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.

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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: Talking Twitter and Stem Cells

One of the fascinating things about the ISSCR (International Society for Stem Cell Research) annual conference is that you learn so much about so many things, ranging from the latest in Parkinson’s research (more on that later this week) to the impact of social media on people’s knowledge about stem cells.

At a poster presentation Wednesday, Julie Robillard, Ph.D., a post doc researcher at the University of British Columbia in Vancouver, BC, talked about the way that people use Twitter to talk about stem cells.

Julie, a neuroscientist by training, became fascinated by the use of social media and has done a number of studies looking at the use of social media for topics like information about aging, gene therapy and now stem cells.

Dr. Julie Robillard at ISSCR 2014.

Dr. Julie Robillard at ISSCR 2014.

She says social media is reshaping how conversations take place between people who are interested in stem cells: anyone from a scientist to a patient to a provider of sham therapies. She says there is a lot of information out there about stem cells but the quality is not always great and in some cases it’s downright questionable.

For her poster presentation, entitled Stem Cells in Social Media: Implications for Public Policy, Julie focused on Twitter and searched for key words such as “stem cell” and “spinal cord injury.”

She said the thing that surprised her most was the sheer diversity of people that were using Twitter to communicate about stem cells: people from 41 different countries with the US, Canada, the UK and Australia the top four. She says this is clear evidence there is worldwide interest in stem cell research. The problem, however, is that the quality of many of the tweets was also widely varied. Some came from researchers and were thoughtful and trying to raise awareness about new research or important questions, but others—many others—were more interested in promoting stem cells as cures for everything from sagging skin or acne to severed spinal cords.

Julie says 15 percent of tweets came from companies involved in stem cell research. In some cases they may be companies who have results about research they are doing, but in others it was to promote a product or treatment that wasn’t necessarily approved or proven. Julie says they’re quite clever about how they do it, using hashtags (i.e. #stemcells) that suggest it came from someone’s personal account rather than a business address, but they then link back to the company site.

News reports, stories in newspapers, on the radio and TV or online are the single biggest drivers of traffic on Twitter and are a reminder of the importance of good journalism when covering these issues. A poorly written or researched story that makes inflated claims about a treatment, or fails to mention that the research was done in mice not people, can get huge play on social media and mislead many people. This is a little worrying when fewer and fewer mainstream media outlets have a dedicated science journalist on staff.

Julie cautions that when you read a tweet and don’t know the person who sent it, it’s a case of buyer-beware, don’t just accept it at face value.

She also says it’s a reminder to those of us trying to inform the public about all the progress being made with stem cell research that we need to be more engaged and more active, so that our voices can help drown out those with bad information or shoddy products to sell.

Kevin McCormack

ISSCR 2014: Learning how we developed as embryos key to turning stem cells into the tissues patients need

The concept that basic lab bench science produces discoveries that eventually lead to therapies is a touchstone of the research enterprise—and the principal was front and center in the opening “presidential” plenary session of the International Society for Stem Cell Research Wednesday afternoon.

Three of the four presenters relied in part on a subset of basic biology sometimes dubbed “reverse translation.” Just as translational research takes basic discoveries and gets them ready to be potential therapies, reverse translation kicks in when animal models or human patients don’t behave the way researchers hoped based on the basic biology. So, researchers must go back to the lab to try to figure out why.

ISSCR 2014 Plenary Session

ISSCR 2014 Plenary Session

In the past couple years many teams have gone back to the bench to figure out how to get pluripotent stem cells, whether embryonic or reprogrammed iPS cells, to become adult tissues that function like their normal counterparts. While this has become relatively routine for a few cell types (most notably heart muscle), others have been quite stubborn and resisted attempts to coax them into behaving like normal adults.

Researchers therefore have turned to a type of biology that was so new when I was an undergrad that when I decided to specialize in it, the only textbooks were compilations of scientific papers. That field, known as molecular developmental biology, seeks to understand all the genetic and molecular switches at work when a fertilized egg matures into an embryo and eventually develops into a newborn organism.

I have written about the field off and on for three decades. That may seem like a long time to answer some pretty fundamental questions, but there is nothing simple about how we are made. Now, with modern genetic tools and other, almost hocus pocus lab techniques, our mysteries our relenting at a much more rapid pace.

Olivier Pourquie of Harvard detailed his work trying to get pluripotent stem cells to become the type of cell needed to repair muscle in muscular dystrophy. When he started the project no one had shown an efficient way to get these cells. So, he tried to recapitulate what happens in the early stages of a developing embryo in a lab dish. He defined three specific steps in getting to the desired muscle precursor cells, found out what genes were turned on in those steps and then set about recreating those steps in the lab. He eventually got cells to become muscle fibers that seem to contract normally in the dish. He now has a pathway to creating cells for therapy.

Gordon Keller of the McEwen Centre for Regenerative Medicine at Canada’s University Health Network talked about one of the toughest nuts to crack in this field. There is a great need for a ready source of blood-forming stem cells to use in cancer therapy. Pluripotent stem cells seem like a natural source, but no one has been able to direct them to become fully mature blood-forming systems that engraft in the test animals. So, Keller resorted to what he called ‘developmental biology in a petri dish.’ He watched for the earliest stages of creating the blood-forming cells and clearly defined how to sort out two different early stage cells. He thinks he has isolated true blood-forming stem cells. They have been transplanted into mice that had their blood systems destroyed. As he said, those mice will let us know in a few months if he succeeded.

We certainly hope Keller did it. This has been such an intractable problem, CIRM held an international workshop on the topic and produced the paper Breaking the Bottleneck: Deriving Definitive Hematopoietic Stem Cells from Human Pluripotent Stem Cells.

The last speaker, Lorenz Studer of New York’s Memorial Sloan Kettering Cancer Center talked about going back to developmental biology to get sufficient numbers of dopamine producing nerves to work in a human-sized brain robbed of those cells by Parkinson’s disease. It had turned out to be much easer to get the number of nerves needed for a pea-brained mouse. He now has a protocol for efficiently generating dopamine-producing nerves and expects to begin a clinical trial in 2017.

I suspect reverse translation in the coming years will make good use of the developmental biology I studied so long ago resulting in many more therapies ready for testing in patients.

Don Gibbons

International Stem Cell Conference Opens with Public Quest to Sort the Real from the Bogus

While the scientific sessions of the International Society for Stem Cell Research don’t begin until this morning, the meeting started last night with one of its most important events: a panel discussion for patient advocates and other members of the public. After presentations by the five speakers it became clear that the dichotomy between real stem cell therapies and bogus ones is breaking down. There is an increasingly large middle zone of potential therapies in sanctioned clinical trials that are not yet proven safe or effective, but usually have sound science behind them.

Kelly McNagny of the University of British Columbia led off talking about the various types of stem cells and noted that most of the current clinical trials involve adult, tissue specific stem cells. He detailed the many reasons why it has taken researchers so many years to bring these cells to the verge of routine clinical use. You have to learn how to efficiently grow them outside the body and get them to behave in a very specific way when they are transplanted into a patient. They have to know how to talk to and respond to the cells around them.

Doing all this, McNagny said, takes a village; a multidisciplinary team of researchers and clinicians. He also said it needed another component, vocal patient advocates to maintain financial support for the work, and to act as a liaison between the patient community and the research community. This call for an active patient community working closely with researchers became a theme for the evening.

Dr. Tim Caufield at the podium

Dr. Tim Caufield at the podium

Tim Caulfield of the University of Alberta, who leads a team conducting some of the most extensive investigation of unregulated stem cell clinics around the world, told the crowd of over 200 that patient groups will have to help educate those who are desperate for hope about the danger of some of these operations. He said he has tracked more than 700 clinics around the world offering to treat many different diseases while offering little scientific rational and no data on results other than anecdotal patient testimonials.

He said these clinics use the legitimate excitement about the potential for stem cell therapies to sell bogus treatments. He dubbed this “scienceploitation.” Their ads, he added, make the public take for granted the effectiveness of the supposed treatments.

The Q&A at the end of the session drew out some advice to help patients sort out claims they find on the internet. Much of what was said echoed advice found on the ISSCR “A Closer Look” web site and on our “Stem Cell Tourism” web page.

Don Gibbons

Stem Cell Researchers from around the Globe Converging in Vancouver with More Talk of Therapies than Ever before

The International Society for Stem Cell Research (ISSCR) officially opens its annual meeting tonight in Vancouver with a public session called “The Real Deal on Stem Cell Therapies.” These preview sessions for the public have become a tradition for the association and generally focus on helping the lay public sort out the legitimate science from the many questionable claims in the field.

The four-day scientific sessions are the largest gathering of stem cell researchers each year with more than 3,000 expected in Vancouver. It provides critical opportunities for scientists to share information and gather informally over coffee or drinks to bounce around ideas. These chats often result in collaborations that accelerate the science.

My colleague Kevin McCormack and I will be roaming the meeting looking for trends and breakthroughs in the science and writing them up quickly for this blog. The first post will be Wednesday morning reporting on tonight’s public event. Other posts are likely to cover progress toward clinical trails in Parkinson’s Disease, diabetes and spinal cord injury, among others.

Our coverage of last year’s public session is here, and one trend we spotted last year was a recognition of the vital importance of the environment where stem cells are grown if you want them to mature into the desired tissue.

Looking forward to spotting new trends over the next few days.

Don Gibbons