Stem cell stories that caught our eye: Prostate cancer and BPA, mini organs and diabetes trial

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.

Latest mini-organ, a prostate, fingers BPA. A team at the University of Illinois, at Chicago, has added the prostate gland to the growing list of “organoids” that have been grown from stem cells in the lab. The tiny gland that produces semen in men has an unusually high rate of cancer compared to other organs. Prior research has linked that cancerous nature to exposure to the hormone estrogen during fetal growth, including synthetic estrogen mimics like the chemical BPA (bisphenol A) found in many plastics.

Unlike the other organs associated with male gender, which form very early in fetal development, the prostate develops later when stem cells’ roles are more narrowly defined to creating specific tissues. The team, led by Gail Prins, had previously shown that prostate stem cells grown in the presence of BPA formed cells more likely to show signs of cancer. But that did not allow them to determine what really triggered the increase in cancer. So, they decided to grow mini prostates and look at all the cells as they developed in the organoid.

“What we were doing originally with the human prostate stem cells is we were mixing and growing them in vivo,” Prins told Medical Daily. “The idea to generate this organoid came from the first author, Esther Calderon-Gierszal; she was my graduate student. ‘They’ve done it for other organs,’ she thought. ‘Let’s try it for a prostate.’”

The researchers pushed embryonic stem cells to grow into the several different tissues found in a prostate gland using a cocktail of hormones. Although much smaller than a normal prostate the cells did self-organize into structures that resembled the gland. When they grew the organoid in the presence of BPA they found an unusually large number of prostate specific stem cells. So, it appears just the increased number of stem cells increases the likelihood a few will go bad and form cancer.

A round up of all the mini-organs. The journal Nature has written a very accessible wrap up in its news section on all the various organs that have been simulated in a lab dish since a Japanese team reported the phenomenon for the first time in 2008. After a fun lead-in explaining the science, Cassandra Willyard runs through what has been accomplished so far in the stomach, kidney, and liver.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

The fun in the opening section comes from the fact that given the right environment, stem cells are pretty darn good at self-organizing into the multiple tissue types that become a specific organ. So much so, that the early teams that saw it in the lab were shocked and did not at first know what they had.

Willyard starts with quotes from Madeline Lancaster, a post-doctoral fellow in a lab at the Institute for Molecular Biotechnology in Vienna, Austria. She found milky looking spheres in the lab cultures and when she cut into them she found multiple types of nerves. So she grabbed her mentor and reported:

“I’ve got something amazing. You’ve got to see it.”

She also discusses the work that led Hans Clevers, a researcher at Hubrecht Institute in Utrecht, the Netherlands, to report the creation of mini-guts in 20009. They grew the cells in a gel that resembled the structure that naturally surrounds cells. In this “at-home” environment stem cells formed much more complex tissue than he had hoped.

“The structures, to our total astonishment, looked like real guts,” Clevers said. “They were beautiful.”

The author also lets Clevers talk about taking his work the next step, using the gut organoids to screen for drugs for related diseases. If you have been following this work, Willyard’s piece is a must read.

Second clinical trial site for diabetes. Opening multiple clinical trial sites accelerates the process of determining whether a new therapy is safe and effective. So we were thrilled to get the announcement from ViaCyte that they would begin enrolling patients at a second location for the diabetes trial we helped them launch by funding the first clinical trial site at the University of California, San Diego.

That trial uses pancreatic cells grown from embryonic stem cells that are protected from immune attack by a semi-permeable pouch. The second site, at the University of Alberta Hospitals in Edmonton, Canada, is being funded in part by Alberta Innovates as well as by the JDRF Canadian Clinical Trials Network. JDRF also helps support the San Diego trial through its US office.

The lead researcher for the Alberta trial, James Shapiro, developed the procedure for transplanting pancreatic tissue from cadavers that became known as “the Edmonton Protocol.” That protocol has changed many lives, but because it requires life-long immunosuppression, doctors only recommend it for the most severe diabetics. The small number of donor pancreases also limits its use. Shapiro commented about the value and need for something like the ViaCyte therapy in a company press release picked up by Yahoo Finance, and dozens of other sites:

“The fact remains that new treatments are sorely needed, not only for the high risk patients but for all patients suffering from this life-altering disease.  The remarkable promise of the (ViaCyte) product candidate is that a virtually limitless source of appropriate human cells can be transplanted without the need for lifetime immunosuppression.”

Bridging the gap: training scientists to speak everyday English

Getting a start in your chosen career is never easy. Without experience it’s hard to get a job. And without a job you can’t get experience. That’s why the CIRM Bridges program was created, to help give undergraduate and Master’s level students a chance to get the experience they need to start a career in stem cell research.

Last week our governing Board approved a new round of funding for this program, ensuring it will continue for another 5 years.

But we are not looking to train just any student; we are looking to recruit and retain students who reflect the diversity of California, students who might not otherwise have a chance to work in a world-class stem cell research facility.

Want to know what that kind of student looks like? What kind of work they do? Well, the Bridges program at City College of San Francisco recently got its latest group of Bridges students to record an “elevator pitch”; that’s a short video where they explain what they do and why it’s important, in language anyone can understand.

They do a great job of talking about their research in a way that’s engaging and informative; no easy matter when you are discussing things as complex as using stem cells to test whether everyday chemicals can have a toxic impact on the developing brain, or finding ways to turn off the chromosome that causes Down’s syndrome.

Regular readers of the CIRM blog know we are huge supporters of anything that encourages scientists to be better communicators. We feel that anyone who gets public funding for their work has an obligation to be able to explain that work in words the public can understand. This is not just about being responsive, there’s also a certain amount of self-interest here. The better the public understands the work that scientists do, and how that might impact their health, the more they’ll support that work.

That’s why one of the new elements we have added to the Bridges program is a requirement for the students to engage in community outreach and education. We want them to be actively involved in educating diverse communities around California about the importance of stem cell research and the potential benefits for everyone.

We have also added a requirement for the students to be directly engaged with patients. Too often in the past students studied solely in the lab, learning the skills they’ll need for a career in science. But we want them to also understand whom these skills will ultimately benefit; people battling deadly diseases and disorders. The best way to do that is for the students to meet these people face-to-face, at a bone marrow drive or at a health fair for example.

When you have seen the face of someone in need, when you know their story, you are more motivated to find a way to help them. The research, even if it is at a basic level, is no longer about an abstract idea, it’s about someone you know, someone you have met.

Global stem cell market predicted to reach $40 billion in five years, even bigger when mixed with new technologies

The global consulting firm Frost and Sullivan held a webinar yesterday in which they noted health care systems everywhere are facing an increasing challenge of costly chronic care. They suggested health care providers have started to embrace regenerative medicine as a viable alternative.

Because of its power to change the course of disease, the consultants called regenerative medicine, and stem cell therapies in particular, a new paradigm in human health.

“Regenerative Medicine initiatives are now attracting new public and private funding,” said the firm’s Jane Andrews in a widely picked up press release, including this post at CNBC. “Although Stem Cell Therapy will continue to be the largest market segment of Regenerative Medicine, cross segment therapies that combine the use of immunology, genetic and stem cell therapy are rapidly advancing,”

CIRM funds projects in all these technologies so it is always nice to see others joining the fight. We recently posted a series of stories about our portfolio of clinical trials that combine cell therapy and gene therapy.

The report predicts the global stem cell therapy market will reach $40 billion in five years by 2020. It also suggests that just the US market will reach $180 billion by 2030.

The firm does raise a cautionary note about the inadequacy of funding for early stage clinical work with these therapies. Our President and CEO Randall Mills has also raised an alarm about this issue and called on industry to increase its support for this work.

Organized by the Asia-Pacific branch of Frost and Sullivan the webinar breaks out the markets for Japan, Korea and Singapore. The webinar itself is available on line.

Even the early worm gets old: study unlocks a key to aging

A new study poses the question, ‘When does aging really begin?’ One glance in the mirror every morning is enough for me to know that regardless of where it begins I know where it’s going. And it’s not pretty.

But enough about me. Getting back to the question about aging, two researchers at Northwestern University have uncovered some clues that may give us a deeper understanding of aging and longevity, and even lead to new ways of improving quality of life as we get older.

The researchers were focused on C. elegans, a transparent roundworm. They initially thought that aging was a gradual process: that it began slowly and then picked up pace as the animal got older. Instead they found that in C. elegans aging begins just as soon as the animal reaches reproductive maturity. It hits its peak of fertility, and it is all downhill from there.

The researchers say that once C. elegans has finished producing eggs and sperm – ensuring its line will continue – a genetic switch is thrown by germline stem cells. This flipped switch begins the aging process by turning off the ‘heat shock response’; that’s a mechanism the body uses to protect cells from conditions that would normally pose a threat or even be deadly.

In a news release Richard Morimoto, the senior author of the study, says that without that protective mechanism in place the aging process begins:

C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was. In a system where we can actually do the experiments, we discover a switch that is very precise for aging. All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses.”

You read that right. In the case of poor old C. elegans the aging process begins just eight hours into adulthood. Of course the lifespan of the worm is only about 3 weeks so it’s not surprising the aging process kicks in quite so quickly.

To further test their findings the researchers carried out an experiment where they blocked the genetic switch from flipping, and the worm’s protective mechanisms remained strong.

Now, taking findings from something as small as a worm and trying to extrapolate them to larger animals is never easy. Nonetheless understanding what triggers aging in C. elegans could help us figure out if a similar process was taking place at the cellular level in people.

Morimoto says that knowledge might help us develop ways to improve our cellular quality of life and delay the onset of many of the diseases of aging:

“Wouldn’t it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress.”

The study is published in the journal Molecular Cell.

Sonic Hedgehog provides pathway to fight blood cancers

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Dr. Catriona Jamieson:
Photo courtesy Moores Cancer Center, UCSD

For a lot of people Sonic Hedgehog is a video game. But for stem cell researcher Dr. Catriona Jamieson it is a signaling pathway in the body that offers a way to tackle and defeat some deadly blood cancers.

Dr. Jamieson – a researcher at the University of California, San Diego (UCSD) – has a paper published online today in The Lancet Haematology that highlights the safety and dosing levels for a new drug to treat a variety of blood cancers. CIRM funding helped Dr. Jamieson develop this work.

The drug targets cancer stem cells, the kind of cell that is believed to be able to lie dormant and evade anti-cancer therapies before springing back into action, causing a recurrence of the cancer. The drug coaxes the cancer stem cells out of their hiding space in the bone marrow and gets them to move into the blood stream where they can be destroyed by chemotherapy.

In a news release Dr. Jamieson says the drug – known by the catchy name of PF-04449913 – uses the sonic Hedgehog signaling pathway, an important regulator of the way we develop, to attack the cancer:

“This drug gets that unwanted house guest to leave and never come back. It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily oral tablet.”

The goal of this first-in-human study was to test the drug for safety; so 47 adults with blood and marrow cancer were given daily doses of the drug for up to 28 days. Those who were able to tolerate the dosage, without experiencing any serious side effects, were then given a higher dose for the next 28 days. Those who experienced problems were taken off the therapy.

Of the 47 people who started the trial in 2010, 28 experienced side effects. However, only three of those were severe. The drug showed signs of clinical activity – meaning it seemed to have an impact on the disease – in 23 people, almost half of those enrolled in the study.

Because of that initial promise it is now being tested in five different Phase 2 clinical trials. Dr. Jamieson says three of those trials are at UCSD:

“Our hope is that this drug will enable more effective treatment to begin earlier and that with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation. It’s all about reducing the burden of disease by intervening early.”

Improving process drives progress in stem cell research

shutterstock_212888935Process is not a sexy word. No one gets excited thinking about improving a process. Yet behind every great idea, behind every truly effective program is someone who figured out a way to improve the process, to make that idea not just work, but work better.

It’s not glamorous. Sometimes it’s not even pretty. But it is essential.

Yesterday in Oakland our governing Board approved two new concepts to improve our process, to help us fund research in a way that is faster, smarter and ultimately helps us better meet our mission of accelerating the development of stem cell therapies for patients with unmet medical needs.

The new concepts are for Discovery – the earliest stage of research – and the Translational phase, a critical step in moving promising therapies out of the lab and toward clinical trials where they can be tested in people.

In a news release C. Randal Mills, Ph.D., CIRM’s President and CEO, said that these additions built on the work started when the agency launched CIRM 2.0 in January for the clinical phase of research:

“What makes this approach different is that under CIRM 2.0 we are creating a pathway for research, from Discovery to Translational and Clinical, so that if a scientist is successful with their research at one level they are able to move that ahead into the next phase. We are not interested in research just for its own sake. We are interested in research that is going to help us help patients.”

In the Discovery program, for example, we will now be able to offer financial incentives to encourage researchers who successfully complete their work to move it along into the Translational phase – either themselves or by finding a scientific partner willing to take it up and move it forward.

This does a number of things. First it helps create a pipeline for the most promising projects so ideas that in the past might have stopped once the initial study ended now have a chance to move forward. Obviously our hope is that this forward movement will ultimately lead to a clinical trial. That won’t happen with every research program we fund but this approach will certainly increase the possibility that it might.

There’s another advantage too. By scheduling the Discovery and Translational awards more regularly we are creating a grant system that has more predictability, making it easier for researchers to know when they can apply for funding.

We estimate that each year there will be up to 50 Discovery awards worth a total of $53 million; 12 Translation awards worth a total of $40 million; and 12 clinical awards worth around $100 million. That’s a total of more than $190 million every year for research.

This has an important advantage for the stem cell agency too. We have close to $1 billion left in the bank so we want to make sure we spend it as wisely as we can.

As Jonathan Thomas, Ph.D. J.D, the Chair of our Board, said, having this kind of plan helps us better plan our financial future;

“Knowing how often these programs are going to be offered, and how much money is likely to be awarded means the Board has more information to work with in making decisions on where best to allocate our funding.”

The Board also renewed funding for both the Bridges and SPARK (formerly Creativity) programs. These are educational and training programs aimed at developing the next generation of stem cell scientists. The Bridges students are undergraduate or Master’s level students. The SPARK students are all still in high school. Many in both groups come from poor or low-income communities. This program gives them a chance to work in a world-class stem cell research facility and to think about a career in science, something that for many might have been unthinkable without Bridges or SPARK.

Process isn’t pretty. But for the students who can now think about becoming a scientist, for the researchers who can plan new studies, and for the patients who can now envision a potential therapy getting into clinical trials, that process can make all the difference.

CIRM Board meeting now underway – key votes expected on new CIRM 2.0 proposals and funding for disease research

The Board meeting is taking place at the Marriott in downtown Oakland. If you would like to hear the discussion there are a number of options:

Dial in Information:
Dial In Number: (866) 254-5938
Access Code: 365023

WebEx Link:
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To join the event as an attendee
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1. Go to https://cirm.webex.com/cirm/onstage/g.php?MTID=ee3fd12036ef7028c9f0596c3…
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We will have a full report on the meeting in Friday’s blog

Cranking up stem cell production for when therapies are approved for widespread use

Getting a cell therapy from the research bench to patients requires leaping many hurdles. Perhaps two of the highest arise when proving the potential therapy is safe enough to begin clinical trials and then when scaling up production to meet the demand of thousands of patients.

Scale up to producing the 100s of billions of cells needed to treat large groups of patients could be a roadblock for therapies.

Scale up to producing the 100s of billions of cells needed to treat large groups of patients could be a roadblock for therapies.

An even dozen CIRM-funded projects have made it over the first hurdle. No doubt those teams have begun planning for that last big jump, but in reality, in most cases the processes needed to make cells for a dozen or a few dozen patients in early trials don’t generally scale to the thousands. When you look at the number of cells needed for one heart repair, for example, around five billion, the numbers are mind bending.

Many organizations focus on this issue as their main goal looking for platforms that can help scale up production for cell therapies across many different diseases. A team at the University of Nottingham in England recently reported results from a $3.6 million project that seems to have created a sizeable piece of the solution. They developed a fully synthetic substrate, which has no chance for contamination, that can grow cells by the billion, both stem cells and the more mature cells normally desired for transplant into patients.

“The possibilities for regenerative medicine are still being researched in the form of clinical trials,” said the project leader Morgan Alexander in a university press release posted by ScienceDaily. “What we are doing here is paving the way for the manufacture of stem cells in large numbers when those therapies are proved to be safe and effective.”

The research team used a high throughput lab technique to test many materials until they finally arrived at the one they reported in the journal Advance Materials.

2,000 year old drug could fight breast cancer

Aspirin: a new option for breast cancer?

Aspirin: a new option for breast cancer?

Aspirin has been around about as long as anyone has been writing about health. Hippocrates, who was born in 460 BC and is frequently referred to as “The Father of Western Medicine”, used willow bark and leaves – which contain the active ingredients found in aspirin – to help ease pain and fevers. Now a new study says it may also be able to help people battling breast cancer.

A study in the journal Laboratory Investigation looked at the ability of acetylsalicylic acid (the chemical name for aspirin) to block the replication of cancer stem cells in breast cancer. Cancer stem cells are thought to be able to evade chemotherapy or other anti-cancer therapies and help the disease spread or metastasize throughout the body.

Sushanta Banerjee and his team at the Cancer Research Unit at the Kansas City (Mo.) Veterans Affairs Medical Center isolated breast cancer cells and then exposed half of them to varying doses of aspirin. The cells exposed to aspirin either stopped growing or died.

Working in the lab is one thing, working in animals can be something completely different, so the researchers next took 20 mice that had aggressive breast tumors. Half were given the human equivalent of a “low dose” aspirin, half received nothing. After 15 days the mice on aspirin had tumors that were almost half the size of the tumors on the non-treated mice.

But the researchers still weren’t done. They also wanted to see if aspirin could help prevent the spread of the cancer in the first place. So they worked with another group of mice: half got aspirin for ten days, the other half got nothing. The entire group was then exposed to cancer cells. After 15 days the mice on aspirin had considerably less cancer than the untreated group.

Banerjee talked about the significance of their findings in an article in Drug Discovery & Development:

“Our studies, for the first time, showed that aspirin can block the self-renewal capacity of breast cancer stem cells, and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs), which are also considered breast cancer residual cells, under tissue culture conditions. In addition, we found that aspirin-pre-exposed cells delay the formation of a palpable tumor in a xenograft mice model.  These studies suggest aspirin can prevent disease relapse, and enhance long-term survival of breast cancer patients.”

The article does discuss some of the limitations of the study – such as the dose involved, the length of follow-up and our ability to extrapolate the findings to people. And of course because of the risk of internal bleeding it’s not recommended that people just start taking aspirin without first consulting their own doctor.

Even so, Ricardo Fodde, Ph.D. an Erasmus Medical Center expert on the use of aspirin to treat cancer, says the findings are important:

“I find the general idea of using aspirin in a cancer therapeutic setting quite exciting.” Aspirin is “an extremely cheap and relatively innocuous—at least when compared with conventional cytotoxic drugs—non-steroid anti-inflammatory drug (NSAID) that possibly targets what is nowadays regarded as the beating heart of the tumor mass: cancer stem cells.”

Last November we wrote about a study showing aspirin might also be useful in fighting colon cancer. You can read about that work here.

Mini-Brains Help Unlock Autism’s Secrets

Some diseases like sickle cell anemia, an inherited blood disorder, can be traced to a single known genetic mutation. But other diseases like autism spectrum disorder (ASD), are so varied in their symptoms and severity that pinpointing the underlying cause is extremely complicated. People with autism typically have difficulties communicating with the world around them, unable to fully process both verbal and non-verbal language, and plagued by repetitive behaviors. Some rare forms of autism appear to be inherited but over 80% of cases are idiopathic, a fancy term for “we don’t know what causes it.”

Process for making organoid

Process for making organoid “mini-brains” from iPS cells derived from patient skin samples (image credit: Keval Tilva, wikipedia)

Last week, a research team at the Yale School of Medicine published data in Cell that appears to unveil some of the mystery behind autism. The scientists relied on induced pluripotent stem cells (iPS) derived from skin samples of people with severe forms of ASD. Rather than maturing the stem cells into a flat layer of brain cells, or neurons, on a plastic petri dish, the Yale team stirred the cells in a bioreactor. This technique allows the cells to mature in a small three-dimensional clump, which self organizes into so-called brain “organoids” or “mini-brains.” The structure of these mini-brains resembles the portions of the developing fetal human brain, the stage at which autism is thought to arise.

An analysis of the mini-brains found no underlying genetic mutations. Instead, the team identified genes involved with cell growth and neuron development that were turned on higher in the ASD vs. non-ASD mini-brains. A closer look at cell growth showed that inhibitory neurons, responsible for keeping nerve signals in check, were increased in number in the ASD mini-brains. Teasing out this discovery further pinpointed a protein, called FOXG1, which was responsible for the increased cell growth of the inhibitory neurons.

Fluorescent microscopy images of minibrain organoids derived from ASD patients (right) and unaffected family members (left). The red and green color indicate the increased presence of inhibitory neurons in the ASD minibrain (right). (Image credit: Mariani et al. Cell Volume 162, Issue 2, p375–390.

Fluorescent microscopy images of minibrain organoids derived from ASD patients (right) and unaffected family members (left). The red and green color indicate the increased presence of inhibitory neurons in the ASD minibrain (right). (Image credit: Mariani et al. Cell Volume 162, Issue 2, p375–390, Fig 4I.)

Here’s the interesting part if you’re still with me: of the four patient samples used in this study, higher levels of FOXG1 protein correlated with more severe ASD. And blocking the production of FOXG1 in the ASD mini-brains reduced the inhibitory neurons back to normal levels. Although this initial finding doesn’t directly link FOXG1 and autism, the results suggest a common disease mechanism: that autism may arise by over producing FOXG1 which in turn creates too many inhibitory neurons during brain development and somehow disrupts connections between neurons.

In an interview with The Scientist, CIRM-funded grantee Alysson Muotri of UCSD, who also studies autism using patient derived iPS cells, finds this possible commonality in ASD remarkable:

“These are patients with idiopathic autism that do not share any genetic causes, and yet the authors find phenotypes shared between their cells. That’s impressive. If someone had asked me, I would have said, ‘You won’t find anything in common, it’s probably going to be a mixed bag.’ But no . . . there seems to be key things that are dysregulated in all of them.”