Dear headline writers: Teeth did not grow from stem cells in urine

Photo by Simon Pearson

Anyone who has spent time working in print journalism knows most headlines are not written by the people who wrote the story. I hope several of the authors of the stories the past two days about teeth grown from stem cells in urine are pissed off (har har) at the headline writers. The headlines, in this case, had little to do with the science.

As most of the stories eventually mentioned, often inappropriately low in the copy, the Chinese team did not grow teeth from stem cells found in urine. Their starting material was not stem cells, but the few live cells we all excrete when we urinate.

The team collected those cells from urine and turned them into embryonic-like stem cells called iPS cells. This is the same process scientists use to convert cells from other sources such as skin or blood into iPS cells. The resulting cells — like all iPS cells — have the ability to form all tissues in the body, including teeth.

But those iPS cells were not able to form teeth by themselves. They only did this when they were mixed with another type of stem cell from mice. When the two-cell type mix was transplanted into the jaws of mice it resulted in “tooth-like structures” 30 percent of the time. And these structures were only about a third as hard as human teeth.

I guess some headlines are just too hard to resist.

Even the news site that gave the most detail about the actual science EmaxHealth had a headline full of errors: “Scientists grow human teeth from stem cells in urine.”

The CBS story did a poor job with the science in the top few paragraphs, but did go on to quote a well respected expert, Chris Mason from University College London saying that the only thing the study showed was that urine would not be a viable way to regenerate teeth:

“It is probably one of the worst sources, there are very few cells in the first place and the efficiency of turning them into stem cells is very low. You just wouldn’t do it this way.”

The study was published in the journal Cell Regeneration.

Complicating this issue for people trying to understand this work is a second study published this week in the journal Stem Cells. The authors from Wake Forest University presented follow-up work to a study they published in 2006 suggesting that a few stem cells can indeed be found in urine (here’s a description of that work). In their latest paper, the authors claim that those stem cells are more versatile than most adult stem cells, a claim that is sure to generate controversy and needs to be replicated.

Don Gibbons

Through their lens: Ryan Fong sees a path to success working in the lab

This summer we’re sponsoring high school interns in stem cell labs throughout California. We asked those students to contribute to our Instagram photos and YouTube videos about life in the lab, and write about their experiences.   

Ryan Fong working in the Good Manufacturing Facility as part of Gerhard Bauer’s lab at UC Davis. He submitted this photo through Instagram to CIRM’s #CIRMStemCellLab collection

My name is Ryan Fong and I will be entering junior year at Sheldon High School. I’ve been working under the mentorship of Dr. Gerhard Bauer at the UC Davis Institute for Regenerative Cures in the Good Manufacturing Practice (GMP) facility. Shout out to the entire GMP staff for being the best – supportive, extremely helpful, and a lot of fun (#TeamGMP!). Additional thanks to Dr. Jan Nolta and the entire Nolta Lab for hosting us these eight weeks.

This entire experience has been beyond amazing. In this world, it’s too easy for even the most ambitious dreamer to lose sight of their goals and fall off the path that would have realized their full potential. The long road to a professional career can seem long and uncertain at times. Amidst the pitfalls of life, new and old responsibilities, seemingly never-ending work, and immediate trials and tribulations, it’s not hard to see how one might lose their way. This program showed me that hard work really will be recognized and rewarded, leading to great things. It’s treated me like the mature individual I’ve always strived to be. Receiving a stipend has allowed this program to be financially feasible and making it all the more real. And finally, it has reassured any doubts my mind might have fostered that I was anything but on the right path to success.

Now, on to my project. Embryonic stem cells (ESCs) were a breakthrough discovery for regenerative medicine, because of their ability to differentiate into all three germ layers, including tissues that won’t normally be repaired in the body, like cardiac or nerve tissue. However, ESCs require the disassembly of a human blastocyst. Induced pluripotent stem cells (iPSCs) are derived from adult cells, without the involvement of an embryo, and also allow future treatments to be made using a patient’s own cells. iPSCs are extremely difficult to obtain, even with careful coddling, babysitting, prayers, etc. (≤0.1% viability) – only a handful of colonies are viable out of millions of cells.

The iPSC induction method I used was based on a HIV-derived lentiviral vector containing four transcription factors, Sox2, Oct4, Klf4, and c-Myc, which upregulate the expression of pluripotency genes still present in a cell’s genome. With these factors, the cell will express these downregulated pluripotency genes – in effect, a slate wiped clean to be differentiated into a cell type of choice.

I worked in the GMP facility here, which meant donning a full coverall gown, gloves which were taped to the cuffs, and surgical mask for hours at a time (you could only see my eyes) all the while practicing special technique for working in this environment. An outside environment has ~35,000,000 particles ≥ 0.5 µm per cubic foot per minute, but in the GMP facility, there are ~100,000 particles ≥ 0.5 µm per cubic foot per minute. Additionally, all work was conducted within a biosafety cabinet, which permits a mere ~100 particles ≥ 0.5 µm per cubic foot per minute. I cultured HEK-293T cells, which were transfected using lisosomes (a technique called lipofection) with DNA plasmids so they could serve as producer cells to manufacture my vector. That same vector was used to transduce human fibroblasts, and after two weeks, several iPSC colonies had been created.

I will remember this experience forever. I’m entering this next school year with my passion for my studies reinvigorated, after seeing how that knowledge translates to the practical, and I really hope that many more students will be able to experience what I experienced in the future through this Creativity program. Thank you CIRM!

Ryan Fong

Through their lens: Sarah Zhang learns about stem cells and HIV

Sarah Zhang working in the lab of Gerhard Bauer at UC Davis. She submitted this photo through Instagram to CIRM’s #CIRMStemCellLab collection

This summer we’re sponsoring high school interns in stem cell labs throughout California. We asked those students to contribute to our Instagram photos and YouTube videos about life in the lab, and write about their experiences.  
My name is Siruo Zhang and for the past eight weeks, I had been interning at the UC Davis Stem Cell Lab. As an intern, I worked under the instructions of Dr. Joseph Anderson and Sharlie Barclay from the HIV team in the lab.

My project is focused on testing for the safety of a combinatorial three gene anti-HIV vector. HIV, otherwise known as Human Immunodeficiency Virus, is a virus that targets and attacks T-cells and CD4 cells within the immune system. Over time, it begins to affect the body’s ability to ward off infections and can subsequently develop into AIDS. Statistics show that by the end of 2011, more than 34 million people worldwide were living with HIV.

Since all of the cells that HIV attacks come from hematopoietic stem cells, gene therapy becomes a reasonable option for treating and curing individuals of HIV. The combinatorial anti-HIV vector is a lentiviral vector that contains three components: the CCR5 shRNA, the TRIM5α, and the TAR decoy. Each component targets a specific stage of HIV’s life cycle, the CCR5 shRNA targets the pre-entry, the TRIM5α targets the post-entry/pre-integration, and the TAR decoy targets the post-integration. The CCR5 shRNA impedes the production of CCR5 by targeting the mRNA of CCR5, so that the viral envelope is unable to fuse with the cell membrane. The TRIM5α prevents virus uncoating, and the TAR decoy inhibits upregulation of HIV transcription.

In addition to these three anti-HIV genes, the vector also contain a CD25 pre-selective marker, which allows us to identify which cells contain the anti-HIV genes and which ones don’t. To test for the safety of this vector system, four experiments were conducted, QPCR testing for proto-oncogene expression, IL2 beta and gamma flow cytometry, CFU assay, and macrophage phenotype flow cytometry.

I enjoyed this internship immensely; I learned a lot of information about HIV and about stem cells. Before this internship, I hardly knew anything about stem cells, but now I can tick off the three properties that make a stem cell a stem cell. Those three properties are self-renewal, multi-potential, and highly proliferative. The most challenging part of this internship was the first week of being in the lab. I’ve never worked in an actual lab before, so everything was new to me. I messed up sometimes at first, but I learned from my mistakes and I tried to avoid it the next time. One of my favorite experiments that I conducted during my duration as an intern was probably plasmid extraction, because I’ve done it more times than I can count.

I would like to thank my mentors, Dr. Anderson and Sharlie Barclay, for being so patient with me and answering all of my questions. Also, I would like to thank Dr. Bauer for teaching me about stem cells. Lastly, I would like to thank CIRM and the UC Davis Stem Cell Program for providing me with this amazing opportunity. As my internship comes near its end, I can probably say that this summer was the most educational and enjoyable summer I’ve ever had. I gained not only knowledge, but also experience of working in a real lab.

Sarah Zhang

18 years in the making, Huntington’s Disease film reaching finish line

Back in 2010, we shot a video about a project to find a stem cell-based therapy for Huntington’s disease. In addition to scientists at UC Davis, the video featured patient advocate Chris Furbee, who has a family history of Huntington’s: he lost his great grandmother, grandfather, aunt and mother to the incurable disease. Chris himself tested positive for the mutant gene that causes the disease in 1996. You can watch that video here.

During our interview with Chris, I learned he was a film buff too and had been working on a documentary, Huntington’s Dance, about his family’s experience with Huntington’s. Here’s how he describes the film:

This film is about my mother, Huntington’s disease and how the knowledge that I was at risk for the disease has profoundly affected my life.

Chris has been working on the film since 1995 and is now ever so close to completing the project. To help get past the last few hurdles, which include sound mixing, producing DVD copies, and distributing the film, Chris has started a fundraising campaign on the crowdfunding website Indie-a-go-go. As Chris says on the his funding page, the impact of the movie could be profound:

Since I was 18 years old I have been raising money for advancing research and education of Huntington’s disease. This film will put a face to Huntington’s and by doing so will generate conversation among the general public that will result in improved care and treatment of those with Huntington’s, and most of all facilitate finding a cure to eradicate the disease throughout the world.

Having talked with Chris about the project it’s exciting to see that he’s so close the finishing. Huntington’s is a devastating disease, but isn’t one that’s widely known. The video will put a face on the disease and help people understand the need for better therapies.

There’s more about CIRM’s projects to find a cure for Huntington’s on our Huntington’s disease fact sheet.

Todd Dubnicoff

The key to longer life: a gene that preserves neural stem cells

Cells becoming neurons (red) in mice lacking FOXO3. Image courtesy of Ashley Webb.

Our grantee Anne Brunet at Stanford University has known for a while now that a protein called FOXO3 has something to do with longer lifespan in both lab animals and people. She and members of her lab also knew that FOXO3 is found in stem cells of the brain and seems to preserve those cells. What they didn’t know is how.

What the first author Ashley Webb discovered is that FOXO3 essentially counteracts a protein being studied by another of our grantees at Stanford–Marius Wernig. Wernig has shown that a protein called Ascl1 prompts cells to become neurons. Webb found that FOXO3 interferes with Ascl1, preventing the cells from becoming neurons and, in the case of neural stem cells, maintaining that critical pool of cells.

Stanford quoted Anne Brunet on their blog:

This was really exciting to us, because ASCL1 has been widely studied, in particular by Marius Wernig, MD, at Stanford, for its ability to convert or ‘reprogram’ cells into neurons. Ashley found that FOXO3 could inhibit the ability of ASCL1 to promote the expression of pro-neuronal genes and the formation of new neurons. This could explain how FOXO3 maintains the pool of adult neural stem cells: by preventing them from undergoing premature differentiation into neurons and by keeping them as “stem cells”.

Now, the question is whether FOXO3 is disrupted in brain diseases related to aging, like Alzheimer’s disease or dementia.

I should note that CIRM played two roles in the discovery of how FOXO3 functions, which was published in the July 25 issue of Cell Reports. One is that Brunet has a New Faculty Award from CIRM. The other is that the scientist who carried out much of this research, Ashley Webb, is married to a CIRM science officer (she doesn’t have CIRM funding).

Amy Adams

Smithsonian discusses new stem cells discovered by CIRM grantee Thea Tlsty

Virginia Hughes wrote for the July-August issue of Smithsonian about the recent work by our grantee Thea Tlsty, who discovered cells in the adult body that can form all tissue types. (We wrote about that work here.)

All previously identified stem cells in adult tissues could only go on to form the cell types found in that tissue. Stem cells lodged in the brain form cell types found in the brain, and blood-forming stem cells form all the cell types of the blood. The cells discovered by Tlsty could form anything. Hughes describes the work like this:

Molecular pathologist Thea Tlsty and colleagues at the University of California, San Francisco, had been studying wound-healing cells in the breast, known to divide furiously in response to injury, when they hit upon a small subset carrying surface molecules similar to those on pluripotent stem cells. About 1 in every 10,000 breast cells appears to belong to a class of stem cells never seen before, now dubbed “endogenous pluripotent somatic” cells.

After putting these cells onto a plastic plate and letting them stew in nutrients and growth factors known to nurture the development of heart muscle cells, Tlsty’s junior colleague Somdutta Roy created heart cells that actually beat in the lab dish. “When she first saw the beating cardiomyocytes, she did a little dance,” Tlsty says. “Then she called everybody in the lab over to look at them.” With other nutrient blends, the team brought neurons, bone, fat and blood vessels to life.

The story goes on to quote two other CIRM grantees. Deepak Srivastava of the Gladsone Institutes says he thinks the cells could have a therapeutic role. Srivastava has been central to a new field of direct reprogramming, in which one type of adult cell is converted directly into a different type of cell. Paul Knoepfler of UC Davis says in the story that it’s still unclear why tissues would contain such cells.

After this Tlsty’s study was published in March, CIRM President Alan Trouson wrote about the work in his monthly science picks:

Like much of science, these results will gain strength when they are replicated by other teams. But Tlsty and her team have already begun looking for similar cells in other tissues in the body.

Amy Adams

CIRM’s Board approves Alpha clinics network to smooth road to stem cell clinical trials

In a much-anticipated move, the CIRM Governing Board gave the green light to a concept plan to develop a statewide network of Alpha stem cell clinics at yesterday’s Board meeting. The proposed plan will allocate $70 million to set up five clinics and a central coordinating center. The network will add momentum to the growing ranks of stem cell therapies headed to the clinical trials phase, as well as provide a meeting ground for the doctors and patients who will be part of the first phase of trials. You can read our press release about the vote here.

Therapeutic clinic networks already exist to offer treatments for diseases such as HIV or cancer, but clinic networks that treat a broad range of diseases, like CIRM’s Alpha stem cell clinics, are rare. DeWitt described the proposed clinics as “the go-to site for a variety of therapies.”

During the Board’s discussion of the concept plan, Michael Friedman, President and CEO for the City of Hope, said of the new collaboration

“I think the timing on this is appropriate. I think the scope and scale sounds very reasonable to me. I think we have the opportunity to correct some things that other technology or disease areas have failed with in the past, such as – simple things, such as standardized data forms…so you don’t have problems with comparability and expensive ways of converting things, of establishing a culture of collaboration.”

Part of the challenge for stem cell therapies is that clinicians will need to ensure the stem cells are handled safely and that researchers have access to specialized equipment for tracking the cells inside patients’ bodies. Doctors will also need a way to follow-up patients after they’ve gotten the treatments. Establishing a network of institutions with this new capacity will smooth the path toward human stem cell therapies

The L.A. Times wrote about the clinics and quoted CIRM President Alan Trounson:

“If we went 10 years and had no clinical treatments, it would be a failure. We need to demonstrate that we are starting a whole new medical revolution.”

Natalie DeWitt, Special Projects officer and Maria Milan, Medical Officer, who presented the proposal to the Board, emphasized that the clinics would build on the chosen institutions’ existing resources — such as research and clinical expertise as well as equipment and space — for a stem cell clinic. Their background material is available on the meeting’s agenda. DeWitt also wrote about the concept for the clinics in a recent blog entry.

In her presentation, DeWitt started with a video made at a workshop in which an international group stem cell and clinical experts met to discuss the unmet needs of researchers hoping to deliver stem cell clinical trials. The concept approved yesterday came out of that discuss. The video is here, and a white paper produced from the workshop is here.

The second arm of the Alpha stem cell clinic network will be a central coordinating center that would be a clearinghouse for stem cell clinical trials. It would provide expertise about the best way to shepherd new treatments through the clinical trial phase.

Milan said the effort will take CIRM to its next phase, which is bringing stem cells to the clinic.

Another major goal of the initiative is to provide reliable information to the public. Right now, patients and their families have few resources to help them navigate the sea of questionable information about stem cells, much of it available online. The Alpha stem cell clinic network would distribute information about potential clinical trials both in the network and outside of it.

CIRM plans to release a Request for Proposals (RFA) for the clinics in October 2013 (that RFA will be available here).

Rina Shaikh-Lesko

Stem cell Stories that caught our eye: Vatican-backed stem cells, epilepsy and stroke.

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.

A stem cell hide and seek with Vatican financing. One of the hallmarks of good science is the ability of other labs to reproduce the results. The lack of this verification always leads to controversy, but in one recent case the controversy has been enhanced by financial contributions to the work from the Vatican.

A few years ago, a team in Louisville claimed to have found cells in adult tissues that, like embryonic stem cells, can be coaxed to turn into many different body tissues. Stem cells found in adult tissues are generally considered to be limited to forming a very narrow range of tissues in the same lineage. The more versatile adult stem cells have been billed as a more ethical embryonic-like stem cell, which is assumed to be the reason for the Vatican funding of the company that holds the license to the Louisville work, Neostem.

Several labs have published on their inability to replicate the work, with the most robust of those studies coming out this week from the lab of CIRM grantee Irving Weissman. This web site picked up the university press release on Irv’s work, which some commentators are calling definitive. However, I have to agree in Christine Gorman’s take on the issue in the Scientific American blog. Because two researchers, one at Yale and one at the University of Michigan, have reported replicating some portion of the Louisville work, this controversy is not going away soon.

Epilepsy in a dish—a testing ground for drugs. We have often written about the power of reprogramming skin cells from patients into embryonic-like stem cells. When you mature those cells into the type of tissue impacted by the disease in a lab dish, you have a little screening factory for testing potential treatments. A team of researchers at the University of Michigan did this with cells from children with a rare form of epilepsy and discovered a defect in the way the nerves from these children move sodium in and out of the cell. This became an immediate target for testing potential drugs. ScienceDaily wrote about the work here. And this video talks about the process of making disease-in-a-dish models using iPS cells.

Brain’s support cells offer hope in stroke. Neurons have long held the starring role in the function of our brains, but in recent years more and more research has shown the importance of the supporting cells called astrocytes. Now, a CIRM-funded researcher at UC Davis has shown that a previously unidentified subset of astrocytes has a superior ability to protect neurons from damage such as the nerve death that occurs after a stroke. You can read about the work here. They developed a method to create large quantities of those cells and in nearly pure form. Both the scale up of quantity and the purity have eluded previous research into astrocytes. Most important, they found that those cells successfully protected neurons in a rat model of stroke.

Light-detecting cells created from stem cells. For the first time a British team created photoreceptors from embryonic stem cells. A key to the process was growing the cells in a three-dimensional culture that more closely mimicked the natural environment than a traditional flat laboratory culture. FierceBiotech wrote about the work here.

Alpha clinics for stem cell testing, therapy. I always enjoy it when writers with the mainstream media report on one of our initiatives and really convey the rational behind what we are funding and what we are trying to accomplish. Yesterday our board approved $70 million to establish five clinics in California that would have all the specialized equipment and expertise to test potential new stem cell therapies and, eventually, to deliver therapies that have been proven. Two writers with the L.A. Times wrote about the initiative; one the day before the vote and one the day after. Both writers noted one goal of the clinics that is near and dear to me, our plan to provide patients with the information they need to make intelligent choices when considering stem cell treatments.

The first article quotes a colleague, Natalie DeWitt, who helped develop the program: “One key activity of the CIMC will be to tell people what is proven and what should be avoided.”

Don Gibbons

Hello and Goodbye – new arrivals and heartfelt farewell

CIRM Chair Jonathan Thomas presents Dr. Philip Pizzo with a resolution honoring his service
It’s never easy to say goodbye to a friend, particularly when it’s someone who has been a part of your organization since the very beginning. But when it’s someone so universally liked as Dr. Philip Pizzo it’s even harder.

The stem cell agency’s July Board meeting was a time to say goodbye to Dr. Pizzo – who has stepped down from his role of Dean at Stanford and as a member of our governing Board – and hello to three new members.

The tributes to Dr. Pizzo were many and heartfelt. Dr. Michael Friedman, the CEO at City of Hope, praised Dr. Pizzo for his “unselfish” service to the people of California, adding:

“I have known Phil for more than 3 decades. He’s one of the few people in the room who remembers me with hair – which tells you how long it’s been! The citizens of California have been very fortunate to have your thoughtful engagement on their behalf over an extended period of time, always asking the question about what is the best science that will help the most people in the shortest space of time.”

Sherry Lansing, Patient Advocate for cancer, called it “truly one of the most bittersweet days since the institute was formed. “ She said he was one of the consciences of the Board:

“For me and all the patient advocates we say thanks. We would go to you to ask questions about the science and you were always so patient in explaining it and never made me feel silly or stupid for not understanding it. You were much more than a source of scientific knowledge, you are a source of ethics for the Board, you cared about what was best for the Board and the patients and that it was always done with integrity and transparency and honesty.”

After others had added their tributes Dr. Pizzo responded in a characteristically modest manner, saying:

“I am deeply humbled to be here and feel I’m almost at the point of listening to an obituary, but it’s very meaningful and the honor has been mine to serve with you. Those of us who have been here since the start remember how hard it was to get this together and how much has been accomplished in the years since.”

He ended by saying though he is stepping down he knows the cause is in good hands and he looks forward to seeing the great progress that is being made continue.
Jonathan Thomas swears in (from left to right) Dr. Lloyd Minor, Al Rowlett, Dr. Lars Berglund 

Picking up the mantle from Dr. Pizzo is Dr. Lloyd Minor, who takes over his old job as Dean of Stanford’s School of Medicine and his seat on the stem cell agency’s Board. After being sworn in he said he was “looking forward to what I know will be an exciting future.”

Al Rowlett, the new Patient Advocate for Mental Health, was also sworn in at the Board meeting and said “I am honored to represent the people of California and I’m hoping to make substantial contributions to the work of the agency. It’s a great honor.”

The third new member is Dr. Lars Berglund from UC Davis, who is the alternate for Ken Burtis.

We welcome our new members and look forward to working with you, and we bid a huge thank you and good luck on your new adventures to Dr. Pizzo. He will be missed but he has left a terrific legacy for the Board to carry on.

Bios of all 29 members are available on our website.

Kevin McCormack

CIRM grantees find network of proteins that control neural stem cells

Image by Sanford-Burnham Medical Research Institute

Today we bring you a story about proteins that help stem cells decide when they should divide to create more specialized cells. Those same proteins also have a role in cancer.

Sound like yesterday’s entry? The difference is that today’s stem cells are in the brain while yesterday’s were in teeth, and the proteins themselves are quite different. But the similarities are many.

At the heart of both papers is the fact that scientists really don’t know what makes stem cells tick. There are also many types of stem cells lodged in tissues throughout the body, and what drives one might not be relevant for another. So scientists who want to harness those cells to treat disease are hard at work trying to learn how the cells work.

Today’s paper, which was published July 24 in the Procedings of the National Academy of Sciences, comes out of the lab of CIRM-grantee Alexey Terskikh of the Sanford-Burnham Medical Research Institute. He studies how human neural stem cells become the neural progenitor cells that go on to produce mature cells of the nervous system (we’ve written about his work in the past). This process is important for understanding and treating diseases of the nervous system.

The work is described on the Sanford-Burnham blog. In it, they outline a series of proteins that work together to turn genes on and off within neural precursor cells. The authors suggest that having found this network of proteins they could conceivably manipulate it to fix diseases where the pathway has broken down.

Amy Adams