Curing the Incurable through Definitive Medicine

“Curing the Incurable”. That was the theme for the first annual Center for Definitive and Curative Medicine (CDCM) Symposium held last week at Stanford University, in Palo Alto, California.

The CDCM is a joint initiative amongst Stanford Healthcare, Stanford Children’s Health and the Stanford School of Medicine. Its mission is to foster an environment that accelerates the development and translation of cell and gene therapies into clinical trials.

The research symposium focused on “the exciting first-in-human cell and gene therapies currently under development at Stanford in bone marrow, skin, cardiac, neural, pancreatic and neoplastic diseases.” These talks were organized into four different sessions: cell therapies for neurological disorders, stem cell-derived tissue replacement therapies, genome-edited cell therapies and anti-cancer cell-based therapies.

A few of the symposium speakers are CIRM-funded grantees, and we’ll briefly touch on their talks below.

Targeting cancer

The keynote speaker was Irv Weissman, who talked about hematopoietic or blood-forming stem cells and their value as a cell therapy for patients with blood disorders and cancer. One of the projects he discussed is a molecule called CD47 that is found on the surface of cancer cells. He explained that CD47 appears on all types of cancer cells more abundantly than on normal cells and is a promising therapeutic target for cancer.

Irv Weissman

Irv Weissman

“CD47 is the first gene whose overexpression is common to all cancer. We know it’s molecular mechanism from which we can develop targeted therapies. This would be impossible without collaborations between clinicians and scientists.”

 

At the end of his talk, Weissman acknowledged the importance of CIRM’s funding for advancing an antibody therapeutic targeting CD47 into a clinical trial for solid cancer tumors. He said CIRM’s existence is essential because it “funds [stem cell-based] research through the [financial] valley of death.” He further explained that CIRM is the only funding entity that takes basic stem cell research all the way through the clinical pipeline into a therapy.

Improving bone marrow transplants

judith shizuru

Judith Shizuru

Next, we heard a talk from Judith Shizuru on ways to improve current bone-marrow transplantation techniques. She explained how this form of stem cell transplant is “the most powerful form of cell therapy out there, for cancers or deficiencies in blood formation.” Inducing immune system tolerance, improving organ transplant outcomes in patients, and treating autoimmune diseases are all applications of bone marrow transplants. But this technique also carries with it toxic and potentially deadly side effects, including weakening of the immune system and graft vs host disease.

Shizuru talked about her team’s goal of improving the engraftment, or survival and integration, of bone marrow stem cells after transplantation. They are using an antibody against a molecule called CD117 which sits on the surface of blood stem cells and acts as an elimination signal. By blocking CD117 with an antibody, they improved the engraftment of bone marrow stem cells in mice and also removed the need for chemotherapy treatment, which is used to kill off bone marrow stem cells in the host. Shizuru is now testing her antibody therapy in a CIRM-funded clinical trial in humans and mentioned that this therapy has the potential to treat a wide variety of diseases such as sickle cell anemia, leukemias, and multiple sclerosis.

Tackling stroke and heart disease

img_1327We also heard from two CIRM-funded professors working on cell-based therapies for stroke and heart disease. Gary Steinberg’s team is using human neural progenitor cells, which develop into cells of the brain and spinal cord, to treat patients who’ve suffered from stroke. A stroke cuts off the blood supply to the brain, causing the death of brain cells and consequently the loss of function of different parts of the body.  He showed emotional videos of stroke patients whose function and speech dramatically improved following the stem cell transplant. One of these patients was Sonia Olea, a young woman in her 30’s who lost the ability to use most of her right side following her stroke. You can read about her inspiring recover post stem cell transplant in our Stories of Hope.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Joe Wu followed with a talk on adult stem cell therapies for heart disease. His work, which is funded by a CIRM disease team grant, involves making heart cells called cardiomyocytes from human embryonic stem cells and transplanting these cells into patient with end stage heart failure to improve heart function. His team’s work has advanced to the point where Wu said they are planning to file for an investigational new drug (IND) application with the US Food and Drug Administration (FDA) in six months. This is the crucial next step before a treatment can be tested in clinical trials. Joe ended his talk by making an important statement about expectations on how long it will take before stem cell treatments are available to patients.

He said, “Time changes everything. It [stem cell research] takes time. There is a lot of promise for the future of stem cell therapy.”

California’s stem cell agency rounds up the year with two more big hits

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CIRM Board meeting with  Jake Javier, CIRM Chair Jonathan Thomas, Vice Chair Sen. Art Torres (Ret.) and President/CEO Randy Mills

It’s traditional to end the year with a look back at what you hoped to accomplish and an assessment of what you did. By that standard 2016 has been a pretty good year for us at CIRM.

Yesterday our governing Board approved funding for two new clinical trials, one to help kidney transplant patients, the second to help people battling a disease that destroys vision. By itself that is a no small achievement. Anytime you can support potentially transformative research you are helping advance the field. But getting these two clinical trials over the start line means that CIRM has also met one of its big goals for the year; funding ten new clinical trials.

If you had asked us back in the summer, when we had funded only two clinical trials in 2016, we would have said that the chances of us reaching ten trials by the end of the year were about as good as a real estate developer winning the White House. And yet……..

Helping kidney transplant recipients

The Board awarded $6.65 million to researchers at Stanford University who are using a deceptively simple approach to help people who get a kidney transplant. Currently people who get a transplant have to take anti-rejection medications for the rest of their life to prevent their body rejecting the new organ. These powerful immunosuppressive medications are essential but also come with a cost; they increase the risk of cancer, infection and heart disease.

icoc_dec2016-3

CIRM President/CEO Randy Mills addresses the CIRM Board

The Stanford team will see if it can help transplant patients bypass the need for those drugs by injecting blood stem cells and T cells (which play an important role in the immune system) from the kidney donor into the kidney recipient. The hope is by using cells from the donor, you can help the recipient’s body more readily adjust to the new organ and reduce the likelihood the body’s immune system will attack it.

This would be no small feat. Every year around 17,000 kidney transplants take place in the US, and many people who get a donor kidney experience fevers, infections and other side effects as a result of taking the anti-rejection medications. This clinical trial is a potentially transformative approach that could help protect the integrity of the transplanted organ, and improve the quality of life for the kidney recipient.

Fighting blindness

The second trial approved for funding is one we are already very familiar with; Dr. Henry Klassen and jCyte’s work in treating retinitis pigmentosa (RP). This is a devastating disease that typically strikes before age 30 and slowly destroys a person’s vision. We’ve blogged about it here and here.

Dr. Klassen, a researcher at UC Irvine, has developed a method of injecting what are called retinal progenitor cells into the back of the eye. The hope is that these cells will repair and replace the cells damaged by RP. In a CIRM-funded Phase 1 clinical trial the method proved safe with no serious side effects, and some of the patients also reported improvements in their vision. This raised hopes that a Phase 2 clinical trial using a larger number of cells in a larger number of patients could really see if this therapy is as promising as we hope. The Board approved almost $8.3 million to support that work.

Seeing is believing

How promising? Well, I recently talked to Rosie Barrero, who took part in the first phase clinical trial. She told me that she was surprised how quickly she started to notice improvements in her vision:

“There’s more definition, more colors. I am seeing colors I haven’t seen in years. We have different cups in our house but I couldn’t really make out the different colors. One morning I woke up and realized ‘Oh my gosh, one of them is purple and one blue’. I was by myself, in tears, and it felt amazing, unbelievable.”

Amazing was a phrase that came up a lot yesterday when we introduced four people to our Board. Each of the four had taken part in a stem cell clinical trial that changed their lives, even saved their lives. It was a very emotional scene as they got a chance to thank the group that made those trials, those treatments possible.

We’ll have more on that in a future blog.

 

 

 

 

How stem cells are helping change the face of medicine, one pioneering patient at a time

One of the many great pleasures of my job is that I get to meet so many amazing people. I get to know the researchers who are changing the face of medicine, but even more extraordinary are the people who are helping them do it, the patients.

Attacking Cancer

Karl

Karl Trede

It’s humbling to meet people like Karl Trede from San Jose, California. Karl is a quiet, witty, unassuming man who when the need arose didn’t hesitate to put himself forward as a medical pioneer.

Diagnosed with throat cancer in 2006, Karl underwent surgery to remove the tumor. Several years later, his doctors told him it had returned, only this time it had spread to his lungs. They told him there was no effective treatment. But there was something else.

“One day the doctor said we have a new trial we’re going to start, would you be interested? I said “sure”. I don’t believe I knew at the time that I was going to be the first one, but I thought I’d give it a whirl.”

Karl was Patient #1 in a clinical trial at Stanford University that was using a novel approach to attack cancer stem cells, which have the ability to evade standard anti-cancer treatments and cause the tumors to regrow. The team identified a protein, called CD47, that sits on the surface of cancer stem cells and helps them evade being gobbled up and destroyed by the patient’s own immune system. They dubbed CD47 the “don’t eat me” signal and created an antibody therapy they hoped would block the signal, leaving the cancer and the cancer stem cells open to attack by the immune system.

The team did pre-clinical testing of the therapy, using mice to see if it was safe. Everything looked hopeful. Even so, this was still the first time it was being tested in a human. Karl said that didn’t bother him.

“It was an experience for me, it was eye opening. I wasn’t real concerned about being the first in a trial never tested in people before. I said we know that there’s no effective treatment for this cancer, it’s not likely but it’s possible that this could be the one and if nothing else, if it doesn’t do anything for me hopefully it does something so they learn for others.”

It’s that kind of selflessness that is typical of so many people who volunteer for clinical trials, particularly Phase 1 trials, where a treatment is often being tried in people for the first time ever. In these trials, the goal is to make sure the approach is safe, so patients are given a relatively small dose of the therapy (cells or drugs) and told ahead of time it may not do any good. They’re also told that there could be some side effects, potentially serious, even life-threatening ones. Still, they don’t hesitate.

Improving vision

Rosie Barrero certainly didn’t hesitate when she got a chance to be part of a clinical trial testing the use of stem cells to help people with retinitis pigmentosa, a rare progressive disease that destroys a person’s vision and ultimately leaves them blind.

Rosalinda Barrero

Rosie Barrero

“I was extremely excited about the clinical trial. I didn’t have any fear or trepidation about it, I would have been happy being #1, and I was #6 and that was fine with me.”

 

Rosie had what are called retinal progenitor cells injected into her eye, part of a treatment developed by Dr. Henry Klassen at the University of California, Irvine. The hope was that those cells would help repair and perhaps even replace the light-sensing cells damaged by the disease.

Following the stem cell treatment, gradually Rosie noticed a difference. It was small things at first, like being able to make out the colors of cups in her kitchen cupboard, or how many trash cans were outside their house.

“I didn’t expect to see so much, I thought it would be minor, and it is minor on paper but it is hard to describe the improvement. It’s visible, it’s visible improvement.”

These are the moments that researchers like Henry Klassen live for, and have worked so tirelessly for. These are the moments that everyone at CIRM dreams of, when the work we have championed, supported and funded shows it is working, shows it is changing people’s lives.

One year ago this month our governing Board approved a new Strategic Plan, a detailed roadmap of where we want to go in the coming years. The plan laid out some pretty ambitious goals, such as funding 50 new clinical trials in the next 5 years, and at our Board meeting next week we’ll report on how well we are doing in terms of hitting those targets.

People like Karl and Rosie help motivate us to keep trying, to keep working as hard as we can, to achieve those goals. And if ever we have a tough day, we just have to remind ourselves of what Rosie said when she realized she could once again see her children.

“Seeing their faces. It’s pretty incredible. I always saw them with my heart so I just adore them, but now I can see them with my eye.”


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Stem cell agency funds clinical trials in three life-threatening conditions

strategy-wide

A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Stem cell stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

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.

zika

Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

jlo

Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”

 

New approach could help turn back the clock and reverse damage for stroke patients

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Stroke: courtesy WebMD

Stroke is the leading cause of serious, long-term disability in the US. Every year almost 800,000 people suffer from a stroke. The impact on their lives, and the lives of those around them can be devastating.

Right now the only treatment approved by the US Food and Drug Administration (FDA) is tissue plasminogen activator or tPA. This helps dissolve the blood clot causing most strokes and restores blood flow to the brain. However, to be fully effective this has to be administered within about 3-4 hours after the stroke. Many people are unable to get to the hospital in time and as a result suffer long-term damage, damage that for most people has been permanent.

But now a new study in Nature Medicine shows that might not be the case, and that this damage could even be reversible.

The research, done by a team at the University of Southern California (USC) uses a one-two punch combination of stem cells and a protein that helps those cells turn into neurons, the cells in the brain damaged by a stroke.

First, the researchers induced a stroke in mice and then transplanted human neural stem cells alongside the damaged brain tissue. They then added in a dose of the protein 3K3A-APC or a placebo.

hey found that mice treated with 3K3A-APC had 16 times more human stem-cell derived neurons than the mice treated with the placebo. Those neurons weren’t just sitting around doing nothing. USC’s Berislav Zlokovic, senior author of the paper, says they were actively repairing the stroke-induced damage.

“We showed that 3K3A-APC helps the grafted stem cells convert into neurons and make structural and functional connections with the host’s nervous system. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies. Functional deficits after five weeks of stroke were minimized, and the mice were almost back to normal in terms of motor and sensorimotor functions. Synapses formed between transplanted cells and host cells, so there is functional activation and cooperation of transplanted cells in the host circuitry.”

The researchers wanted to make sure the transplanted cell-3K3A-ACP combination was really the cause of the improvement in the mice so they then used what’s called an “assassin toxin” to kill the neurons they had created. That reversed the improvements in the treated mice, leaving them comparable to the untreated mice. All this suggests the neurons had become an integral part of the mouse’s brain.

So how might this benefit people? You may remember that earlier this summer Stanford researchers produced a paper showing they had helped some 18 stroke patients, by injecting stem cells from donor bone marrow into their brain. The improvements were significant, including in at least one case regaining the ability to walk. We blogged about that work here

In that study, however, the cells did not become neurons nor did they seem to remain in the brain for an extended period. It’s hoped this new work can build on that by giving researchers an additional tool, the 3K3A-ACP protein, to help the transplanted cells convert to neurons and become integrated into the brain.

One of the other advantages of using this protein is that it has already been approved by the FDA for use in people who have experienced an ischemic stroke, which accounts for about 87 percent of all strokes.

The USC team now hope to get approval from the FDA to see if they can replicate their experiences in mice in people, through a Phase 2 clinical trial.

 

 

 

 

 

 

 

Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


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Helping stem cells sleep can boost their power to heal

Mouse muscle

Mighty mouse muscle cells

We are often told that sleep is one of the most important elements of a healthy lifestyle, that it helps in the healing and repair of our heart and blood vessels – among other things.

It turns out that sleep, or something very similar, is equally important for stem cells, helping them retain their power or potency, which is a measure of their effectiveness and efficiency in generating the mature adult cells that are needed to repair damage. Now researchers from Stanford, with a little help from CIRM, have found a way to help stem cells get the necessary rest before kicking in to action. This could pave the way for a whole new approach to treating a variety of genetic disorders such as muscular dystrophy.

Inside out

One problem that has slowed down the development of stem cell therapies has been the inability to manipulate stem cells outside of the body, without reducing their potency. In the body these cells can remain quiescent or dormant for years until called in to action to repair an injury. That’s because they are found in a specialized environment or niche, one that has very particular physical, chemical and biological properties. However, once the stem cells are removed from that niche and placed in a dish in the lab they become active and start proliferating and changing into other kinds of cells.

You might think that’s good, because we want those stem cells to change and mature, but in this case we don’t, at least not yet. We want them to wait till we return them to the body to do their magic. Changing too soon means they have less power to do that.

Researchers at Stanford may have found a way to stop that happening, by creating an environment in the lab that more closely resembles that in the body, so the stem cells remain dormant longer.

As senior author, Thomas Rando, said in a Stanford news release, they have found a way to keep the stem cells dormant longer:

Dr. Thomas Rando, Stanford

Dr. Thomas Rando, Stanford

“Normally these stem cells like to cuddle right up against their native muscle fibers. When we disrupt that interaction, the cells are activated and begin to divide and become less stemlike. But now we’ve designed an artificial substrate that, to the cells, looks, smells and feels like a real muscle fiber. When we also bathe these fibers in the appropriate factors, we find that the stem cells maintain high-potency and regenerative capacity.”

Creating an artificial home

When mouse muscle stem cells (MuSCs) are removed from the mouse they lose their potency after just two days. So the Stanford team set out to identify what elements in the mouse niche helped the cells remain dormant. They identified the molecular signature of the quiescent MuSCs and used that to help screen different compounds to see which ones could help keep those cells dormant, even after they were removed from the mouse and collected in a lab dish.

They whittled down the number of potential compounds involved in this process from 50 to 10, and then tested these in different combinations until they found a formulation that kept the stem cells quiescent for at least 2 days outside of the mouse.

But that was just the start. Next they experimented with different kinds of engineered muscle fibers, to simulate the physical environment inside the mouse niche. After testing various materials, they found that the one with the greatest elasticity was the most effective and used that to create a kind of scaffold for the stem cells.

The big test

The artificial niche they created clearly worked in helping keep the MuSCs in a dormant state outside of the mouse. But would they work when transplanted back into the mouse? To answer this question they tested these stem cells to see if they retained their ability to self-renew and to change into other kinds of cells in the mouse. The good news is they did, and were far more effective at both than MuSCs that had not been stored in the artificial niche.

So, great news for mice but what about people, would this same approach work with human muscle stem cells (hMuSCs)? They next tested this approach using hMuSCs and found that the hMuSCs cultured on the artificial niche were more effective at both self-renewal and retaining their potency than hMuSCs kept in more conventional conditions, at least in the lab.

In the study, published in the journal Nature Biotechnology, the researchers say this finding could help overcome some of the challenges that have slowed down the development of effective therapies:

“Research on MuSCs, hematopoietic stem cells and neural stem cells has shown that very small numbers of quiescent stem cells, even single cells, can replace vast amounts of tissue; culture systems that that maintain stem cell quiescence may allow these findings to be translated to clinical practice. In addition, the possibility of culturing hMuSCs for longer time periods without loss of potency in order to correct mutations associated with genetic disorders, such as muscular dystrophy, followed by transplantation of the corrected cells to replace the pathogenic tissue may enable improved stem cell therapeutics for muscle disorders.”

Glimpse the future at a fun-filled Festival of Science

Hands-on science and fun

Hands-on science and fun

Imagine a giant circus but instead of performing animals you have a Robot Zoo; instead of scary clowns you have colorful chemicals in glass beakers. That’s what AT&T Park will look like this Saturday when the 5th Annual Discovery Day opens its doors.  It’s a hands-on, eye-opening, brain-engaging celebration of science for everyone.

It’s a lot of fun

You’ll get a chance to learn about the science of sports – an appropriate subject as you’ll be doing it at the home of the 3-time World Champions of baseball, the San Francisco Giants. You’ll also be able to experience some of the training it takes to become an astronaut, without any of that pesky going-into-space business.

All in all you’ll be able to visit more than 150 hands-on exhibits and activities spread throughout the park, put together by the top science organizations, institutions and companies from all over the Bay Area. We’re talking Stanford University, UCSF, The Tech Museum, the Exploratorium, KQED, US Geological Society and the list goes on and on.

Meet the future right now

Today's scientists inspiring tomorrow's

Today’s scientists inspiring tomorrow’s

You’ll get to meet the scientists who are exploring outer space and the depths of the ocean, who are doing cutting edge research into health and who are pushing the boundaries of scientific knowledge.

And you will get a chance to meet us, the CIRM Team. We’re going to be there all day talking about the exciting progress being made in the field of stem cell research, and about the 15 clinical trials we are currently funding in heart disease, diabetes, cancer, HIV/AIDS and blindness (to name just a few).

You can find us on the Promenade level at booth P50. We’re easy to spot. We’re the coolest ones around. And if you have kids who enjoy PlayDoh, we will give them a chance to use the fun stuff to make stem cells.

But best of all Discovery Day is a chance for kids to learn how amazing science can be, to meet the scientists who are helping shape their future, and to consider a future as scientists themselves. And for the rest of us, it’s a chance to remind ourselves why we fell in love with science to start with.

And as if that wasn’t enough, the whole shebang is FREE.

The event is this Saturday, November 7 from 10am – 4pm. For details on where it is and how to get there – go to Discovery Day

Fun on the field at AT&T Park

Fun on the field at AT&T Park

CIRM-funded team traces molecular basis for differences between human and chimp face

So similar yet so different
Whenever I go to the zoo, I could easily spend my entire visit hanging out with our not-so-distant relatives, the chimpanzees. To say we humans are similar to them is quite an understatement. Sharing 96% of our DNA, chimps are more closely related to us than they are to gorillas. And when you just compare our genes – that is, the segments of DNA that contain instructions for making proteins – we’re even more indistinguishable.

Chimps and Humans: So similar yet so different

Chimps and Humans: So similar yet so different

And yet you wouldn’t mistake a human for a chimp. I mean, I do have hairy arms, but they’re not that hairy. So what accounts for our very different appearance if our genes are so similar?

To seek out answers, a CIRM-funded team at Stanford University used both human and chimp induced pluripotent stem cells (iPSCs) to derive cranial neural crest cells (CNCCs). This cell type plays a key role in shaping the overall structure of the face during the early stages of embryo development. In a report published late last week in Cell, the team found differences, not in the genes themselves, but in gene activity between the human and chimp CNCCs.

Enhancers: Volume controls for your genes
Pinpointing the differences in gene activity relied on a comparative analysis of so-called enhancer regions of human and chimp DNA. Unlike genes, the enhancer regions of DNA do not provide instructions for making proteins. Instead they dictate how much protein to make by acting like volume control knobs for specific genes. A particular volume level, or gene activity, is determined by specific combinations of chemical tags and DNA-binding proteins on an enhancer region of DNA.

Enhancers: DNA segments that act like a volume control know for gene activity (Image source: xxxx)

Enhancers: DNA segments that act like a volume control knobs for gene activity (Image source: FANTOM Project, University of Copenhagen)

The researchers used several sophisticated lab techniques to capture a snapshot of this enhancer tagging and binding in the CNCCSs. They mostly saw similarities between human and chimp enhancers but, as senior author Joanna Wysocka explains in a Stanford University press release, they did uncover some differences:

“In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development.”

PAX Humana: A genetic basis for our smaller jawline and snout?
For example, their analysis revealed that the genes PAX3 and PAX7 are associated with chimp-biased enhancer regions, and they had higher levels of activity in chimp CNCCs. These results get really intriguing once you learn a bit more about the PAX genes: other studies in mice have shown that mutations interfering with PAX function lead to mice with smaller, lower jawbones and snouts. So the lower level of PAX3/PAX7 gene activity in humans would appear to correlate with our smaller jaws and snout (mouth and nose) compared to chimps. Did that just blow your mind? How about this:

The researchers also found a variation in the enhancer region for the gene BMP4. But in this case, BMP4 was highly related to human-biased enhancer regions and had higher activity in humans compared to chimps. Previous mouse studies have shown that forcing higher levels of BMP4 specifically in CNCCs leads to shorter lower and upper jawbones, rounder skulls, and eyes positioned more to the front of the face. These changes caused by BMP4 sound an awful lot like the differences in human and chimp facial structures. It appears the Stanford group has established a terrific strategy for tracing the genetic basis for differences in humans and chimps.

So what’s next? According to Wysocka, the team is digging deeper into their data:

“We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences. It’s becoming clear that these cellular pathways can be used in many ways to affect facial shape.”

And in the bigger picture, the researchers also suggest that this “cellular anthropology” approach could also be applied to a human to human search for DNA enhancer regions that play a role in the variation between healthy and disease states.