Has the promise of stem cells been overstated?

One of the most famous stem cell scientists in the world said on Monday that the promise of stem cell treatments has in some ways been overstated.

In an interview with the New York Times, Dr. Shinya Yamanaka, one of the recipients of the 2012 Nobel Prize in Medicine for his discovery of induced pluripotent stem cells (iPS cells), said, “we can help just a small portion of patients by stem cell therapy.”

Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

He explained that there are only 10 target diseases that he believes will benefit directly from stem cell therapies including, “Parkinson’s, retinal and corneal diseases, heart and liver failure, diabetes, spinal cord injury, joint disorders and some blood disorders. But maybe that’s all. The number of human diseases is enormous.”

This is a big statement coming from a key opinion leader in the field of stem cell research, and it’s likely to spur a larger conversation on the future of stem cell treatments.

Yamanaka also touched on another major point in his interview – progress takes time.

In the ten years since his discovery of iPS cells, he and other scientists have learned the hard way that the development of stem cell treatments can be time consuming. While autologous iPS cell treatments (making stem cell lines from a patient and transplanting them back into that patient) have entered clinical trials to treat patients with macular degeneration, a disease that causes blindness, the trials have been put on hold until the safety of the stem cell lines being used are confirmed.

At the World Alliance Forum in November, Yamanaka revealed that generating a single patient iPS cell line can cost up to one million dollars which isn’t feasible for the 1000’s of patients who need them. He admitted that the fate of personalized stem cell medicine, which once seemed so promising, now seems unrealistic because it’s time consuming and costly.

But with any obstacle, there is always a path around it. Under Yamanaka’s guidance, Japan is generating donor iPS cell lines that can be used to treat a large portion of the Japanese population. Yamanaka said that 100 lines would cover 100 million people in Japan and that 200 lines would be enough to cover the US population. iPS cell banks are being generated around the world, meaning that one day the millions of people suffering from the target diseases Yamanaka mentioned could be treated or even cured. Would this not fulfill a promise that was made about the potential of stem cell treatments?

Which brings me to my point, I don’t believe the promise of stem cells has been overstated. I think that it has yet to be realized, and it will take more research and more time to get there. As a community, we need to be understanding, patient, and supportive.

In my opinion (as a scientist aside from my role at CIRM), I believe that Yamanaka’s interview failed to reveal his optimism about the future of stem cell treatments. What I took from Yamanaka’s comments is that stem cell treatments can help a small number of patients with specific diseases right now. That’s not to say that stem cell research won’t produce promising treatments for other diseases in the future.

Retinal diseases and blood disorders are easier to target with stem cell treatments because only one type of cell needs to be replaced. It makes sense to tackle those diseases first and make sure that these stem cell treatments are effective and safe in patients before we focus on more complicated diseases where multiple cell types or organs are involved.

Part of the reason why scientists are unsure whether stem cell treatments can treat complex diseases is because we still don’t know the details of what causes these diseases. After we know more about what’s going wrong, including all the cell types and molecules involved, research might reveal new ways that stem cells could be used to help treat those diseases. Or on the other hand, stem cells could be used to model those diseases to help discover new drug treatments.

I’ve heard Yamanaka talk many times and recently I heard him speak at the World Alliance Forum in November, where he said that the two biggest hurdles we are facing for stem cell treatments to be successful is time and cost. After we overcome these hurdles, his outlook was optimistic that stem cell treatments could improve people’s lives. But he stressed that these advances will take time.

He shared a similar sentiment at the very end of the NY Times interview by referencing his father’s story and the decades it took to cure hepatitis C,

“You know, my father had a small factory. He injured his leg in the factory when I was in junior high. He had a transfusion, and he got hepatitis C. He passed away in 1989. Twenty-five years later, just two years ago, scientists developed a very effective cure. We now have a tablet. Three months and the virus is gone — it’s amazing. But it took 25 years. iPS cells are only 10 years old. The research takes time. That’s what everybody needs to understand.”

Yamanaka says more time is needed for stem cell treatments to become effective cures, but CIRM has already witnessed success. In our December Board meeting, we heard from two patients who were cured of genetic blood diseases by stem cell treatments that CIRM funded. One of them was diagnosed with severe combined immunodeficiency (SCID) and the other had chronic granulomatous disease (CGD). Both had their blood stem cells genetically engineered to removed disease-causing mutations and then transplanted back into their body to create a healthy immune system and cure them of their disease.

Hearing how grateful these patients and their families were to receive life-saving stem cell treatments and how this research brings new hope to other patients suffering from the same diseases, in my mind, fulfills the promise of stem cell research and makes funding stem cell treatments worth it.

I believe we will hear more and more of these success stories in the next decade and CIRM will most certainly play an important role in this future. There are others in the field who share a similar optimism for the future of stem cell treatments. Hank Greely, the Director for Law and the Biosciences at Stanford University, said in an interview with the Sacramento Bee about the future of CIRM,

Hank Greely, Stanford University

Hank Greely, Stanford University

“The next few years should determine just how good California’s investment has been. It is encouraging to see CIRM supporting so many clinical trials; it will be much more exciting when – and I do expect ‘when’ and not ‘if’ – one of those trials leads to an approved treatment.”

 


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Stem cell and gene therapy research gets a good report card from industry leader

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Panel discussion at ARM State of the industry briefing: left to Right Robert Preti, Chair ARM; Jeff Walsh, bluebird bio; Manfred Rudiger, Kiadis Pharma; Barbara Sasu, Pfizer;  Thomas Farrell, Bellicum Pharmaceuticals. Photo courtesy ARM.

The state of the regenerative medicine field is strong and getting stronger. That was the bottom line verdict at the 2017 Cell and Gene Therapies State of the Industry briefing in San Francisco.

The briefing, an annual update on the field presented by the Alliance for Regenerative Medicine (ARM), gave a “by the numbers” look at the field and apart from one negative spot everything is moving in the right direction.

Robert Preti, Chair of ARM’s Board, said worldwide there are more than 750 regenerative companies working in the stem cell and gene therapy space. And those companies are increasingly moving the research out of the lab and into clinical trials in people.

For example, at the end of 2016 there were 802 clinical trials underway. That is a 21 percent growth over 2015. Those breakdown as follows:

Phase 1 – 271 (compared to 192 in 2015)

Phase 2 – 465 (compared to 376 in 2015)

Phase 3 – 66 (compared to 63 in 2015)

The bulk of these clinical trials, 45 percent, are focused on cancer. The second largest target, 11 percent, is on heart disease. The number of trials for neurological disorders and rare diseases are also growing in number.

Preti says the industry is at an important inflection point right now and that this growth is presenting new problems:

“The pipeline of products is robust and the technologies supporting that pipeline is even more robust. The technologies that are fueling the growth in clinical activity have accelerated so fast that we on the manufacturing side are playing catchup. We are at a point where we have to get serious about large scale commercial production.”

Preti also talked about “harmonization” of the regulatory process and the need to have a system that makes it easier for products approved for clinical trials in one country, to get approval for clinical trials in other countries.

Michael Werner, the executive director of ARM, said the organization has played a key role in helping promote the field and cited the recently passed 21st Century Cures Act as “a major win and a powerful statement of ARM’s leadership in this sector.”

But there was one area where the news wasn’t all positive, the ability of companies to raise capital. In 2015 companies raised $11 billion for research. In 2016 it was less than half of that, $5.3 billion.

With that somber note in mind it was appropriate that the panel discussion that followed the briefing was focused on the near-term and long-term challenges facing the field if it was to be commercially successful.

One of the big challenges was the issue of regulatory approval, and here the panel seemed to be more optimistic than in previous years.

Manfred Rüdiger of Kiadis Pharma said he was pleasantly surprised at how easy it was to work with different regulatory agencies in the US, Canada and Europe.

“We used them as a kind of free consultancy service, listening to their advice and making the changes they suggested so that we were able to use the same manufacturing process in Europe and Canada and the US.”

Jeff Walsh of bluebird bio, said the key to having a good working relationship with regulatory agencies like the Food and Drug Administration (FDA) is simple:

“Trust and transparency between you and the regulatory agencies is essential, it’s a critical factor in advancing your work. The agencies respond well when you have that trust. One thing we can’t be is afraid to ask. The agencies will tell you where their line is, but don’t be afraid to ask or to push the boundaries. This is new for everyone, companies and regulators, so if you are pushing it helps create the environment that allows you to work together to develop safe therapies that benefit patients.”

Another big issue was scalability in manufacturing; that it’s one thing to produce enough of a product to carry out a clinical trial but completely different if you are hoping to use that same product to treat millions of people spread out all over the US or the world.

And of course cost is always something that is front and center in people’s minds. How do you develop therapies that are not just safe and effective, but also affordable? How do companies ensure they will get reimbursed by health insurers for the treatments? No one had any simple answer to what are clearly very complex problems. But all recognized the need to start thinking about these now, long before the treatments themselves are even ready.

Walsh ended by saying:

“This is not just about what can you charge but what should you charge. We have a responsibility to engage with the agencies and ultimately the payers that make these decisions, in the same way we engage with regulatory agencies; with a sense of openness, trust and transparency. Too often companies wait too long, too late before turning to the payers and trying to decide what is appropriate to charge.”

 

 

Cured by Stem Cells

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To get anywhere you need a good map, and you need to check it constantly to make sure you are still on the right path and haven’t strayed off course. A year ago the CIRM Board gave us a map, a Strategic Plan, that laid out our course for the next five years. Our Annual Report for 2016, now online, is our way of checking that we are still on the right path.

I think, without wishing to boast, that it’s safe to say not only are we on target, but we might even be a little bit ahead of schedule.

The Annual Report is chock full of facts and figures but at the heart of it are the stories of the people who are the focus of all that we do, the patients. We profile six patients and one patient advocate, each of whom has an extraordinary story to tell, and each of whom exemplifies the importance of the work we support.

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Brenden Whittaker: Cured

Two stand out for one simple reason, they were both cured of life-threatening conditions. Now, cured is not a word we use lightly. The stem cell field has been rife with hyperbole over the years so we are always very cautious in the way we talk about the impact of treatments. But in these two cases there is no need to hold back: Evangelina Padilla Vaccaro and Brenden Whittaker have been cured.

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Evangelina: Cured

 

In the coming weeks we’ll feature our conversations with all those profiled in the Annual Report, giving you a better idea of the impact the stem cell treatments have had on their lives and the lives of their family. But today we just wanted to give a broad overview of the Annual Report.

The Strategic Plan was very specific in the goals it laid out for us. As an agency we had six big goals, but each Team within the agency, and each individual within those teams had their own goals. They were our own mini-maps if you like, to help us keep track of where we were individually, knowing that every time an individual met a goal they helped the Team get closer to meeting its goals.

As you read through the report you’ll see we did a pretty good job of meeting our targets. In fact, we missed only one and we’re hoping to make up for that early in 2017.

But good as 2016 was, we know that to truly fulfill our mission of accelerating treatments to patients with unmet medical needs we are going to have do equally well, if not even better, in 2017.

That work starts today.

 

Translating great stem cell ideas into effective therapies

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CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Advancements in gene editing make blind rats see light

Gene editing is a rapidly advancing technology that scientists are using to manipulate the genomes of cells with precision and accuracy. Many of these experiments are being conducted on stem cells to genetic mutations in an attempt to find cures for various diseases like cancer, HIV and blindness.

Speaking of blindness, researchers from the Salk Institute reported today that they’ve improved upon the current CRISPR/Cas9 gene editing technology and found a more efficient way to edit the genomes of cells in living animals. They used their technology on blind rats that had a genetic disease called retinitis pigmentosa (RP) and found that the rats were able to see light following the treatment.

The really exciting part about their findings is that their CRISPR technology works well on dividing cells like stem cells and progenitor cells, which is typically how scientists use the CRISPR technology, but it also works on adult cells that do not divide – a feat that hasn’t been accomplished before.

Their results, which were published today in the journal Nature, offer a new tool that scientists can use to target cells that no longer divide in tissues and organs like the eye, brain, pancreas and heart.

According to a Salk news release:

“The new Salk technology is ten times more efficient than other methods at incorporating new DNA into cultures of dividing cells, making it a promising tool for both research and medicine. But, more importantly, the Salk technique represents the first time scientists have managed to insert a new gene into a precise DNA location in adult cells that no longer divide, such as those of the eye, brain, pancreas or heart, offering new possibilities for therapeutic applications in these cells.”

CRISPR gene edited neurons, which are non-dividing brain cells, are shown in green while cell nuclei are shown in blue. (Salk)

CRISPR gene edited neurons, which are non-dividing brain cells, are shown in green while cell nuclei are shown in blue. (Salk)

Salk Professor and senior author on the study, Juan Carlos Izpisua Belmonte, explained the big picture of their findings:

“We are very excited by the technology we discovered because it’s something that could not be done before. For the first time, we now have a technology that allows us to modify the DNA of non-dividing cells, to fix broken genes in the brain, heart and liver. It allows us for the first time to be able to dream of curing diseases that we couldn’t before, which is exciting.”

If you want to learn more about the science behind their new CRISPR gene editing technology, check out the Salk news release and coverage in Genetic Engineering & Biotechnology News. You can also watch this short three minute video about the study made by the Salk Institute.

Three stories give us a glimpse of the real possibilities for stem cell therapies

Today we’re featuring a guest blog by Lisa Willemse about the Till and McCulloch Stem Cell Meeting in Canada. Enjoy!

Stem cell treatments should be incredibly easy. Or rather, that’s what some clinics or products would have you believe. Because, on the surface, a one-stop-shop for injectable cells to cure just about any condition or topical creams to peel away the scourge of time are very easy.

Attend one stem cell research conference and you’ll be convinced that it’s much more complicated. It’s a sea of reagents and transcription factors and unknown cause-and-effect. Many researchers will spend their entire career working on just one unknown and their caution and concern when it comes to the notion of a cure is justifiable.

Whistler (Courtesy of Lisa Willemse)

Whistler (Courtesy of Lisa Willemse)

Which makes it all the more impactful when you attend a research conference and hear three talks, back-to-back, that demonstrate that we’re ticking off some of those unknowns and getting much closer to real – not sham – therapies. Therapies with a sound scientific basis that are well planned and done with patient safety (not sales) in mind. Last week’s Till and McCulloch Meetings, held in Whistler, British Columbia gave us a sense of what is possible for three conditions: macular degeneration (vision), septic shock and a rare neurologic disease (Stiff Person Syndrome). Other blogs have covered  different aspects of this meeting here and here.

Vision Repair – Age-related Macular Degeneration (AMD)

As the world’s first clinical trial to use induced pluripotent stem cells launched amid sweeping regulatory changes in Japan, Dr. Masayo Takahashi’s treatment protocol for AMD has received no small amount of scrutiny. After a brief hiatus, the trial was back on track earlier this year and Takahashi’s presentation at this meeting was highly anticipated.

Dr. Masayo Takahashi

Dr. Masayo Takahashi

It did not disappoint. Takahashi spent the better part of her time outlining the steps taken to reach the point where the clinical trial was possible, including multiple studies in mice and further refinement of the treatment to ensure it would be stable in humans even with genetic changes over time. Given that one of the reasons the trial was put on hold was due to genetic mutations found in the cells prepared for the second potential human transplant, Takahashi’s careful work in ensuring the product was safe bodes well for the future of this trial.

The first patient was treated in 2014, a 78-year-old woman with wet AMD in the right eye, and although only minimal visual improvement was documented, the patient anonymously told the Japan Times, “I’m glad I received the treatment. I feel my eyesight has brightened and widened.”

Takahashi also alluded to some of the other challenges she’d had to overcome to make this trial a reality, including would-be critics who told her that the nervous system and the retina were too complicated to regenerate. Takahashi’s response? “You don’t know stem cells [and] you don’t understand the needs of the patient.”

While it was unclear when the next patient will receive treatment, Takahashi did say that three new applications for clinical trials using her refined protocols have been submitted for approval.

Septic shock  

Septic shock is not a condition that gets a lot of attention, most likely because it’s not a primary illness, but a secondary one; a drastic and often fatal immune response that severely reduces blood pressure and cell metabolism. It accounts for 20% of all intensive care unit (ICU) admissions and is the most common cause of non-coronary mortality in the ICU. For those who survive septic shock, there are significant and long-term health consequences.

Over 100 clinical trials have attempted to improve outcomes for patients with septic shock, but not one has been successfully translated into the clinical setting. Supportive care remains the mainstay of therapy.

Dr. Lauralyn McIntyre

Dr. Lauralyn McIntyre

This was the sober backdrop painted by critical care physician, Dr. Lauralyn McIntyre as she began her talk on the world’s first stem cell clinical trial for septic shock she is co-leading in Ottawa with Dr. Duncan Stewart.

Like Takahashi, McIntyre spent a good deal of time explaining the rationale and research that underpin the trial, which takes advantage of the immune-modulating properties of mesenchymal stromal cells (also called mesenchymal stem cells or MSCs) to suppress and reverse the effects of septic shock. This work includes reviews of more than 50 studies that looked at the effects of MSCs in both human trials and animal studies.

McIntyre also discussed research she did with mice in 2010 as a proof-of-concept, where the MSC therapy was delayed for six days. This delay is important as it better simulates the time frame in which most patients arrive in the hospital. As McIntryre pointed out, if the therapy only worked when given within hours of disease development, what good would it be for patients who come in on day six?

Fortunately, the therapy worked in the mice, even after a delayed timeframe, providing a green light for safety testing in humans. The small first human trial is currently underway for nine patients (with a control arm of 21) with results not yet published – although one of the patients shared his experience earlier this year. McIntyre relayed that the early data is very encouraging – enough that the team is moving ahead with a Phase 2 randomized trial in 10 centres across Canada in 2017.

Stiff Person Syndrome

Tina Ceroni’s story is much more personal. She is only the second person in the world to have received an experimental stem cell treatment for Stiff Person Syndrome, a rare neurologic condition that causes uncontrolled and sustained contractions of the arm, leg or other muscles. Often misdiagnosed initially as Multiple Sclerosis or anxiety/depression, SPS is also an autoimmune disease for which the cause is unknown.

Tina Ceroni

Tina Ceroni (The Ottawa Hospital)

I’ve written about Tina’s story before – about how she was hospitalized 47 times in one year and how a chance meeting with another SPS patient propelled Ceroni on a journey that included an intensive stem cell therapy under the guidance of Dr. Harry Atkins at the Ottawa Hospital, in which her blood stem cells were harvested from her bone marrow and used to repopulate her system after her immune system was wiped clean with chemotherapy.

Now a stem cell advocate, Ceroni’s story keeps getting better – not merely in how powerfully and passionately she tells it, but in the continued good health she enjoys after her treatment and in her efforts to share it more broadly.

Most importantly, she drives home a key message:

“My story underscores the importance of clinical trials…. My experience will help to change the future for others. I am living proof that a clinical trial for stem cell therapy can have a life-changing outcome.”

“Often hope is the only medicine we have.”

It’s important that patients like Ceroni continue share their story, not just with the research community to give a human face to the work they do, but to show that solid research is making an impact, one that can be measured in lives saved.


Lisa Willemse

Lisa Willemse

This article is published simultaneously, with permission by the author, Lisa Willemse, on the Ontario Institute for Regenerative Medicine (OIRM) Expression blog.

Eggciting News: Scientists developed fertilized eggs from mouse stem cells

A really eggciting science story came out early this week that’s received a lot of attention. Scientists in Japan reported in the journal Nature that they’ve generated egg cells from mouse stem cells, and these eggs could be fertilized and developed into living, breathing mice.

This is the first time that scientists have reported the successful development of egg cells in the lab outside of an animal. Many implications emerge from this research like gaining a better understanding of human development, generating egg cells from other types of mammals and even helping infertile women become pregnant.

Making eggs from pluripotent stem cells

The egg cells, also known as oocytes, were generated from mouse embryonic stem cells and induced pluripotent stem cells derived from mouse skin cells in a culture dish. Both stem cell types are pluripotent, meaning that they can generate almost any cell type in the human body.

After generating the egg cells, the scientists fertilized the eggs through in vitro fertilization (IVF) using sperm from a healthy male mouse. They allowed the fertilized eggs to grow into two cell embryos which they then transplanted into female mice. 11 out of 316 embryos (or 3.5%) produced offspring, which were then able to reproduce after they matured into adults.

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These mice were born from artificial eggs that were made from stem cells in a dish. (K. Hayashi, Kyushu University)

Not perfect science

While impressive, this study did identify major issues with its egg-making technique. First, less than 5% of the embryos made from the stem-cell derived eggs developed into viable mice. Second, the scientists discovered that some of their lab-grown eggs (~18%) had abnormal numbers of chromosomes – an event that can prevent an embryo from developing or can cause genetic disorders in offspring.

Lastly, to generate mature egg cells, the scientists had to add cells taken from mouse embryos in pregnant mice to the culture dish. These outside cells acted as a support environment that helped the egg cells mature and were essential for their development. The scientists are working around this issue by developing artificial reagents that could hopefully replace the need for these cells.

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)

Will human eggs be next?

A big discovery such as this one immediately raises ethical questions and concerns about whether scientists will attempt to generate artificial human egg cells in a dish. Such technology would be extremely valuable to women who do not have eggs or have problems getting pregnant. However, in the wrong hands, a lot could go wrong with this technology including the creation of genetically abnormal embryos.

In a Nature news release, Azim Surani who is well known in this area of research, said that these ethical issues should be discussed now and include the general public. “This is the right time to involve the wider public in these discussions, long before and in case the procedure becomes feasible in humans.”

In an interview with Phys.org , James Adjaye, another expert from Heinrich Heine University in Germany, raised the point that even if we did generate artificial human eggs, “the final and ultimate test for fully functional human ‘eggs in a dish’ would be the fertilization using IVF, which is also ethically not allowed.”

Looking forward, senior author on the Nature study, Katsuhiko Hayashi, predicted that in a decade, lab-grown “oocyte-like” human eggs will be available but probably not at a scale for fertility treatments. Because of the technical issues his study revealed, he commented, “It is too preliminary to use artificial oocytes in the clinic.”

From Pig Parts to Stem Cells: Scientist Douglas Melton Wins Ogawa-Yamanaka Prize for Work on Diabetes

Since the 1920s, insulin injections have remained the best solution for managing type 1 diabetes. Patients with this disease do not make enough insulin – a hormone that regulates the sugar levels in your blood – because the insulin-producing cells, or beta cells, in their pancreas are destroyed.

Back then, it took two tons of pig parts to make eight ounces of insulin, which was enough to treat 10,000 diabetic patients for six months. Biotech and pharmaceutical companies have since developed different types of human insulin treatments that include fast and long acting versions of the hormone. It’s estimated that $22 billion will be spent on developing insulin products for patients this year and that costs will rise to $32 billion in the year 2019.

These costs are necessary to keep insulin-dependent diabetes patients alive and healthy, but what if there was a different, potentially simpler solution to manage diabetes? One that looks to insulin-producing beta cells as the solution rather than daily hormone shots?

Douglas Melton Receives Stem Cell Prize for Work on Diabetes

Harvard scientist Douglas Melton envisions a world where one day, insulin-dependent diabetic patients are given stem cell transplants rather than shots to manage their diabetes. In the 90s, Melton’s son was diagnosed with type 1 diabetes. Motivated by his son’s diagnosis, Melton dedicated the focus of his research on understanding how beta cells develop from stem cells in the body and also in a cell culture dish.

Almost 30 years later, Melton has made huge strides towards understanding the biology of beta cell development and has generated methods to “reprogram” or coax pluripotent stem cells into human beta cells.

Melton was honored for his important contributions to stem cell and diabetes research at the second annual Ogawa-Yamanaka Stem Cell Prize ceremony last week at the Gladstone Institutes. This award recognizes outstanding scientists that are translating stem cell research from the lab to clinical trials in patients.

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Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, explained why Melton was selected as this year’s prize winner:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“Doug’s research on genetic markers expressed during pancreas development have led to a reliable way to reprogram stem cells into human beta cells. His work provides the foundation for the ultimate goal of transplantable, patient-specific beta cells.”

 

Making Beta Cells for Patients

During the awards ceremony, Melton discussed his latest work on generating beta cells from human stem cells and how this technology could transform the way insulin-dependent patients are treated.

Douglas Melton, Harvard University.

Douglas Melton, Harvard University.

“I don’t mean to say that this [insulin treatment] isn’t a good idea. That’s keeping these people alive and in good health,” said Melton during his lecture. “What I want to talk about is a different approach. Rather than making more and better insulins and providing them by different medical devices, why not go back to nature’s solution which is the beta cells that makes the insulin?”

Melton first described his initial research on making pancreatic beta cells from embryonic and induced pluripotent stem cells in a culture dish. He described the power of this system for not only modeling diabetes, but also screening for potential drugs, and testing new therapies in animal models.

He also mentioned how he and his colleagues are developing methods to manufacture large amounts of human beta cells derived from pluripotent stem cells for use in patients. They are able to culture stem cells in large spinning flasks that accelerate the growth and development of pluripotent stem cells into billions of human beta cells.

Challenges and Future of Stem-Cell Derived Diabetes Treatments

Melton expressed a positive outlook for the future of stem cell-derived treatments for insulin-dependent diabetes, but he also mentioned two major challenges. The first is the need for better control over the methods that make beta cells from stem cells. These methods could be more efficient and generate higher numbers of beta cells (beta cells make up 16% of stem cell-derived cells using their current culturing methods). The second is preventing an autoimmune attack after transplanting the stem-cell derived beta cells into patients.

Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.

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He mentioned a CIRM-funded clinical trial by ViaCyte, which is testing an encapsulation device that is placed under the skin. The device contains embryonic stem cell-derived pancreatic progenitor cells that develop into beta cells that secrete insulin into the blood stream. The device also prevents the immune system from attacking and killing the beta cells.

Melton also discussed a biological approach to protecting transplanted beta cells. In collaboration with Dan Anderson at MIT, they coated stem cell-derived beta cells in a biomaterial called alginate, which comes from seaweed. They injected alginate microcapsule-containing beta cells into diabetic mice and were able control their blood sugar levels.

At the end of his talk, Melton concluded that he believes that beta cell transplantation in an immunoprotective device containing stem cell-derived cells will have the most benefit for diabetes patients.

Gladstone Youtube video of Douglas Melton’s lecture at the Ogawa-Yamanaka Prize lecture.


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Stem Cell Experts Discuss the Ethical Implications of Translating iPSCs to the Clinic

Part of The Stem Cellar blog series on 10 years of iPSCs.

This year, scientists are celebrating the 10-year anniversary of Shinya Yamanaka’s Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs). These are cells that are very similar biologically to embryonic stem cells and can develop into any cell in the body. iPSCs are very useful in scientific research for disease modeling, drug screening, and for potential cell therapy applications.

However, with any therapy that involves testing in human patients, there are ethical questions that scientists, companies, and policy makers must consider. Yesterday, a panel of stem cell and bioethics experts at the Cell Symposium 10 Years of iPSCs conference in Berkeley discussed the ethical issues surrounding the translation of iPSC research from the lab bench to clinical trials in patients.

The panel included Shinya Yamanaka (Gladstone Institutes), George Daley (Harvard University), Christine Mummery (Leiden University Medical Centre), Lorenz Studer (Memorial Sloan Kettering Cancer Center), Deepak Srivastava (Gladstone Institutes), and Bioethicist Hank Greely (Stanford University).

iPSC Ethics Panel

iPSC Ethics Panel at the 10 Years of iPSCs Conference

Below is a summary of what these experts had to say about questions ranging from the ethics of patient and donor consent, genetic modification of iPSCs, designer organs, and whether patients should pay to participate in clinical trials.

How should we address patient or donor consent regarding iPSC banking?

Multiple institutes including CIRM are developing iPSC banks that store thousands of patient-derived iPSC lines, which scientists can use to study disease and develop new therapies. These important cell lines wouldn’t exist without patients who consent to donate their cells or tissue. The first question posed to the panel was how to regulate the consent process.

Christine Mummery began by emphasizing that it’s essential that companies are able to license patient-derived iPSC lines so they don’t have to go back to the patient and inconvenience them by asking for additional samples to make new cell lines.

George Daley and Hank Greely discussed different options for improving the informed consent process. Daley mentioned that the International Society for Stem Cell Research (ISSCR) recently updated their informed consent guidelines and now provide adaptable informed consent templates that can be used for obtaining many type of materials for human stem cell research.  Daley also mentioned the move towards standardizing the informed consent process through a single video shared by multiple institutions.

Greely agreed that video could be a powerful way to connect with patients by using talented “explainers” to educate patients. But both Daley and Greely cautioned that it’s essential to make sure that patients understand what they are getting involved in when they donate their tissue.

Greely rounded up the conversation by reminding the audience that patients are giving the research field invaluable information so we should consider giving back in return. While we can’t and shouldn’t promise a cure, we can give back in other ways like recognizing the contributions of specific patients or disease communities.

Greely mentioned the resolution with Henrietta Lack’s family as a good example. For more than 60 years, scientists have used a cancer cell line called HeLa cells that were derived from the cervical cancer cells of a woman named Henrietta Lacks. Henrietta never gave consent for her cells to be used and her family had no clue that pieces of Henrietta were being studied around the world until years later.

In 2013, the NIH finally rectified this issue by requiring that researchers ask for permission to access Henrietta’s genomic data and to include the Lacks family in their publication acknowledgements.

Hank Greely, Stanford University

Hank Greely, Stanford University

“The Lacks family are quite proud and pleased that their mother, grandmother and great grandmother is being remembered, that they are consulted on various things,” said Hank Greely. “They aren’t making any direct money out of it but they are taking a great deal of pride in the recognition that their family is getting. I think that returning something to patients is a nice thing, and a human thing.”

What are the ethical issues surrounding genome editing of iPSCs?

The conversation quickly focused on the ongoing CRISPR patent battle between the Broad Institute, MIT and UC Berkeley. For those unfamiliar with the technique, CRISPR is a gene editing technology that allows you to cut and paste DNA at precise locations in the genome. CRISPR has many uses in research, but in the context of iPSCs, scientists are using CRISPR to remove disease-causing mutations in patient iPSCs.

George Daley expressed his worry about a potential fallout if the CRISPR battle goes a certain way. He commented, “It’s deeply concerning when such a fundamentally enabling platform technology could be restricted for future gene editing applications.”

The CRISPR patent battle began in 2012 and millions of dollars in legal fees have been spent since then. Hank Greely said that he can’t understand why the Institutes haven’t settled this case already as the costs will only continue to rise, but that it might not matter how the case turns out in the end:

“My guess is that this isn’t ultimately going to be important because people will quickly figure out ways to invent around the CRISPR/Cas9 technology. People have already done it around the Cas9 part and there will probably be ways to do the same thing for the CRISPR part.”

 Christine Mummery finished off with a final point about the potential risk of trying to correct disease causing mutations in patient iPSCs using CRISPR technology. She noted that it’s possible the correction may not lead to an improvement because of other disease-causing genetic mutations in the cells that the patient and their family are unaware of.

 Should patients or donors be paid for their cells and tissue?

Lorenz Studer said he would support patients being paid for donating samples as long as the payment is reasonable, the consent form is clear, and patients aren’t trying to make money off of the process.

Hank Greely said the big issue is with inducement and whether you are paying enough money to convince people to do something they shouldn’t or wouldn’t want to do. He said this issue comes up mainly around reproductive egg donation but not with obtaining simpler tissue samples like skin biopsies. Egg donors are given money because it’s an invasive procedure, but also because a political decision was made to compensate egg donors. Greely predicts the same thing is unlikely to happen with other cell and tissue types.

Christine Mummery’s opinion was that if a patient’s iPSCs are used by a drug company to produce new successful drugs, the patient should receive some form of compensation. But she said it’s hard to know how much to pay patients, and this question was left unanswered by the panel.

Should patients pay to participate in clinical trials?

George Daley said it’s hard to justify charging patients to participate in a Phase 1 clinical trial where the focus is on testing the safety of a therapy without any guarantee that there will be beneficial outcome to the patient. In this case, charging a patient money could raise their expectations and mislead them into thinking they will benefit from the treatment. It would also be unfair because only patients who can afford to pay would have access to trials. Ultimately, he concluded that making patients pay for an early stage trial would corrupt the informed consent process. However, he did say that there are certain, rare contexts that would be highly regulated where patients could pay to participate in trials in an ethical way.

Lorenz Studer said the issue is very challenging. He knows of patients who want to pay to be in trials for treatments they hope will work, but he also doesn’t think that patients should have to pay to be in early stage trials where their participation helps the progress of the therapy. He said the focus should be on enrolling the right patient groups in clinical trials and making sure patients are properly educated about the trial they are participating.

Thoughts on the ethics behind making designer organs from iPSCs?

Deepak Srivastava said that he thinks about this question all the time in reference to the heart:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“The heart is basically a pump. When we traditionally thought about whether we could make a human heart, we asked if we could make the same thing with the same shape and design. But in fact, that’s not necessarily the best design – it’s what evolution gave us. What we really need is a pump that’s electrically active. I think going forward, we should remove the constraint of the current design and just think about what would be the best functional structure to do it. But it is definitely messing with nature and what evolution has given us.”

Deepak also said that because every organ is different, different strategies should be used. In the case of the heart, it might be beneficial to convert existing heart tissue into beating heart cells using drugs rather than transplant iPSC-derived heart cells or tissue. For other organs like the pancreas, it is beneficial to transplant stem cell-derived cells. For diabetes, scientists have shown that injecting insulin secreting cells in multiple areas of the body is beneficial to Diabetes patients.

Hank Greely concluded that the big ethical issue of creating stem cell-derived organs is safety. “Biology isn’t the same as design,” Greely said. “It’s really, really complicated. When you put something into a biological organism, the chances that something odd will happen are extremely high. We have to be very careful to avoid making matters worse.”

For more on the 10 years of iPSCs conference, check out the #CSStemCell16 hashtag on twitter.

CIRM’s Randy Mills: New FDA rules for stem cells won’t fix the problem

For the last two days the Food and Drug Administration (FDA) has been holding a hearing in Bethesda, Maryland on new regulations that would tighten control over stem cell treatments. The FDA invited public testimony during the hearing on the regulations that would impact many of the clinics that currently offer unproven therapies

The testimony has been impassioned to say the least. Supporters of the clinics say they offer a valuable service and that patients should be allowed to decide for themselves how they want their own cells to be used. Opponents say the clinics are little more than snake oil sales people, offering bogus, unproven treatments.

One of those presenting was Randy Mills, CIRM’s President and CEO. Randy has been very vocal in the past about the need for the FDA to change the way it regulates stem cell therapies.

In California Healthline Randy explained why he thinks the rules the FDA is proposing will not fix the problem, and may even make it worse:

FDA Must Find A Middle Ground For Sake Of Patients

randy

Randy Mills

We aren’t happy, as a lot of people aren’t happy, with the proliferation of these stem cell clinics — some of which are probably doing good work. But some are clearly making rather outlandish claims for which there’s no real data. 

There are a couple of conditions coming together to create this storm.

One is that the need is very real. These patients are really struggling. They don’t have alternatives. They’re desperate and they need help. It’s not in the realm of possibility to talk to somebody who is suffering as badly as these patients are and to say, ‘You have to wait a few more decades for the science to catch up.’

On the other hand, we have a regulatory paradigm that only provides two pathways to put a cell therapy onto the market. One pathway is the most intense regulatory requirement anywhere in the world for any product — the biologics license application through the FDA, which takes 10 to 20 years and costs over $1 billion.

The other is through the exemptions the FDA has made, which require absolutely no pre-market approval whatsoever. You can be on the market in days, with no data.

The regulatory burden associated with one is massive and the other is almost nonexistent.

So it’s not at all surprising that we’re seeing a proliferation of these stem cell clinics popping up that are operating under the assumption that they fall under the exemption.

What the FDA is doing now is saying, ‘We’re not happy with this. We’re going to define some terms more narrowly than in the past … and make it more difficult to legally be on the market under the less burdensome regulatory pathway.’

That’s what this meeting is about.

The problem with their strategy is twofold. It doesn’t address the patients, or the need side of the equation. And I don’t think it has a chance of actually working because the FDA will acknowledge that they do not have the resources to enforce these types of regulations at the clinic level.

They would have to be essentially regulating the practice of physicians, which is well beyond their capabilities. Even if they were able to enforce it, it would just drive these patients somewhere else.

We’re advocating for the creation of some middle pathway that would bring essentially unregulated therapies into the regulatory fold, but in a manner which could be complied with.

I would rather know these clinics are being regulated and collecting data than have them operating under the radar screen of the FDA. I would like there to be a formal pre-market review of these therapies before they’re put on the market. I would like there to be safety and efficacy data.

I’m going to try hard to get the FDA to see that just plugging this hole won’t make the problem go away.

Thinking that they’re going to strengthen the regulation and that patients are going to be satisfied that there’s absolutely no chance for help is naive.

There isn’t a lot of evidence to suggest these types of procedures are overly risky. It’s not that they don’t have risk, but everything in medicine does. If you’re a patient who has absolutely no alternative, you’re probably willing to take the chance.