Precious Cargo: Scientists Hijack Red Blood Cells to Serve as Potential Therapeutic Delivery System

A unique property of red blood cells is now being harnessed to help deliver microscopic cargo to sites throughout the body, according to research published today in the Proceedings of the National Academy of Sciences.

Red blood cells represent an ideal therapeutic delivery system.

Red blood cells represent an ideal therapeutic delivery system.

There are anywhere from 3 to 6 million red blood cells in the human body at any given time, and they are tasked with one main job: transport oxygen throughout the body. But researchers, led by Drs. Harvey Lodish and Hidde Ploegh from the Whitehead Institute, wondered if these cells could transport other important molecules. As Lodish explained in today’s news release:

“We wanted to create high-value red blood cells that do more than simply carry oxygen. Here we’ve laid out the technology to make mouse and human red blood cells that…can potentially be used for therapeutic purposes.”

Red blood cells are unusual in that, once mature, they ditch their nucleus—and the DNA housed within. This is an attractive characteristic for a potential therapy: without any genetic material, there is no risk that manipulating the DNA could result in later tumor formation.

So Lodish, an expert in the biology of red blood cells, and his team used this characteristic to their advantage. They introduced a set of genes into early stage red blood cells, called ‘progenitors,’ that still had their nucleus. These genes, when activated instructed the cell to produce a particular type of protein that latched itself to the surface of the cell. Then, when the cells matured and jettisoned their nuclei, the proteins remained on the cells’ surface.

And while this method, called ‘sortagging,’ here involved a protein sticking to the cellular surface, the researchers argue that the same method could be applied to stick virtually any type of molecule to the cell. As Ploegh explained:

“Because the modified human red blood cells can circulate in the body for up to four months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin. The result would be long-lasting reserves of antitoxin antibodies.”

The research team envisions this approach being useful for everything from carrying proteins to break up blood clots to those that alleviate chronic inflammation. One of the most exciting possibilities, according to Ploegh, would be using this method to suppress the body’s unwanted immune response after being treated with protein-based therapies.

The possibilities, it would seem, are endless.

Stem cell stories that caught our eye: fingering chemical cancer cause, treating leukemia and getting better ID on cells

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.

Stem cells model environmental damage. Using human embryonic stem cells to generate prostate tissue in mice, a team at the University of Illinois has shown how the endocrine-disrupting chemical BPA can lead to prostate cancer. They implanted the cells, derived from human stem cells, along with supportive rodent cells in mice and then fed the mice a diet with low levels of BPA. As the cells matured into prostate tissue in the animals the chemical seemed to reprogram the cells in a manner that raises the risk for cancer. The team reported its work at the annual meeting of the Endocrine Society in Chicago this week and the association’s press release was picked up by Bio-Medicine.

Protecting stem cell “home” may be new therapy. A Spanish team has discovered that certain rare leukemias, known as myeloproliferative disorders, seem to be triggered by damage to the area where stem cells hang out in our bone marrow known as the stem cell niche. Normally the niche controls the behavior of blood-forming stem cells but when it gets inflamed that control breaks down the team reported in the journal Nature. But there is good news, they tested a currently available drug in an animal model and it seemed to reverse the damage to the niche and return normal stem cell controls. ScienceDaily ran a story about the work.

Clever trick could make stem cell frequent fliers. Researchers often share stem cells with colleagues around the world by freezing them first. But in some uses, it would be better if the cells could be shipped in living cultures. That usually requires some sort of electrical motor to agitate the vials to keep the cells from clumping, but airlines don’t allow running electric motors in cargo on planes. So a group of engineering students at the University of California, San Diego, has taken cues from old pendulum clocks and developed a spring powered motor that can keep the cells agitated. As our field gets ready to commercialize cell products, there may be times this could help centralize mass production of cells for shipping. Medical Design Technology explained the students’ project.

Getting a better ID on the “other” bone marrow stem cell. Most people know that our bone marrow has blood-forming stem cells, but it also has mesenchymal stem cells (MSCs). Those cells can form bone, cartilage and fat and release proteins that seem to direct the work of other stem cells. Those skills have led to more than 200 clinical trials investigating the potential of MSCs to treat many diseases. But those trials have often produced results that are hard to interpret, and many researchers in the field say part of the problem comes from our inability to accurately identify true MSCs resulting in most clinical trials using a mixed population of cells. Now one of the leaders in the field, Sean Morrison at the University of Texas Southwest Medical Center, reports that his team has found a reliable marker for MSCs known as leptin receptor. His current work was in mice, but if it can be duplicated with human cells, it could increase the chances for valuable data coming from MSC trials.

Don Gibbons

BIO International Panel Showed Stem Cell Science Poised to Make a Difference in Medical Practice Soon

When the biotechnology trade association began holding annual conferences in 1993, they drew 1,400 to the first event. This year BIO International expected nearly 20,000 here in San Diego. Among the dozens of concurrent sessions each day of this four-day scramble, stem cells got one track on one day this year. But listening to the progress being made by our presenters yesterday, our field is set to grow at the pace this meeting has—and could dominate the medical sessions here within the next decade.


After setting the scene with our opening panel yesterday, four subsequent panels confirmed the vast near-term potential painted by the opening speakers. They revealed a field maturing rapidly and starting to be a valued research tool of the bigger companies that have dominated the biotech industry, at the same time it is starting to deliver therapies to patients.

The second panel displayed the robust power of stem cells to model disease better than animal models ever could. These cells also let researchers dive much deeper into the genetic causes of disease, particularly diseases with multiple genes involved. Anne Bang from the Sanford-Burnham Institute mentioned her role in a consortium organized by the National Institutes of Health that is looking at the many genes involved in a type of heart weakening called left ventricular hypertrophy. Because different ethnicities tend to respond differently to drugs used for the condition, the consortium teams are creating iPS-type stem cell lines from 125 Caucasian patients and 125 African-American patients with various forms of the condition.

Their goal is to personalize and improve therapy across both patients groups. The way cells behave in the lab can tell the researchers much more relevant information than most animal models, so drugs developed based off their discoveries should have a better chance of success. All four panelists agreed that the field needs enough drugs developed with these tools to show that they do indeed have a better success rate. That track record should start to develop over the next few years.

The third panel talked about the shift in the medical mindset that will happen when genetically modified stem cells can change the care of chronic diseases from daily therapy to cures. Louis Bretton of Calimmune discussed how his company is trying to do this for HIV, which we blogged about yesterday when they announced promising first phase results from their first four patients. Faraz Ali of bluebird bio showed that his company has already made this life-changing shift for two patients with the blood disorder Beta Thalassemia. Like most patients with the disease they had been dependent on regular transfusions to survive, but when they received transplants of their own stem cells genetically modified to produce the correct version of a protein that is defective in the disease, they were able to live without transfusions.

The fourth panel provided proof that the field is maturing in that they discussed the many hurdles and pitfalls in taking those final steps to prepare a cell therapy to be a commercial product. The three big hurdles—financing, regulatory approval and reimbursement by insurers—all required creativity by the companies outlined in the two case studies. They are working through them but it is anything but a straightforward path. This is the area I hear the most hand wringing about in the halls of meetings in our field.

The last panel showed that one way around some of those end stage hurdles is to reach across borders. Four panelists discussed specific examples of ways international collaborations have accelerated their work toward developing therapies. CIRM has more than 20 collaborative agreements with funding agencies around the world, many of them painstakingly nurtured by our former president Alan Trounson. He gave the final presentation of the panel talking about one of his new projects, building an international stem cell bank with enough cell lines that almost everyone could get donor cells that were immunologically matched.

Our board chair, Jonathan Thomas, moderated the last panel and ended with a tribute to Alan noting that his build-out of our international program would be one of his many lasting legacies.
Don Gibbons

At BIO2014 Stem Cells Shine as Path for Changing How Medicine is Researched and Practiced

For the first time ever at BIO International, the largest annual biotechnology conference in North America, stem cells and regenerative medicine are being showcased today in an all-day forum. This morning kicked off with a panel discussing how stem cells are shifting the paradigm in how we research disease, discover drugs and treat patients.

Panelists speak at "Regenerative Medicine: Propelling a Paradigm Shift in Medicine and Healthcare Delivery"

Panelists speak at “Regenerative Medicine: Propelling a Paradigm Shift in Medicine and Healthcare Delivery”

With a nearly full room, former CIRM president Alan Trounson led four panelists through a lively discussion of how stem cells are accelerating the discovery of the fundamental mechanisms of disease, while also helping to make drug discovery a much more targeted process and, most importantly, beginning to deliver life-changing therapies to patients.

Catriona Jamieson, a CIRM grantee from the University of California, San Diego, showed how she had uncovered how cancer cells develop stem cell-like properties in order to evade treatment. She has, in turn, found three molecular pathways the cells use to make this transformation and has drugs being tested to block those pathways. But not everyone responds to those various drugs the same way, so her goal is to analyze the genetics of each patient and deliver what she has dubbed “precision regenerative medicine.”

Next, Eric Michael David from Organovo talked about the company’s ability to 3-D print small portions of liver or kidney tissue and have it function like the real thing. The long-term goal is to create tissue of sufficient quality to implant in patients, but until that is perfected their system is being widely used to screen potential drugs to see how they affect the various tissues. Understanding this potential toxicity early stands to save drug companies millions—and potentially billions—of dollars by not taking drugs destined to fail into costly phase 3 large-scale clinical trials. Or, even worse, find out about toxicity through surveillance after the drug is on the market with the associated product liability costs.

David said that between 1990 and 2010 160 drugs failed in phase 3 or post marketing, and unfortunately all the drugs in a company’s development pipeline share the cost of those failures. This gives new stem cell technologies the ability to significantly drive down drug costs.

Then, Donna Skerret from Mesoblast, which may be the largest stem cell company in the world, made it clear that while mesenchymal stem cells, which form the basis of their products have the ability to impact several diseases, we still don’t know the full mechanism for all those effects. They can reduce scar formation and moderate an overactive immune response, but the exact method of action for each still needs to be worked out. She called them drug delivery devices because they secrete various proteins that affect the cells around them. Mesoblast currently has therapies in phase 3 clinical trials for heart disease and other therapies in late stage phase 2 trials.

Perry Karsen of Celgene talked about his company’s work with placental-derived stem cells. He too discussed ongoing and much needed work to understand why they are having some of the effects they are having in order to maximize their therapeutic potential. But even now, he said, “We see cell therapies as having the ability to completely change how medicine is practiced by the end of the decade.”

All the panelists talked about needing to use what Karsen called “the full research ecosystem,” forming collaborations between academic researchers and industry. Donna noted that Mesoblast is relying on academic partners to help define the mechanism of action of their cells.

Forming these partnerships to accelerate getting treatments to patients has always been a core part of CIRM’s function.

An outline of all five panels of the Regenerative Medicine Forum can be seen here. We organized the day along with the Alliance for Regenerative Medicine and the International Society for Stem Cell Research.
Don Gibbons

Innovative Stem Cell Therapy for HIV Passes Milestone

Milestones are useful things. They measure how far we have come on a journey, and give us a sense that we are on the right path. One of the projects we are helping fund just passed a big milestone, and it’s given the researchers the go-ahead to move on to the next, perhaps even more important stage.

Left to Right: CIRM President and CEO C. Randal Mills, Calimmune CEO Louis Breton, Calimmume Chief Scientific Officer Geoff Symonds at today's news conference in San Diego.

Left to Right: CIRM President and CEO C. Randal Mills, Calimmune CEO Louis Breton and Calimmume Chief Scientific Officer Geoff Symonds at today’s news conference in San Diego.

The project is Calimmune’s stem cell gene modification study, which takes blood stem cells from people who are HIV-positive, genetically modifies them so they carry a gene that blocks the AIDS virus from infecting cells, and then re-introduces the modified cells to the patient. The hope is that those stem cells will then create a new blood system that is resistant to HIV.

The milestone it passed is that the Data Safety Monitoring Board (DSMB) looked at the results from the first group of four patients treated with this approach, found that there were no serious adverse events or dangerous side effects from it, and gave Calimmune the go-ahead to start treating the next group of patients.

In a news release we put out jointly with Calimmune, their CEO Louis Breton said this is a big step forward for them:

“We are very excited and encouraged by this development. This recommendation from the DSMB is an important step in bringing this one-time therapy to the patients, and takes us closer to our ultimate goal of eradicating AIDS.”

It’s a pretty big deal for us too, as our President and CEO C. Randal Mills noted in the same release:

“The mission of CIRM is to efficiently accelerate the development of stem cell treatments for patients suffering from unmet medical conditions. While still early in clinical development this announcement demonstrates real progress towards this mission. The accomplishments of Calimmune’s team is a great example of how CIRM partnerships are working to impact patient’s lives today.”

Now, just treating four people might not seem particularly impressive, after all HIV/AIDS has killed more than 25 million people worldwide and has infected another 25 million more – around 1.1 million here in the U.S. But every treatment has to begin with a simple premise, that whatever you do is not going to hurt the patient. Getting the green light from the Data Safety Monitoring Board, an independent panel of experts who review data and advise the researchers doing clinical trials, shows this approach appears to be safe.

The next step is to repeat this same process in 3 or 4 more patients but to give those patients a preconditioning regimen, treating them with a medication before returning their modified stem cells to them, to try and make the therapy more effective. This could show that the therapeutic approach, called Cal-1, is not only safe but also is working to protect patients against HIV.

If the safety data from that second group also looks good, then Calimmune can move on to the next group of patients. Each step, no matter how small, moves us ever closer to our end goal of developing a cure for HIV/AIDS.

That’s still a very distant goal right now, but with each milestone we pass it shows that we are heading in the right direction.

Want to know more about Calimmune’s path towards clinical trial? Check out Calimmune CEO Louis Breton’s recent video describing their progress towards a cure for HIV.

Kevin McCormack

When Hope Runs up against Reality: Balancing Patient Optimism with Medical Evidence

One of the big concerns among scientists – including many at the International Society for Stem Cell Research (ISSCR) conference in Vancouver, Canada – is that patient expectations about stem cells are often greater than researchers are able to deliver today. That can result in patients in search of a cure heading to overseas clinics that offer unproven therapies.

Megan Munsie – head of the Education, Ethics, Law and Community Awareness Unit at the University of Melbourne in Australia – wanted to find out what happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence. So she started with a small survey of 16 Australians, patients and patient-caretakers, who had travelled outside Australia for stem cell treatments for a variety of diseases including MS and cerebral palsy.

She says there were a number of interesting findings:

  • They all considered themselves pro-active and well-informed
  • They rejected advice from their own doctor but instead relied on the overseas doctor selling them the treatment for advice
  • They felt they had no choice but to travel overseas because they were running out of time and options in Australia
  • They didn’t consider the health risks, believing that the worst that would happen is that the “treatment” wouldn’t work and they would have spent a lot of money for nothing

Perhaps the most surprising finding was that all of them talked about the “benefits” they gained from going abroad for the treatment, that it gave them a sense of hope even if there was no evidence of medical benefit.

What happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence?

What happens when patients’ hopes for new treatments come into conflict with scientific views on medical evidence?

This led to a bigger study where Munsie surveyed patients and patient advocates but also stem cell scientists and physicians. Not surprisingly the researchers had a very different view of the subject than the patients.

Researchers/doctors said they felt that patients don’t understand science and don’t appreciate the subtleties of clinical trials

  • They said patients were basing their decisions not on science but desperation
  • They considered overseas providers as dubious, selling hope and taking advantage of a vulnerable patient population

What was interesting, however, is that many doctors said they didn’t try to persuade their patients not to go, instead they chose to respect their autonomy but did at least try to give them the facts so that they could make a decision based on knowledge not ignorance.

When asked why they didn’t tell patients not to go, they said they respected the patients’ need for hope and didn’t want to take that away from them because they had nothing they could offer to replace it.

Munsie says recently some doctors have started offering these kinds of unproven therapies in Australia. She talked to four of them asking how they could justify it. All four said there is a huge unmet medical need and it was better to offer these therapies in Australia than have patients travel to other countries for them. They also said that they felt competent to provide treatment because they had undergone some kind of training or had a license to use equipment needed for the therapy.

Ironically while they all considered themselves legitimate providers of a needed medical therapy – albeit an unproven one – and only interested in the science, they regarded others doing the same as “cowboys” and only interested in the money.

When asked if they would support more regulation of the kinds of therapies they were already offering they said yes, saying that the other doctors who claimed they were “self-regulating” is like “giving the keys to the asylum to the lunatics.”

Munsie says it’s clear that it’s not just patients who could benefit from some guidance on expectations about stem cell therapies.

She says we need to do a better job of managing patient expectations without robbing them of a sense of hope, perhaps by offering them information that is more tailored to their particular needs.

We also need to manage what she called “the unbridled enthusiasm of providers” who are offering speculative treatments as “medical practice”. That might take regulatory change by the government.

She says it’s difficult to strike a balance between hope and scientific evidence, in maintaining a patient’s sense of optimism while acknowledging the reality of the science and the risks posed by unproven treatments.

Kevin McCormack

Stem Cell Stories that Caught our Eye: Speeding Stroke Recovery, HIV Clinical Trial, New Method for Growing Heart Cells

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.

Transplanting cells to speed stroke recovery. Stroke remains one of the most common forms of death and disability, yet utilization of therapies that can break down the blood clots that cause most forms of stroke lags; these therapies are only effective when used within 3 to 4 hours of the stroke but most patients arrive at the hospital too late. Now scientists from Shanghai Jiao Tong University may have a different solution that can repair damage already done.

Scientists have recently been looking to stem cell transplantation as a way to restore blood vessels or brain tissue destroyed by a stroke, but early experiments revealed limited effectiveness. In this study, which was published this week in Stem Cell Reports, the researchers coaxed embryonic stem cells further along in the development process before implanting them—which appears to have done the trick.

Using animal models, the team—led by Dr. Wei-Qiang Gao—transplanted two different types of so-called ‘precursor cells’ which have the ability to turn into the major types of brain and blood-vessel cells, the types of cells that are lost during a stroke.

Gao argues that this kind of transplantation is superior to previous methods because the two types of precursor cells can actually support each other in order to promote cell growth, and thus lays the foundation for new stem cell-based therapies to speed up recovery for stroke survivors.

CIRM-Funded Clinical Trial to Treat HIV. A team comprised of the City of Hope in Los Angeles, Sangamo Biosciences and the University of Southern California have developed an innovative approach to eradicating HIV.

With support from a CIRM grant, the researchers are developing a combination stem cell and gene therapy approach that is based on the success of the so-called “Berlin patient,” an HIV-positive man who was essentially cured after a bone-marrow transplant to treat his leukemia. In this instance, the bone marrow donor had a unique HIV-resistant mutation. The transplant transferred this mutation to the Berlin patient, and scientists have since been looking for a way to replicate this mutation on a larger scale. As explained in this week’s news release:

“Using an enzyme called a zinc-finger nuclease (ZFN), the research team can …“edit” the HIV patient’s stem cell genes so that, like the Berlin patient’s donor, they can no longer produce the protein. No protein, no HIV infection. The virus might then disappear from the body.

This study will be the first trial of ZFN technology in human stem cells. Earlier clinical studies in HIV-positive patients show that the ZFN method is generally safe when used with white blood cells called lymphocytes. And in one patient, the therapy was associated with temporary control of HIV without antiviral medication.”

The team hopes to begin testing this approach by the fall of 2014 on HIV patients who have not responded well to traditional therapies. CIRM funds a team that uses a different approach to gene editing that began a clinical trial last summer. You can read about both on our HIV fact sheet.

Building a Better Heart Cell. Stanford stem cell scientist Dr. Joseph Wu and his team have devised an improved method for generating large batches of heart muscle cells, known as cardiomyocytes, faster and cheaper than ever before. This new technique, described in the latest issue of Nature Methods, solves a long-standing problem in the field of regenerative medicine. As Wu explained in the Stanford University School of Medicine’s blog Scope:

“In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost….[Our] system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes.”

This research, which was supported by a grant from CIRM, stands to improve scientists’ ability to use patient-derived cells not only to better understand how a heart becomes a heart, but also to test drugs that treat various types of heart disease.

ISSCR 2014: Tony Atala, Jason Burdick and the Power of Tissue Engineering

The progress in tissue engineering in just the past two decades has been like the construction industry moving from simple lean-to structures to homes with plumbing, heating and cooling systems. We are not yet ready to build a high-rise—think of a beating functioning heart—but we are making major strides toward that goal.

One of the founders of the field, Wake Forest’s Dr. Tony Atala, led off this morning plenary session at the annual meeting of the International Society for Stem Cell Research. He started trying to build simple organs in 1990. His talk nicely mapped his progress through four levels of complexity of structure.

Tony Atala speaks about tissue engineering in a 2011 TED talk (credit: Wikipedia)

Tony Atala speaks about tissue engineering in a 2011 TED talk (credit: Wikipedia)

The first level, accomplished by a few teams, was our largest organ, skin, which is relatively simple because it is flat. Next, came simple hollow organs like blood vessels and the urethra that carries urine from the bladder. He followed that with more complex hollow organs, first the bladder and more recently the vagina. Last up were complex solid organs: the heart and the penis. He expects to begin clinical trials with the latter soon, which is eagerly anticipated by our military dealing with the aftermath IED explosive injuries from the wars in Iraq and Afghanistan.

He noted that researchers in the field quickly learned that just throwing cells on scaffolds and hoping they knew what to do was not enough in most cases. They need to grow blood vessels so they can get nourishment and communicate with their surroundings and they often have to make multiple cell types. His own work here benefited from a bit of geographic serendipity. His lab at the time was on the same floor as Judah Folkman’s at Harvard affiliated Children’s Hospital. Folkman is the father of the field of angiogenesis, the art of growing blood vessels.

Atala showed slides comparing injecting cells where you need new muscle, to cells plus scaffold, and finally to the two combined with a vessel growth factor. The three-way combo far outperformed the others. He published his first study using this technique for a hollow simple organ, the urethra, in 2011. At that point his patients had been living with the functional new organ for six years. They work and last.

Researchers almost always place a cell-scaffold complex in a soup of nutrients and growth factors called a bioreactor before implanting it. But at the time of implant, the organ is not mature. Atala said the body acts like a “finishing bioreactor” to fill out and strengthen the organ, which becomes fully mature around six months after implant. He showed images of this in-body growth in his first patients who had been born without a complete vagina and were given a fully functioning organ. He just published that study two months ago, eight years after the implants in order to make sure they stayed functional over time.

He then showed his animal model work creating a penis in rabbits. Being a highly vascular organ it required much more structure. He used a donor organ that had all its cells chemically washed away to leave just the intracellular scaffold. This structure helped guide the blood vessel growth and the rabbits succeeded in mating and having offspring.

His lab has begun early stage work for both liver and heart. They have created miniature livers about the size of a half dollar that are able to produce the appropriate proteins and metabolize drugs. They have used a 3-D printer to build two chambers of a heart that are able to beat in a dish, but their structure has not been stable. So, he noted much more work lies ahead for complex organs.

The second speaker, Jason Burdick from the University of Pennsylvania, concentrated on making better scaffolds for the stem cells, which can have three enhanced properties:

  1. they can be instructive, they can tell cells what to do;
  2. they can be dynamic, they can react to their environment and the cells around them;
  3. they can lead to heterogeneity, they can provide varied instructions so you get the different cell types that you need for a complex tissue.

He discussed two examples, the first was growing better cartilage (as he joked, for injured World Cup soccer players). One problem with early gels used as scaffold was they held the cells individually apart from each other limiting their ability to communicate with each other. This cell-to-cell cross talk is key to tissue maturation. He showed how you could chemically alter the gel to enhance this communication. He also showed how you could implant the gels with microspheres loaded with growth factors to deliver instructions to the cells.

Burdick’s second example focused on minimizing injury after an induced heart attack in rodents. But instead of loading the gel with cells, they loaded it with microspheres that release chemicals that summons the stem cells waiting quietly in reservoirs in all of us. They saw sustained release of the chemicals for 21 days and significant improvement in heart function.

But he closed with a fun twist. The first heart experiment used a strict time-release formulation. He said it would be much better if the chemicals were released at the points the heart needs it the most. So, he is working on a system that releases the chemical based on the levels of an enzyme the heart makes when it is injured. He is hoping this right-amount-at-the-right-time formula will be even better.

We have a short video of the highlights of a workshop we held on tissue engineering that you can watch to get a better feel for where the field is going.

Don Gibbons

ISSCR 2014: Lorenz Studer talks Parkinson’s cells

Two presentations at the International Society for Stem Cell (ISSCR) conference, from two different sides of the pond, looked at ways to get stem cell therapies out of the lab and into patients. They both focused on the problems that need to be overcome, but came to the positive conclusion that this could be done.

Lorenz Studer, from the Sloan Kettering Institute for Cancer Research, has been working since 1995 to try and find a renewable source of cells to treat Parkinson’s Disease. He thinks he’s finally found it.


Let’s back up a little. Studer says the key movement problems seen in people with Parkinson’s (tremors, rigidity, difficulty moving) are caused by a loss of the dopamine-producing neurons in their brain. The good news is that this creates a great target for researchers to try and find a replacement. The bad news is it’s devilishly difficult producing the right kind of cell to survive and function in the brain.

In the 1980s fetal tissue transplants were tried to treat the disease and while these tissues seemed to engraft into the brain and have survived, in some cases, for more than 30 years, they only benefitted a small number of patients and had some unexpected side effects in others. So Studer focused his approach using dopamine-producing neurons (the kind that are destroyed by Parkinson’s disease) that derived from human embryonic stem cells (hESC).

He found that these hESC dopamine neurons worked well in animal models, surviving term and mirroring the normal development of a human neuron.

Studer says new MRI technology means we can be much more precise in where we place these cells in the brain, ensuring that they go exactly where we want them.

So Studer feels he has the right cells in the right number and the ability to place them in the right location. But that still left a number of questions: how do we know they are engrafting into the brain and producing dopamine, and is that producing any impact on behavior?

Studer turned to optogenetics, the use of light to control neurons, to assess and measure what was happening in the brain with these transplanted cells. He put markers into the neurons that were being transplanted and then used pulses of light to switch them on and off. Turning the cells off stopped the dopamine production; turning them back on increased it. They found that the cells were indeed functioning and producing the dopamine.

That still left the question of whether that actually changed behavior. So he devised a study comparing mice with healthy brains to those with Parkinson’s-like lesions on one side of the brain. He put the mice in a tunnel with food pellets on either side of it. The mice with a healthy brain went along the tunnel and ate food from both sides. The other mice ate food almost completely from just one side: the side opposite where the lesion in their brain was.

Then Studer transplanted the dopamine-producing neurons into the study mice and repeated the experiment. This time they ate from both sides of the tunnel suggesting the transplanted cells were producing dopamine, affecting behavior in a positive way.

He hopes to be in clinical trails in patients in late 2016 or early 2017.

For Roger Barker of the University of Cambridge, UK, finding the right cells was only one of four basic questions that need to be considered when trying to take stem cell therapies into clinical trials:

  1. What is the evidence that cell therapies work in replacement
  2. Can you make an authentic, effective cell replacement
  3. How can you test such therapies in patients
  4. Are these competitive to existing therapies

Question 1
Baker says numerous studies in animals over the years have shown that using dopamine-producing stem cells to replace the damaged cells can increase dopamine levels.

A European contingent called TransEuro is about to start a clinical trial to see if this also works well in people. This consortium is using fetal tissue and will treat patients with more early stage disease when, at least in theory, it’s more likely to respond to the therapy. They hope to transplant their first patient in the next four weeks.

Question 2
Can you make an authentic dopamine producing neuron? Baker said Studer’s work suggests you can, as long as it is a form of the cell called an A9 NIGRAL dopaminergic neuron. Barker says even these cells are not perfect cells but they have enough qualities to suggest they are worth trying.

Question 3
Barker says many therapies have been tested in early stage clinical trials in the past that, based on preclinical evidence, weren’t good candidates. When they failed they set the field back by creating the impression that stem cells wouldn’t work for this kind of approach when the real lesson is that stem cells may well work, but they have to be the right ones, used in the right way.

He says GFORCE—a consortium featuring CIRM, and groups in New York, the UK and Japan—is now working as a group to set common standards and agreed upon best practices, so future trials can be compared to each other rather than stand alone.

Here at the stem cell agency we have also created a Regenerative Medicine Consortium to bring together leading companies, academic and funding institutions to share best practices and resources, and to help speed up this process and make it more consistent and efficient.

Question 4
Many existing therapies today work very well in helping control some of the symptoms, at least in the early stages. To be effective these new stem cell therapies have to be at least as good—and at least as affordable—as existing treatments. Whether that proves to be the case will determine whether, even if they show they are effective, they become widely available.

Both scientists acknowledge we have come a long way in recent years. Both also acknowledge we still have a long way to go. But at least now we seem to all be asking the same questions and that is a clear sign of progress.

At the stem cell agency we have invested more than $43 million in 23 different research projects aimed at finding new treatments for Parkinson’s.
Kevin McCormack

ISSCR 2014: If we learn how to help our stem cells keep their balance we might reduce the effects of aging

The effects of aging come from a decline in our stem cells’ ability to do their job. Four speakers on the second day of the International Society for Stem Cell Research (ISSCR) conference laid out how this happens and showed the results of some early attempts to make our aging stem cells perform like young whippersnappers.

Part of the discussion centered on finding balance in our systems, kind of like Goldilocks looking for the bed that was not too hard and not too soft. Scientists refer to this balance in a living organism as homeostasis. We need our stem cells active enough to conduct routine repair and replacement but not so active they cause cancer.

Heinrich Jasper of the Buck Institute for Research on Aging talked about using a fruit fly model to track how stem cell homeostasis gets thrown off in the intestine as the flies age. This is a great model because a five day-old fly can be considered a geezer, which speeds up the research.


He found that the issue is not a drop off in the number of stem cells, but rather an over production to such an extent that they cannot integrate with the surrounding tissue. The team’s sleuthing uncovered a complex set of interactions including oxidative stress—the over-exposure to oxygen containing chemical compounds like the ones you try to moderate with anti-oxidant foods and supplements. The bacteria that naturally live in the gut also changed, becoming more abundant and less diverse, which seemed to be a response to a down regulation of the immune response. He said, the map of these interactions and some of the genetic triggers provides targets for potential intervention in the effects of aging on the stem cells.

Amy Wagers from Harvard gave some more detail on work we have described before doing “parabiosis” experiments. That is when you connect the blood circulation of two different animals. This lets you expose the stem cells of old animals to the blood from young ones. The rational for the work comes from the fact that many of our systems start to show signs of aging around the same time. So, she thought that might mean there is a global regulator of the process, and a good place for a master switch to come in contact with tissue all over the body is the blood stream.

She used new systems for screening large numbers of chemical compounds to find proteins that were abundant in young blood but not old blood. She honed in on one called GDF-11. When she injected the substance into old mice daily for a couple weeks she saw the same effects as hooking their blood stream up to younger mice. Their muscle was better able to repair damage and they had better grip strength. (Having not shaken the hand of a mouse, I am not sure how she measured that, but I trust her.) She found improved repair function in the heart and brain as well.

Shyh-Chang Ng talked about work he began in George Daly’s lab at Harvard and has continued in his first faculty post at the Genome Institute of Singapore. They worked on the nematode, a small worm. Some years ago they had found that the protein Lin 28 regulates the ability of stem cells to replicate and that it declines with age. In recent research he found out part of why the decline results in aging. When it is present it improves the metabolism of our mitochondria, the tiny organs within all our cells that provide energy for the cell to function.

Next, Gabrielle Kardon from the University of Utah talked about the loss of muscle mass we all begin to experience around the age of 45 (around 17 months old for mice). The loss of muscle mass makes us more vulnerable to injury and to the insulin resistance that is the hallmark of type 2 diabetes. The muscle stem cells that are supposed to help keep our muscle in shape are called satellite cells, but exactly what they do is not well understood. So Kardon used genetic tricks to label them and monitor their activity. She found that they were important for repair as well as for maintaining homeostasis, but their activity varied between types of muscle, like the muscle in the diaphragm versus in our legs.

All this work provides clues to intervening to allow healthier aging. The technical term for muscle mass loss with aging is Sarcopenia. From now on when someone tells me I look tired, I will just tell them, “nah it is just my sarcopenia acting up, but we are working on that.”
Don Gibbons