cells post-implantation, and the improvements we are seeing in upper extremity motor function highlight the promising findings coming from this Phase 1/2a clinical trial, which will guide us as we work to design future studies.”

There you are! Finding the “elusive” human pancreatic progenitor cells – the story behind our cool Instagram image of the week.

Don’t you hate it when you lose something and can’t find it? Well imagine the frustration of scientists who were looking for a group of cells they were sure existed but for decades they couldn’t locate them. Particularly as those cells might help in developing new treatments for diabetes.

Diabetes-Research-Institute_University-of-Miami-Miller-School-of-MedicineWell, rest easy, because scientists at the Diabetes Research Institute at the University of Miami finally found them.

In a study, published in Genetic Engineering and Biotechnology News, the researchers show how they found these progenitor cells in the human pancreas, tucked away in the glands and ducts of the organ.

In type 1 diabetes, the insulin-producing cells in the pancreas are destroyed. Finding these progenitor cells, which have the ability to turn into the kinds of cells that produce insulin, means researchers could develop new ways to regenerate the pancreas’ ability to function normally.

That’s a long way away but this discovery could be an important first step along that path.

Creating partnerships to help get stem cell therapies over the finish line

Lewis, Clark, Sacagawea

Lewis & Clark & Sacagawea:

Trying to go it alone is never easy. Imagine how far Lewis would have got without Clark, or the two of them without Sacagawea. Would Batman have succeeded without Robin; Mickey without Minnie Mouse? Having a partner whose skills and expertise complements yours just makes things easier.

That’s why some recent news about two CIRM-funded companies running clinical trials was so encouraging.

Viacyte Gore

First ViaCyte, which is developing an implantable device to help people with type 1 diabetes, announced a collaborative research agreement with W. L. Gore & Associates, a global materials science company. On every level it seems like a natural fit.

ViaCyte has developed a way of maturing embryonic stem cells into an early form of the cells that produce insulin. They then insert those cells into a permeable device that can be implanted under the skin. Inside the device, the cells mature into insulin-producing cells. While ViaCyte has experience developing the cells, Gore has experience in the research, development and manufacturing of implantable devices.

Gore-tex-fabricWhat they hope to do is develop a kind of high-tech version of what Gore already does with its Gore-Tex fabrics. Gore-Tex keeps the rain out but allows your skin to breathe. To treat diabetes they need a device that keeps the immune system out, so it won’t attack the cells inside, but allows those cells to secrete insulin into the body.

As Edward Gunzel, Technical Leader for Gore PharmBIO Products, said in a news release, each side brings experience and expertise that complements the other:

“We have a proven track record of developing and commercializing innovative new materials and products to address challenging implantable medical device applications and solving difficult problems for biologics manufacturers.  Gore and ViaCyte began exploring a collaboration in 2016 with early encouraging progress leading to this agreement, and it was clear to us that teaming up with ViaCyte provided a synergistic opportunity for both companies.  We look forward to working with ViaCyte to develop novel implantable delivery technologies for cell therapies.”

AMD2

How macular degeneration destroys central vision

Then last week Regenerative Patch Technologies (RPT), which is running a CIRM-funded clinical trial targeting age-related macular degeneration (AMD), announced an investment from Santen Pharmaceutical, a Japanese company specializing in ophthalmology research and treatment.

The investment will help with the development of RPT’s therapy for AMD, a condition that affects millions of people around the world. It’s caused by the deterioration of the macula, the central portion of the retina which is responsible for our ability to focus, read, drive a car and see objects like faces in fine details.

RPE

RPT is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. Because these cells exist in a thin sheet in the back of the eye, the company is assembling these sheets in the lab by growing the RPE cells on synthetic scaffolds. These sheets are then surgically implanted into the eye.

In a news release, RPT’s co-founder Dennis Clegg says partnerships like this are essential for small companies like RPT:

“The ability to partner with a global leader in ophthalmology like Santen is very exciting. Such a strong partnership will greatly accelerate RPT’s ability to develop our product safely and effectively.”

These partnerships are not just good news for those involved, they are encouraging for the field as a whole. When big companies like Gore and Santen are willing to invest their own money in a project it suggests growing confidence in the likelihood that this work will be successful, and that it will be profitable.

As the current blockbuster movie ‘Beauty and the Beast’ is proving; with the right partner you can not only make magic, you can also make a lot of money. For potential investors those are both wonderfully attractive qualities. We’re hoping these two new partnerships will help RPT and ViaCyte advance their research. And that these are just the first of many more to come.

Stem cells stories that caught our eye: switching cell ID to treat diabetes, AI predicts cell fate, stem cell ALS therapy for Canada

Treating diabetes by changing a cell’s identity. Stem cells are an ideal therapy strategy for treating type 1 diabetes. That’s because the disease is caused by the loss of a very specific cell type: the insulin-producing beta cell in the pancreas. So, several groups are developing treatments that aim to replace the lost cells by transplanting stem cell-derived beta cells grown in the lab. In fact, Viacyte is applying this approach in an ongoing CIRM-funded clinical trial.

In preliminary animal studies published late last week, a Stanford research team has shown another approach may be possible which generates beta cells inside the body instead of relying on cells grown in a petri dish. The CIRM-funded Cell Metabolism report focused on alpha cells, another cell type in pancreas which produces the hormone glucagon.

glucagon

Microscopy of islet cells, round clusters of cells found in the pancreas. The brown stained cells are glucagon-producing alpha cells. Credit: Wikimedia Commons

After eating a meal, insulin is critical for getting blood sugar into your cells for their energy needs. But glucagon is needed to release stored up sugar, or glucose, into your blood when you haven’t eaten for a while. The research team, blocked two genes in mice that are critical for maintaining an alpha cell state. Seven weeks after inhibiting the activity of these genes, the researchers saw that many alpha cells had converted to beta cells, a process called direct reprogramming.

Does the same thing happen in humans? A study of cadaver donors who had been recently diagnosed with diabetes before their death suggests the answer is yes. An analysis of pancreatic tissue samples showed cells that produced both insulin and glucagon, and appeared to be in the process of converting from beta to alpha cells. Further genetic tests showed that diabetes donor cells had lost activity in the two genes that were blocked in the mouse studies.

It turns out that there’s naturally an excess of alpha cells so, as team lead Seung Kim mentioned in a press release, this strategy could pan out:

image-img-620-high

Seung Kim. Credit: Steve Fisch, Stanford University

“This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells.”

Using computers to predict cell fate. Deep learning is a cutting-edge area of computer science that uses computer algorithms to perform tasks that border on artificial intelligence. From beating humans in a game of Go to self-driving car technology, deep learning has an exciting range of applications. Now, scientists at Helmholtz Zentrum München in Germany have used deep learning to predict the fate of cells.

170221081734_1_900x600

Using deep learning, computers can predict the fate of these blood stem cells.
Credit: Helmholtz Zentrum München.

The study, published this week in Nature Methods, focused on blood stem cells also called hematopoietic stem cells. These cells live in the bone marrow and give rise to all the different types of blood cells. This process can go awry and lead to deadly disorders like leukemia, so scientists are very interested in exquisitely understanding each step that a blood stem cell takes as it specializes into different cell types.

Researchers can figure out the fate of a blood stem cells by adding tags, which glow with various color, to the cell surface . Under a microscope these colors reveal the cells identity. But this method is always after the fact. There no way to look at a cell and predict what type of cell it is turning into. In this study, the team filmed the cells under a microscope as they transformed into different cell types. The deep learning algorithm processed the patterns in the cells and developed cell fate predictions. Now, compared to the typical method using the glowing tags, the researchers knew the eventual cell fates much sooner. The team lead, Carsten Marr, explained how this new technology could help their research:

“Since we now know which cells will develop in which way, we can isolate them earlier than before and examine how they differ at a molecular level. We want to use this information to understand how the choices are made for particular developmental traits.”

Stem cell therapy for ALS seeking approval in Canada. (Karen Ring) Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that kills off the nerve cells responsible for controlling muscle movement. Patients with ALS suffer from muscle weakness, difficulty in speaking, and eventually breathing. There is no cure for ALS and the average life expectancy after diagnosis is just 2 – 5 years. But companies are pursuing stem cell-based therapies in clinical trials as promising treatment options.

One company in particular, BrainStorm Cell Therapeutics based in the US and Israel, is testing a mesenchymal stem cell-based therapy called NurOwn in ALS patients in clinical trials. In their Phase 2 trials, they observed clinical improvements in slowing down the rate of disease progression following the stem cell treatment.

In a recent update from our friends at the Signals Blog, BrainStorm has announced that it is seeking regulatory approval of its NurOwn treatment for ALS patients in Canada. They will be working with the Centre for Commercialization of Regenerative Medicine (CCRM) to apply for a special regulatory approval pathway with Health Canada, the Canadian government department responsible for national public health.

In a press release, BrainStorm CEO Chaim Lebovits, highlighted this new partnership and his company’s mission to gain regulatory approval for their ALS treatment:

“We are pleased to partner with CCRM as we continue our efforts to develop and make NurOwn available commercially to patients with ALS as quickly as possible. We look forward to discussing with Health Canada staff the results of our ALS clinical program to date, which we believe shows compelling evidence of safety and efficacy and may qualify for rapid review under Canada’s regulatory guidelines for drugs to treat serious or life-threatening conditions.”

Stacey Johnson who wrote the Signals Blog piece on this story explained that while BrainStorm is not starting a clinical trial for ALS in Canada, there will be significant benefits if its treatment is approved.

“If BrainStorm qualifies for this pathway and its market authorization request is successful, it is possible that NurOwn could be available for patients in Canada by early 2018.  True access to improved treatments for Canadian ALS patients would be a great outcome and something we are all hoping for.”

CIRM is also funding stem cell-based therapies in clinical trials for ALS. Just yesterday our Board awarded Cedars-Sinai $6.15 million dollars to conduct a Phase 1 trial for ALS patients that will use “cells called astrocytes that have been specially re-engineered to secrete proteins that can help repair and replace the cells damaged by the disease.” You can read more about this new trial in our latest news release.

Don’t Sugar Coat it: A Patient’s Perspective on Type 1 Diabetes

John Welsh

John Welsh

“In the weeks leading up to my diagnosis, I remember making and drinking Kool-Aid at the rate of about a gallon per day, and getting up to pee and drink Kool-Aid several times a night. The exhaustion and constant thirst and the weight loss were pretty scary. Insulin saved my life, and it’s been saving my life every day for the past 40 years.” – John Welsh

 

In honor of diabetes awareness month, we are featuring a patient perspective on what it’s like to live with type 1 diabetes (T1D) and what the future of stem cell research holds in terms of a cure.

T1D is a chronic disease that destroys the insulin producing cells in your pancreas, making it very difficult for your body to maintain the proper levels of sugar in your blood. There is no cure for T1D and patients take daily shots of insulin and closely monitor their blood sugar to stay healthy and alive.

Stem cell research offers an alternative strategy for treating T1D patients by potentially replacing their lost insulin producing cells. We’ve written blogs about ongoing stem cell research for diabetes on the Stem Cellar (here) but we haven’t focused on the patient side of T1D. So today, I’m introducing you to John Welsh, a man whose has lived with T1D since 1976.

John Welsh is a MD/PhD scientist and currently works at a company called Dexcom, which make a continuous glucose monitoring (CGM) device for diabetes patients. He is also an enrolled patient in CIRM-funded stem cell clinical trial (also funded by JDRF) for T1D sponsored by the company ViaCyte. The trial is testing a device containing stem cell-derived pancreatic cells that’s placed under the skin to act as a transplanted pancreas. You can learn more about it here.

I reached out to John to see if he wanted to share his story about living with diabetes. He was not only willing but enthusiastic to speak with me. As you will read later, one of John’s passions is a “good story”. And he sure told me a good one. So before you read on, I recommend grabbing some coffee or tea, going to a quiet room, and taking the time to enjoy his interview.


Q: Describe your career path and your current job.

JW: I went to college at UC Santa Cruz and majored in biochemistry and molecular biology. I then went into the medical scientist training program (combined MD/PhD program) at UC San Diego followed by research positions in cell biology and cancer biology at UC San Francisco and Novartis. I’ve been a medical writer specializing in medical devices for type 1 diabetes since 2009. At Dexcom, I help study the benefits of CGM and get the message out to healthcare professionals.

Q: How has diabetes affected your life and what obstacles do you deal with because of diabetes?

JW: I found out I had T1D at the age of 13, and it’s been a part of my life for 40 years. It’s been a big deal in terms of what I’m not allowed to do and figuring out what would be challenging if I tried. On the other hand, having diabetes is a great motivator on a lot of levels personally, educationally and professionally. Having this disease made me want to learn everything I could about the endocrine system. From there, my interests turned to biology – molecular biology in particular – and understanding how molecules in cells work.

The challenge of having diabetes also motivated me to do things that I might not have thought about otherwise – most importantly, a career that combined science and medicine. Having to stay close to my insulin and insulin-delivery paraphernalia (early on, syringes; nowadays, the pump and glucose monitor) meant that I couldn’t do as many ridiculous adventures as I might have otherwise.

Q: Did your diagnosis motivate you to pursue a scientific career?

JW: Absolutely. If I hadn’t gotten diabetes, I probably would have gone into something like engineering. But my parents were both healthcare professionals, so a career in medicine seemed plausible. The medical scientist MD/PhD training program at UC San Diego was really cool, but very competitive. Having first-hand experience with this disease may have given me an inside track with the admissions process, and that imperative – to understand the disease and how best to manage it – has been a great motivator.

There’s also a nice social aspect to being surrounded by people whose lives are affected by T1D.

Q: Describe your treatment regimen for T1D?

JW: I travel around with two things stuck on my belly, a Medtronic pump and a Dexcom Continuous Glucose Monitor (CGM) sensor. The first is an infusion port that can deliver insulin into my body. The port lasts for about three days after which you have to take it out. The port that lives under the skin surface is nine millimeters long and it’s about as thick as a mechanical pencil lead. The port is connected to a tube and the tube is connected to a pump, which has a reservoir with fast-acting insulin in it.

The insulin pump is pretty magical. It’s conceptually very simple, but it transforms the way a lot of people take insulin. You program it so that throughout the day, it squirts in a tiny bit of basal insulin at the low rate that you want. If you’re just cruising through your day, you get an infusion of insulin at a low basal rate. At mealtimes, you can give yourself an extra squirt of insulin like what happens with normal people’s pancreas. Or if you happen to notice that you have a high sugar level, you can program a correction bolus which will help to bring it back to towards the normal range. The sensor continuously interrogates the glucose concentration in under my skin. If something goes off the rails, it will beep at me.

dexcom_g4_platinum_man

Dexcom continuous glucose monitor.

As good as these devices are, they’re not a cure, they’re not perfect, and they’re not cheap, so one of my concerns as a physician and as a patient is making these transformative devices better and more widely available to people with the disease.

Q: What are the negative side effects associated with your insulin pump and sensor?

JW:  If you have an insulin pump, you carry it everywhere because it’s stuck onto you. The pump is on you for three days and it does get itchy. It’s expensive and a bit uncomfortable. And when I take my shirt off, it’s obvious that I have certain devices stuck on me.  This is a big disincentive for some of my type 1 friends, especially those who like to wear clothes without pockets. And every once-in-a-while, the pump will malfunction and you need a backup plan for getting insulin when it breaks.

On the other hand, the continuous glucose monitoring (CGM) is wonderful especially for moms and dads whose kids have T1D. CGM lets parents essentially spy on their kids. You can be on the sidelines watching your kid play soccer and you get a push notification on your phone saying that the glucose concentration is low, or is heading in that direction. The best-case scenario is that this technology helps people avoid dangerous and potentially catastrophic low blood sugars.

Q: Was the decision easy or hard to enroll in the ViaCyte trial?

JW: It was easy! I was very excited to learn about the ViaCyte trial and equally pleased to sign up for it. When I found out about it from a friend, I wanted to sign up for it right away. I went to clinicaltrials.gov and contacted the study coordinator at UC San Diego. They did a screening interview over the phone, and then they brought me in for screening lab work. After I was selected to be in the trial, they implanted a couple of larger devices (about the size of a credit card) under the skin of my lower back, and smaller devices (about the size of a postage stamp) in my arm and lower back to serve as “sentinels” that were taken out after two or three months.

ViaCyte device

ViaCyte device

I’m patient number seven in the safety part of this trial. They put the cell replacement therapy device in me without any pre-medication or immunosuppression. They tested this device first in diabetic mice and found that the stem cells in the device differentiated into insulin producing cells, much like the ones that usually live in the mouse pancreas. They then translated this technology from animal models to human trials and are hoping for the same type of result.

I had the device transplanted in March of 2015, and the plan is for in the final explant procedure to take place next year at the two-year anniversary. Once they take the device out, they will look at the cells under the microscope to see if they are alive and whether they turned into pancreatic cells that secrete insulin.

It’s been no trouble at all having this implant. I do clinic visits regularly where they do a meal challenge and monitor my blood sugar. My experience being a subject in this clinical study has been terrific. I met some wonderful people and I feel like I’m helping the community and advancing the science.

Q: Do you think that stem cell-derived therapies will be a solution for curing diabetes?

JW: T1D is a great target for stem cell therapy – the premise makes a lot of sense — so it’s logical that it’s one of the first ones to enter clinical trials. I definitely think that stem cells could offer a cure for T1D. Even 30 years ago, scientists knew that we needed to generate insulin producing cells somehow, protect them from immunological rejection, and package them up and put them somewhere in the body to act like a normal pancreas. The concept is still a good concept but the devil is in the implementation. That’s why clinical trials like the one CIRM is funding are important to figure these details out and advance the science.

Q: What is your opinion about the importance of stem cell research and advancing stem cell therapies into clinical trials?

JW: Understanding how cells determine their fate is tremendously important. I think that there’s going to be plenty of payoffs for stem cell research in the near term and more so in the intermediate and long term. Stem cell research has my full support, and it’s fun to speculate on how it might address other unmet medical needs. The more we learn about stem cell biology the better.

Q: What advice do you have for other patients dealing with diabetes or who are recently diagnosed?

JW: Don’t give up, don’t be ashamed or discouraged, and gather as much data as you can. Make sure you know where the fast-acting carbohydrates are!

Q: What are you passionate about?

JW: I love a good story, and I’m a fan of biological puzzles. It’s great having a front-row seat in the world of diabetes research, and I want to stick around long enough to celebrate a cure.


Related links:

Scientists Make Insulin-Secreting Cells from Stem Cells of Type 1 Diabetes Patients

Stem cell research for diabetes is in a Golden Age. In the past few years, scientists have developed methods to generate insulin-secreting pancreatic beta cell-like cells from embryonic stem cells, induced pluripotent stem cells (iPS cells), and even directly from human skin. We’ve covered a number of recent studies in this area on our blog, and you can read more about them here.

Patients with type 1 diabetes (T1D) suffer from an autoimmune response that attacks and kills the beta cells in their pancreas. Without these important cells, patients can no longer secrete insulin in response to increased glucose or sugar levels in the blood. Cell replacement is evolving into an attractive therapeutic option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots that many T1D patients currently take.

Cell replacement therapy for type 1 diabetes

Stem cells are the latest strategy that scientists are pursuing for T1D cell replacement therapy. The strategy involves generating beta cells from pluripotent stem cells, either embryonic or iPS cells, that function similarly to beta cells found in a healthy human pancreas. Making beta cells from a patient’s own iPS cells is the ideal way to go because this autologous form (self to self) of transplantation would reduce the chances  of transplant rejection because a patient’s own cells would be put back into their body.

Scientists have generated beta cell-like cells from iPS cells derived from T1D patients previously, but the biological nature and function of these cells wasn’t up to snuff in a side by side comparison with beta cells from non-diabetic patients. They didn’t express the appropriate beta cell markers and failed to secrete the appropriate levels of insulin when challenged in a dish and when transplanted into animal models.

However, a new study published yesterday in Nature Communications has overcome this hurdle. Teams from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute have developed a method that makes beta cells from T1D patient iPS cells that behave very similarly to true beta cells. This discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future.

These beta cells could be the real deal

Their current work is based off of an earlier 2014 study – from the lab of Douglas Melton at Harvard – that generated functional human beta cells from both embryonic and iPS cells of non-diabetic patients. In the current study, the authors were interested in learning whether it was possible to generate functional beta cells from T1D patients and whether these cells would be useful for transplantation given that they could potentially be less functional than non-diabetic beta cells.

The study’s first author, Professor Jeffrey Millman from the Washington University School of Medicine, explained:

Jeffrey Millman

Jeffrey Millman

“There had been questions about whether we could make these cells from people with type 1 diabetes. Some scientists thought that because the tissue would be coming from diabetes patients, there might be defects to prevent us from helping the stem cells differentiate into beta cells. It turns out that’s not the case.”

After generating beta cells from T1D iPS cells, Millman and colleagues conducted a series of experiments to test the beta cells both in a dish and in mice. They found that the T1D-derived beta cells expressed the appropriate beta cell markers, secreted insulin in the presence of glucose, and responded well to anti-diabetic drugs that stimulated the beta cells to secrete even more insulin.

When T1D beta cells were transplanted into mice that lacked an immune system, they survived and functioned similarly to transplanted non-diabetic beta cells. When the mice were treated with a drug that killed off their mouse beta cells, the surviving human T1D beta cells were successful in regulating the blood glucose levels in the mice and kept them alive.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients. (Nature Communications)

Big Picture

The authors concluded that the beta cells they generated from T1D iPS cells were indistinguishable from healthy beta cells derived from non-diabetic patients. In a news release, Millman commented on the big picture of their study:

“In theory, if we could replace the damaged cells in these individuals with new pancreatic beta cells — whose primary function is to store and release insulin to control blood glucose — patients with type 1 diabetes wouldn’t need insulin shots anymore. The cells we’ve manufactured sense the presence of glucose and secrete insulin in response. And beta cells do a much better job controlling blood sugar than diabetic patients can.”

He further commented that the T1D- derived beta cells “could be ready for human research in three to five years. At that time, Millman expects the cells would be implanted under the skin of diabetes patients in a minimally invasive surgical procedure that would allow the beta cells access to a patient’s blood supply.”

“What we’re envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin,” he said.

In fact, such devices already exist. CIRM is funding a type 1 diabetes clinical trial sponsored by the San Diego based company ViaCyte. They are currently testing a combination drug delivery system that implants a medical device capsule containing pancreatic progenitor cells derived from human embryonic stem cells. Once implanted, the progenitor cells are expected to specialize into mature pancreatic cells including beta cells that secrete insulin.


Related Links:

Stem cells from “love-handles” could help diabetes patients

Love handles usually get a bad rap, but this week, a study from Switzerland claims that stem cells taken from the fat tissue of “love handles” could one day benefit diabetes patients.

An islet of a mouse pancreas containing beta cells shown in green. (wikipedia)

An islet of a mouse pancreas containing beta cells shown in green. (wikipedia)

The study, which was published in Nature Communications, generated the much coveted insulin-secreting pancreatic beta cells from human induced pluripotent stem cells (iPS cells) in a dish. When exposed to glucose (sugar), beta cells secrete the hormone insulin, which can tell muscle and fat tissue to absorb excess glucose if there is too much around. Without these important cells, your body wouldn’t be able to regulate the sugar levels in your blood, and you would be at high risk for getting diabetes.

Diabetic patients can take daily shots of insulin to manage their disease, but scientists are looking to stem cells for a more permanent solution. Their goal is to make bonafide beta cells from human pluripotent stem cells in a dish that behave exactly the same as ones living in a normal human pancreas. Current methods to make beta cells from stem cells are complex, too often yield inconsistent results and generate multiple other cell types.

Turning fat tissue into pancreatic cells

The Switzerland study developed a novel method for making beta cells from iPS cells that is efficient and gives more consistent results. The iPS cells were genetically reprogrammed from mesenchymal stem cells that had been extracted from the fat tissue of a 50-year old woman. To create insulin-secreting beta cells, the group developed a synthetic control network that directed the iPS cells step by step down the path towards becoming pancreatic beta cells.

The synthetic control network coordinated the expression of genes called transcription factors that are important for pancreatic development. The network could be thought of as an orchestra. At the start of a symphony, the conductor signals to different instrument groups to begin and then directs the tempo and sound of the performance, making sure each instrument plays at the right time.

In the case of this study, the synthetic gene network coordinates expression of three pancreatic transcription factors: Ngn2, Pdx1, and MafA. When the expression of these genes was coordinated in a precise way that mimicked natural beta cell development, the pancreatic progenitor cells developed into functioning beta-like cells that secreted insulin in the presence of glucose.

The diagram shows the dynamics of the most important growth factors during differentiation of human induced pluripotent stem cell to beta-like cells. Credit: ETH Zurich

The diagram shows the dynamics of the most important transcription factors during differentiation of human induced pluripotent stem cell to beta-like cells. Credit: ETH Zurich

Pros of love handle-derived beta cells

This technology has advantages over current stem cell-derived beta cell generating methods, which typically use combinations of genetic reprogramming factors, chemicals, or proteins. Senior author on the study, Martin Fussenegger, explained in a news release that his study’s method has more control over the timing of pancreatic gene expression and as a result is more efficient, having the ability to turn three out of four fat stem cells into functioning beta cells.

Another benefit to this technology is the potential for making personalized stem cell treatments for diabetes sufferers. Patient-specific beta cells derived from iPS cells can be transplanted without fear of immune rejection (it’s what’s called an autologous stem cell therapy). Some diabetes patients have received pancreatic tissue transplants from donors, but they have to take immunosuppressive drugs and even then, there is no guarantee that the transplant will survive and work properly for an extended period of time.

Fussenegger commented:

“With our beta cells, there would likely be no need for this action, since we can make them using endogenous cell material taken from the patient’s own body. This is why our work is of such interest in the treatment of diabetes.”

More work to do

While these findings are definitely exciting, there is still a long road ahead. The authors found that their beta cells did not perform at the same level as natural beta cells. When exposed to glucose, the stem cell-derived beta cells failed to secrete the same amount of insulin. So it sounds like the group needs to do some tweaking with their method in order to generate more mature beta cells.

Lastly, it’s definitely worth looking at the big picture. This study was done in a culture dish, and the beta cells they generated were not tested in animals or humans. Such transplantation experiments are necessary to determine whether love-handle derived beta cells will be an appropriate and effective treatment for diabetes patients.

A CIRM funded team at San Diego-based company ViaCyte seems to have successfully gotten around the issue of maturing beta cells from stem cells and is already testing their therapy in clinical trials. Their study involves transplanting so-called pancreatic progenitor cells (derived from embryonic stem cells) that are only part way down the path to becoming beta cells. They transplant these cells in an encapsulated medical device placed under the skin where they receive natural cues from the surrounding tissue that direct their growth into mature beta cells. Several patients have been transplanted with these cells in a CIRM funded Phase 1/2 clinical trial, but no data have been released as yet.


Related Links:

Stem cell stories that caught our eye: sexual identity of organs, upping the game of muscle stem cells, mini guts produce insulin

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

A new sexual identity crisis—in our organs. With the transition from Mr. to Ms. Jenner and other transsexual news this year, it seems inevitable that a research paper would come out suggesting we may all have some mosaic sexual identity. A team in the U.K. found that the stem cells that develop our organs can have varying sexual identities and that can impact the function of the organ.

The organ in question in this case, intestines in fruit flies, is smaller in males than in females. By turning on and off certain genes the researchers at the Medical Research Council’s Clinical Science Centre found that making stem cells in the gut more masculine reduced their ability to multiply and produced smaller intestines. They also found that female intestines were more prone to tumors, just as many diseases are more common in one sex than the other.

In an interview with Medical News Today, Bruno Hudry, the first author on the paper, which is published in Nature, talked about the likelihood that we all have some adult cells in us with genes of the opposite sex.

 “This study shows that there is a wider spectrum than just two sexes. You can be chromosomally, hormonally or phenotypically female but still having some specific adult stem cells (here the stem cells of the intestine) acting like male. So it is hard to say if someone is “really” male or female. Some people are simply a mosaic of male and female cells within a phenotypically ‘male’ or ‘female’ body.”

Hurdry speculated that if the results are duplicated in humans it could provide a window into other sex-linked differences in diseases and could be a matching factor added to the standard protocol for blood and organ donations.

 

Reprogramming stomach to produce insulin.  The stem cells in our gut show an efficiency not seen in most of our organs. They produce a new lining for our stomach and intestine every few days. On the opposite end of the spectrum, the insulin-producing cells in our pancreas rank poorly in self renewal. So, what if you could get some of those vigorous gut stem cells to make insulin producing beta cells? Turns out you can and they can produce enough insulin to allow a diabetic mouse to survive.

mini stomach

A mini-gut with insulin-producing cells (red) and stem cells (green).

A team at the Harvard Stem Cell Institute manipulated three genes known to be associated with beta cell development and tested the ability of many different tissues—from tail to snout—to produce beta cells. A portion of the stomach near the intestine, which naturally produces other hormones, easily reprogrammed into insulin producing cells. More important, if the first batch of those cells was destroyed by the team, the remaining stem cells in the tissue quickly regenerated more beta cells. Since a misbehaving immune system causes type 1 diabetes, this renewal ability could be key to preventing a return of the disease after a transplant of these cells.

In the lab the researchers pushed the tissue from the pylorous region of the stomach to self-organize into mini-stomachs along with the three genetic factors that drive beta cell production.  When transplanted under the skin of mice that had previously had their beta cells destroyed, the mice survived. The genetic manipulations used in this research could not be used in people, but the team is working on a system that could.

 “What is potentially really great about this approach is that one can biopsy from an individual person, grow the cells in vitro and reprogram them to beta cells, and then transplant them to create a patient-specific therapy,” said Qiao Zhou, the senior author. “That’s what we’re working on now. We’re very excited.”

Medicalxpress ran a story about the work published in Cell Stem Cell.

 

muscle stem cells

Muscle stem cells generate new muscle (green) in a mouse.

Better way to build muscle.  Stem cells behave differently depending on what environment they find themselves in, but they are not passive about their environment. They can actively change it. A CIRM-funded team at Sanford Burnham Prebys Medical Discovery Institute (SBP) found that fetal muscle stem cells and adult muscle stem cells make very different changes in the micro-environment around them.

Fetal muscle stem cells become very good at generating large quantities of new muscle, while the adult stem cells take the role of maintaining themselves for emergencies. As a result, when major repair is needed like in muscular dystrophies and aging, they easily get overwhelmed. So the SBP team looked for ways to make the adult stem cells behave more like their fetal predecessors.

 “We found that fetal MuSCs remodel their microenvironment by secreting specific proteins, and then examined whether that same microenvironment can encourage adult MuSCs to more efficiently generate new muscle. It does, which means that how adult MuSCs normally support muscle growth is not an intrinsic characteristic, but can be changed,” said Matthew Tierney, first author of the study in an institute press release distributed by Newswise.

The results point to paths for developing therapies for a number of muscle wasting conditions.