3D Printing Cells with DNA Velcro


The complex, 3D micro-anatomy of the human liver. (Image source: WikiMedia Commons)

One of the Holy Grails of stem cell research is growing body parts to replace those damaged by disease or injury. Enormous strides have been made in a key first step: mastering recipes for maturing stem cells into various specialized cell types. But a lawn of, say, liver cells in a petri dish is not a functioning liver. Organs have complex, three-dimensional structures with intricate communication between multiple cell types.

Scientists are actively devising methods to overcome this challenge. For instance, cultivating cells onto biological scaffolds help mold the cells into the shape of a particular organ or tissue. And retooled 3D printers using “bio ink” can seed layers of different cells onto these scaffolds to create specified structures.

This week, a UCSF team added an ingenious new tool to this tissue engineering tool kit.  As reported on Monday in Nature Methods, the lab of Zev Gartner took advantage of DNA’s Velcro-like chemistry to build layers of different cell types in a specified pattern.

DNA – it’s not just for genetics anymore


A DNA fragment is made of two complimentary strands that bind together with high specificity. (Image source: Visionlearning)

DNA is a molecule made of two thin strands. Each strand is specifically attracted to the other based on a unique sequence of genetic information. So if two strands of a short DNA fragment are peeled apart, they will only rejoin to each other and not some other fragment with a different sequence.  While DNA usually resides in the nucleus of a cell, the team worked out a method to temporarily attach copies of a strand of DNA on the outside of, let’s call it, “cell A”. The opposite strand of that DNA fragment was attached to “cell B”. When mixed together the two cells became attached to each other via the matching DNA sequences. Other cells with different DNA fragments floated on by.

The screen shot below from a really neat time-lapse video, which accompanies the research publication, shows how a rudimentary 3D cell structure could be built with a series of different cell-DNA fragment combinations. In this case, the team first attached DNA fragments onto a petri dish in a specific pattern. At the thirty-second mark in the video, you can see that cells with matching DNA fragments have attached to the DNA on the dish.

Screen Shot 2015-09-02 at 8.48.16 AM

This video demonstrates the assembly of 3D cell structures with the help of DNA “Velcro” (image source: Todhunter et al. Nature Methods 2015 Aug 31st)

The new technique, dubbed DNA programmed assembly of cells (DPAC), opens up a lot possibilities according to Gartner in a UCSF press release:

 “We can take any cell type we want and program just where it goes. We can precisely control who’s talking to whom and who’s touching whom at the earliest stages. The cells then follow these initially programmed spatial cues to interact, move around, and develop into tissues over time.”

The Quest still continues with possible victories along the way

 Of course, this advance is still a far cry from the quest for whole organs derived from stem cells. The cell assemblies using DPAC can only be grown up to about 100 microns, the thickness of a human hair. Beyond that size, the innermost cells get starved of oxygen and nutrients. Gartner says that obstacle is a current focus in the lab:

“We’re working on building functional blood vessels into these tissues. We can get the right cells in the right positions but haven’t figured out how to perfuse them with blood or a substitute efficiently yet.”

In the meantime, building these small 3D “organoids” from stem cells certainly could be put to good use as a means to test drug toxicity on human tissue or as a way to study human disease.

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CIRM-funded clinical trial for spinal cord injury reports promising results

Today, the Menlo Park-based biotech company Asterias Biotherapeutics reported positive results from the first three patients treated in its Phase 1/2a clinical study using stem cell therapy to treat patients with spinal cord injury. This trial is funded by a CIRM Strategic Partnerships Award grant of $14.3 million.

asteriasAsterias has developed a stem cell therapy called AST-OPC1 that uses oligodendrocyte progenitor cells (OPCs), a kind of cell found in the nervous system, to treat patients that have suffered from different types of spinal cord injury. Damage to the spinal cord causes a range of paralysis based on where it occurs. People with spinal cord trauma to the mid-back often retain the use of their hands and arms but can no longer walk and may lose bladder function. Patients with spinal cord injuries in their neck  can be paralyzed completely from their neck down.

astopc1OPCs are precursors to an important cell type in the central nervous system called the oligodendrocyte. These cells are responsible for forming a conductive sheet around nerve cells that allows nerves to send electrical signals and messages safely from one nerve to another. Both OPCs and oligodendrocytes provide support and protection to nerves in the spinal cord and brain, and they can also facilitate repair of damaged nerves by secreting survival and growth factors as well as promoting the formation of new blood vessels.

In this first part of the Phase 1/2a clinical trial three patients with complete cervical (neck) spinal cord injuries were given a “low dose” of two million AST-OPC1 cells to test the safety and feasibility of their stem cell treatment. The first patient was treated at the Shepard Center in Atlanta,  and at the two month post-injection assessment, the patient experienced no side effects and an improvement from a complete to an incomplete injury on the ASIA impairment injury scale. The other two patients received injections at the Rush University Medical Center in Chicago. Both procedures were reported to have gone smoothly, and the patients are still being monitored.

Asterias plans to treat a second group of patients with higher doses of AST-OPC1 cells (10-20 millions cells). Chief Medical Officer Dr. Edward Wirth explained their strategy:

 The safety data in the first cohort now paves the way for testing the higher doses of AST-OPC1 (10-20 million cells) that we believe correspond most closely to the doses that showed the greatest efficacy in animal studies.

If both the low dose and high dose groups report no serious side effects, Asterias will turn to the Food and Drug Administration (FDA) for approval to expand the patient population of this clinical trial phase from 13 patients up to 40. Asterias hopes that adding more patients “will increase the statistical confidence of the safety and efficacy readouts, reduce the risks of the AST-OPC1 program and position the product for potential accelerated regulatory approvals.”

Spinal cord injury affects more than 12,000 people every year. It remains a major unmet medical need without any FDA-approved therapies or medical devices that improve or restore patient spinal cord function. CIRM is hopeful that Asterias will continue to see positive results with the SCiStar trial and will be able to progress its AST-OPC1 program into late-stage clinical trials and eventually into an FDA-approved stem cell therapy for spinal cord injury.

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Cell mate: the man who makes stem cells for clinical trials

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.

Da Mayor and the clinical trial that could help save his vision

Former San Francisco Mayor and California State Assembly Speaker Willie Brown is many things, but shy is not one of them. A profile of him in the San Francisco Chronicle once described him as “Brash, smart, confident”. But for years Da Mayor – as he is fondly known in The City – said very little about a condition that is slowly destroying his vision. Mayor Brown has retinitis pigmentosa (RP).

RP is a degenerative disease that slowly destroys a person’s sight vision by attacking and destroying photoreceptors in the retina, the light-sensitive area at the back of the eye that is critical for vision. At a recent conference held by the Everylife Foundation for Rare Diseases, Mayor Brown gave the keynote speech and talked about his life with RP.

Willie Brown

He described how people thought he was being rude because he would walk by them on the streets and not say hello. The truth is, he couldn’t see them.

He was famous for driving fancy cars like Bentleys, Maseratis and Ferraris. When he stopped doing that, he said, “people thought I was broke because I no longer had expensive cars.” The truth is his vision was too poor for him to drive.

Despite its impact on his life RP hasn’t slowed Da Mayor down, but now there’s a new clinical trial underway that might help him, and others like him, regain some of that lost vision.

The trial is the work of Dr. Henry Klassen at the University of California, Irvine (UCI). Dr. Klassen just announced the treatment of their first four patients, giving them stem cells that hopefully will slow down or even reverse the progression of RP.

“We are delighted to be moving into the clinic after many years of bench research,” Klassen said in a news release.

The patients were each given a single injection of retinal progenitor cells. It’s hoped these cells will help protect the photoreceptors in the retina that have not yet been damaged by RP, and even revive those that have become impaired but not yet destroyed by the disease.

The trial will enroll 16 patients in this Phase 1 trial. They will all get a single injection of retinal cells into the eye most affected by the disease. After that, they’ll be followed for 12 months to make sure that the therapy is safe and to see if it has any beneficial effects on vision in the treated eye, compared to the untreated one.

In a news release Jonathan Thomas, Ph.D., J.D., Chair of the CIRM Board said it’s always exciting when a therapy moves out of the lab and into people:

“This is an important step for Dr. Klassen and his team, and hopefully an even more important one for people battling this devastating disease. Our mission at CIRM is to accelerate the development of stem cell therapies for patients with unmet medical needs, and this certainly fits that bill. That’s why we have invested almost $19 million in helping this therapy reach this point.”

RP hasn’t defeated Da Mayor. Willie Brown is still known as a sharp dresser and an even sharper political mind. His message to the people at the Everylife Foundation conference was, “never give up, keep striving, keep pushing, keep hoping.”

To learn more about the study or to enroll contact the UCI Alpha Stem Cell Clinic at 949-824-3990 or by email at stemcell@uci.edu.

And visit our website to watch a presentation about the trial (link) by Dr. Klassen and to hear brief remarks from one of his patients.

Going back to figure out how the embryo makes muscles led team to way to mass produce muscle fibers

Sometimes in science what seems like the simpler task turns out to be the hardest. We have written extensively about research teams building mini-organs in lab dishes turning stem cells into multiple layers of tissues organized and functioning, at least in part, like the kidney, liver or stomach they mimic. Given these successes and the relative simplicity of our muscles, you would have thought we would have petri dishes with bulging biceps by now. We don’t. But a team at Harvard and Brigham and Women’s hospital has made a major stride toward that goal.

Smooth muscle cells grown from embryonic stem cells (courtesy Sanford-Burnham Institute).

Smooth muscle cells grown from embryonic stem cells (courtesy Sanford-Burnham Institute).

While previous work has created small amounts of short muscle fibers from stem cells, the Brigham group created large quantities of millimeter-long muscle fibers. This level of muscle development could produce therapeutic quantities of new muscle that would be needed to treat patients with muscular dystrophy. This goal has sent many teams back to the lab looking for better ways to direct stem cells to become muscle.

The current work, published this week in Nature Biotechnology, went back to the basics and tried to understand each step that a stem cell goes through on the way to becoming muscle in the embryo. Medical Daily wrote a piece on the work, and used a quote in the Brigham press release from the senior author Olivier Pourquie:

“We analyzed each stage of early development and generated cell lines that glowed green when they reached each stage. Going step by step, we managed to mimic each stage of development and coax cells toward muscle cell fate.”

Stem cell scientist often find that going back to learn and mimic the natural steps of development works better than guessing what factors are most important in a cell’s fate. Now that they hold a map to the path between stem cell and muscle fibers, they can use it to study many different muscle diseases and work toward therapies for those often-untreatable conditions.

“This has been the missing piece: the ability to produce muscle cells in the lab could give us the ability to test out new treatments and tackle a spectrum of muscle diseases,” Pourquie said.

CIRM funds a dozen projects working to understand and develop therapies for muscle disease.

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.

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.

Pushing, pulling and dragging stem cell research forward

Government agencies are known for many things, but generally speaking a willingness to do some voluntary, deep self-examination is not one of them. However, for the last few weeks CIRM has been doing a lot of introspection as we develop a new Strategic Plan, a kind of road map for where we are heading.

Patient Advocate meeting in Los Angeles: Photo courtesy Cristy Lytal USC

Patient Advocate meeting in Los Angeles:
Photo courtesy Cristy Lytal USC

But we haven’t been alone. We’ve gone to San Diego, Los Angeles and San Francisco to talk to Patient Advocates in each city, to get their thoughts on what we need to focus on for the future. Why Patient Advocates? Because they are the ones with most skin in the game. They are why we do this work so it’s important they have a say in how we do it.

As Chris Stiehl, a Patient Advocate for type 1 diabetes, said in San Diego: “Let the patient be in the room, let them be part of the conversation about these therapies. They are the ones in need, so let them help make decisions about them right from the start, not at the end.”

A Strategic Plan is, on the surface, a pretty straightforward thing to put together. You look at where you are, identify where you want to go, and figure out the best way to get from here to there. But as with many things, what seems simple on the surface often turns out to be a lot more complicated when looked at in more depth.

The second bit, figuring out where you want to go, is easy. We want to live up to our mission of accelerating the development of stem cells therapies to patients with unmet medical needs. We don’t want to be good at this. We want to be great at this.

Dr. C. Randal Mills talking to Patient Advocates in LA: Photo courtesy Cristy Lytal, USC

Dr. C. Randal Mills talking to Patient Advocates in LA: Photo courtesy Cristy Lytal, USC

The first part, seeing where you are, is a little tougher: it involves what our President and CEO, Dr. Randy Mills, “confronting some brutal facts”, being really honest in assessing where you are because without that honesty you can’t achieve anything.

So where are we as an agency? Well, we have close to one billion dollars left in the bank, we have 12 projects in clinical trials and more on the way, we have helped advance stem cells from a fledgling field to a science on the brink of what we hope will be some remarkable treatments, and we have a remarkable team ready to help drive the field still further.

But how do we do that, how do we identify the third part of the puzzle, getting from where we are to where we want to be? CIRM 2.0 is part of the answer – developing a process to fund research that is easier, faster and more responsive to the needs of the scientists and companies developing new therapies. But that’s just part of the answer.

Some of the Patient Advocates asked if we considered focusing on just a few diseases, such as the ten largest killers of Americans, and devoting our remaining resources to fixing them. And the answer is yes, we looked at every single option. But we quickly decided against that because, as Randy Mills said:

“This is not a popularity contest, you can’t judge need by numbers, deciding the worth of something by how many people have it. We are disease agnostic. What we do is find the best science, and fund it.”

Another necessary element is developing better ways to attract greater investment from big pharmaceutical companies and venture capital to really help move the most promising projects through clinical trials and into patients. That is starting to happen, not as fast as we would like, but as our blog yesterday shows things are moving in this direction.

And the third piece of the pie is getting these treatments through the regulatory process, getting the Food and Drug Administration (FDA) to approve therapies for clinical trials. And this last piece clearly hit a nerve.

Many Patient Advocates expressed frustration at the slow pace of approval for any therapy by the FDA, some saying it felt like they just kept piling up obstacles in the way.

Dr. Mills said the FDA is caught between a rock and a hard place; criticized if it approves too slowly and chastised if it approves too fast, green lighting a therapy that later proves to have problems. But he agreed that changes are needed:

“The regulatory framework works well for things like drugs and small molecules that can be taken in pills but it doesn’t work well for cellular therapies like stem cells. It needs to do better at that.”

One Advocate suggested a Boot Camp for researchers, drilling them in the skills they’ll need to get FDA approval. Others suggested applying political pressure from Patient Advocacy groups to push for change.

As always there are no easy answers, but the meeting certainly raised many great questions. Those are all helping us focus our thinking on what needs to be in the Strategic Plan.

Randy ended the Patient Advocate events by saying the stem cell agency “is in the time business. What we do is time sensitive.” For too many people that time is already running out. We have to do everything we can to change that.

Two studies show genes and their switches critical to brain cancer’s resistance to therapy

Two California teams discovered genetic machinery that cancer stem cells in high-grade brain cancers use to evade therapy. One CIRM-funded team at Cedars-Sinai in Los Angeles pinpointed a family of genes that turn off other genes that chemotherapy targets —effectively hiding them from the chemo. The other team at the University of California, San Diego (UCSD), found a culprit switch among the molecules that surround genes in the DNA.

Chemical switches like those found at UCSD control much of how our cells function. These so called epigenetic markers can toggle between on and off states and result in two cells with the same genes behaving differently. That is what the San Diego team found when they transplanted cells from the same glioblastoma brain cancer into different mice. Some readily formed new tumors and some did not.

“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen. “This plasticity represents a mechanism by which glioblastoma develops resistance to therapy.”

The switch the cancer stem cells used in this case is called LSD1 and the researchers hope to be able to learn how to manipulate that switch to make the brain cancer stem cells more vulnerable to therapy.

Brain caner cells (left) that don’t readily form new tumors can spontaneously acquire cancer stem cell characteristics (right).

Brain caner cells (left) that don’t readily form new tumors can spontaneously acquire cancer stem cell characteristics (right).

The family of genes fingered by the Cedars team control the on-off status of a number of genes associated with cancer stem cells. That family, called Ets factors, is quite large but the brain tumor model used by the team allows them to quickly determine which genes are being impacted by the Ets factors.

“The ability to rapidly model unique combinations of driver mutations from a patient’s tumor enhances our quest to create patient-specific animal models of human brain tumors,” said Moise Danielpour the senior author on the study

The team’s next step: testing the function of the various Ets factors to see what their specific roles are in tumor progression.

Given the dismal five-year survival rate for high-grade brain cancers these advances in understanding their genetic machinery should push the field toward better therapy.

The Cedars team published in the journal Cell Reports and Health Canal picked up the hospital’s press release. The UCSD team published in the Proceedings of the National Academy of Sciences and Science Daily picked up the university’s press release. CIRM funds a number of projects working on new therapies for brain cancer.