How a skin cells becomes an iPS cell revealed

iPS cells (taken by Kathrin Plath, UCLA)

Today we revisit the ongoing saga of how best to create iPS cells. When last we visited the Confusing (and ongoing) story of iPS vs. embryonic stem cells it was spring 2011, and several papers had just come out revealing both pros and cons of working with iPS cells.

(Just a refresher – these are the cells that behave like embryonic stem cells in a lab dish but are created from a person’s own cells, usually skin cells.)

Since the last installment, the field has seen a few papers published showing new and better ways of creating iPS cells, and several papers in which iPS cells have been used to mimic diseases in a lab dish (we blogged about that work here).

Today’s installment comes from stem cell leader Rudolph Jaenisch of MIT, who has recently published a paper examining how it is, exactly, that an adult cell like a skin cell loses its identity and takes on an embryonic-like state.

Why do you care? As long as the cell gets to the embryonic state, why worry about the mechanics of the process? Right?

It matters because this paper shows how much there is still to learn about iPS cells, and ways of creating the safest iPS cells for use in therapies. Stem cell blogger and CIRM grantee at UC Davis Paul Knoepfler wrote not one but two blogs attempting to summarize this extremely dense paper (here’s the first). Both are worth a read if you are interested in understanding the paper’s findings.

Knoepfler himself recently published a paper showing similarities between the process of creating iPS cells and the process of a normal cell turning into a cancer cell.

For our purposes, the take-away is this: There’s a lot we don’t know about iPS cells and the best, safest ways of creating them. Actually, there’s a lot we don’t know about embryonic stem cells too. And the question is whether what we don’t know can hurt us.

CIRM is currently funding projects using both embryonic and iPS cells that are expected to reach clinical trials within a few years (here’s more about why we think it’s important to fund work with both cell types). One goal of our ongoing funding of basic stem cell biology awards—including studies such as Knoepfler’s—is to make sure the field is working with the safest, most effective cells in those therapies.

A.A.

Francisco Prieto: California’s investment in stem cell research gives patients a reason to hope

Francisco Prieto

Patient advocates are an integral part of everything we do here at the stem cell agency, helping shape every aspect of our work, from the way we operate to the research we fund.

One of the current patient advocates on our board is Dr. Francisco Prieto, and he has just written a wonderful article for the Sac Sierra Medical Society journal about Prop 71 which created the agency, CIRM, and the work that we do. It’s a great read; a powerful reminder of why we came into being and what our vision is. But it’s more than that. It’s a great insight into the role that the patient advocates play in helping us do that work, in helping us realize that vision. A link to the full issue is here. Prieto’s piece starts on page 8.

In the article Francisco says he was surprised to be asked to be part of the agency’s governing board, referring to himself as “a humble family doctor.” He is being far too modest. He may be a family physician but he is also an assistant clinical professor at the University of California Davis, and the President of the Sacramento Sierra Chapter of the American Diabetes Association.

Like every other member of our governing board, the Independent Citizen’s Oversight Committee (ICOC) he brings a wealth of experience, compassion and dedication to the role (here are bios of all board members). But he also admits to being a tad overwhelmed by some of the science that he ran into:

Even with my medical training, the scientific material I had to learn about was a bit daunting. I had no idea when I joined the board that Sonic Hedgehog is a mammalian- signaling pathway and not just a video game. Furthermore, articles about long non-coding RNAs and Notch signaling rarely made it onto my reading list.

As someone who is also relatively new to this world I completely understand how he feels. It can be intimidating to be surrounded by so many PhDs who chat about the latest scientific research the way some people discuss the latest episode of ‘American Idol’.

Francisco says with time and study he and other patient advocates became more comfortable with the material, and then he goes on to quote one of his colleagues on the board, Jeff Sheehy, about the importance of their work:

“The presence of vocal, engaged patient advocates has added an indispensable dimension to the proceedings in measuring research quality. Advocates tend to focus on a project’s ability to benefit people – not just drive scientific curiosity – which keeps even basic biomedical research grounded in its ability to produce concrete health benefits.”

Francisco ends by reminding us that one of the most important things that CIRM has done, other than funding groundbreaking research of course, is to give patients and their families a sense of hope. Our goal as always is to push for therapies and, ultimately, even cures. But between now and then, giving people whose lives are filled with fear and uncertainty a sense of hope is no small accomplishment.

K.M.

Lifespan drops in some groups: points to need for better prevention, new therapies

Geoff Lomax is CIRM’s Senior Officer to the Standards Working Group

Lifespan from 1990 to 2008 for groups of women, from The New York Times

The New York Times recently reported new evidence that life expectancy among some groups has fallen by and average of four years since 1990.

There is perhaps no more poignant measure of health improvement. Life expectancy has increased dramatically over the past century in the United States — from 49.2 years at the start of the 20th century to 77.5 years in 2003 (from the Congressional Research Service).

Although that overall trend has continued through 2008, white men and women without degrees for the first time saw a decline in life expectancy.

The improvements in life expectancy over the past century came about in two waves. In the early twentieth century public health investments – ranging from sanitation systems to vaccination programs – resulted in a dramatic increase in life expectancy.

Later in the century, innovations in science and medicine enabled treatments for a host of other life-threatening diseases, and the results have been impressive. For example, bone marrow transplantation, first attempted in 1957, has prevented deaths from childhood leukemia. Today, the national Marrow Donor Program includes over 9 million donors and nearly 145,000 umbilical cord blood units, the largest and most racially and ethnically diverse registry of its kind in the world.

In other conditions such as heart disease, cancer and HIV/AIDS, medical advances over the past 20 years have allowed people to live significantly longer after diagnosis.

Given this progress, the new results are a disappointment. The New York Times quotes John G. Haaga, head of the Population and Social Processes Branch of the National Institute on Aging, who was not involved in the new study.

“We’re used to looking at groups and complaining that their mortality rates haven’t improved fast enough, but to actually go backward is deeply troubling.”

What is also troubling is the lack of a clear explanation for the apparent trend. The New York Times wrote:

The reasons for the decline remain unclear, but researchers offered possible explanations, including a spike in prescription drug overdoses among young whites, higher rates of smoking among less educated white women, rising obesity, and a steady increase in the number of the least educated Americans who lack health insurance.

Improvements in health and longevity are among our greatest achievements as a society. There, improvements have come about largely because of public investment in efforts to simultaneously prevent and treat disease.

Clearly, this recent study points to the fact that sustaining improvements in longevity and quality of life is a challenge. Addressing this challenge will require continued investment into both disease prevention and also new therapies. At CIRM, we are committed to the new therapies part of the longevity equation. We’ve partnered with international collaborators, federal agencies, and industry to be part of a worldwide effort to deliver new therapies to those who need them.

G.L.

CIRM translating research into therapies: Collaborating with the FDA and industry

Cynthia Schaffer is Contract Administrator and Compliance Officer at CIRM

One of the roles CIRM plays is in collaborating with outside groups to help our grantees get the information they need to move their possible therapies into clinical trials. That includes working closely with both the Food and Drug Adminstration (FDA) and the Alliance for Regenerative Medicine (ARM).

Our latest work with FDA will be a free webinar on September 27th, which will discuss the immune response in stem cell based therapy. Theresa Chen of the FDA is one of three speakers for the webinar. We hope you will join us and learn more about the regulatory perspective on immune rejection concerns as well as how to overcome the immune rejection challenge.

CIRM has held two of these free webinars each year for the past 3 years, all with FDA speakers. Recordings and reference materials from past webinars are available on our website. Scientists can join these online sessions from their own desk or from on the road and submit questions that are answered directly by the FDA and the two leading experts who present their research and current findings.

The FDA very graciously donates their time to speak on these webinars because they too have pledged to maintain an active dialogue with the industry and provide education on their regulatory expectations for product development in the regenerative medicine field. CIRM science officer Kevin Whittlesey recently wrote a paper with Celia Witten of the FDA about the role of the FDA in reaching out to regenerative medicine community, including webinars such as these.

In that paper they point out that the communication goes both ways:

Appropriate regulation requires a strong understanding of the latest scientific developments to meet current and future regulatory needs and challenges.”

 So the FDA benefits by learning from the other speakers in the webinar – what is the current state of the technology, what are investigator’s current thoughts on best practices and the latest research findings, etc. They also learn what the industry is facing by listening to the questions asked and the discussion of the challenges during the Q&A sessions. A group of FDA employees attend each of these CIRM sponsored webinars, and the wide variety of other workshops and meetings that CIRM hosts throughout the year.

These webinars with the FDA are just one way CIRM is trying to help our grantees get their therapies into clinical trials. We’re also partnering with ARM to sponsor the 2012 Stem Cell Meeting on the Mesa Investor & Partnering Forum and Scientific Symposium to be held in La Jolla on October 29-31. ARM was formed in 2010 and has since developed into an amazing advocacy organization dedicated to the advancement of regenerative medicine (see link to ARM website). CIRM will have six of its grantees presenting at the Investor & Partnering Forum (registration and more information is available here).

I’ve written in the past about the effort CIRM has made in the past year to reach out to industry and to help the entire community share best practices and resource. Efforts like these are part of how CIRM hopes to speed the pace of translating research into clinical trials and eventually bring new therapies to patients.

C.S.

"Family guy" in favor of stem cell research

It’s not often that a TV cartoon show that is described as “Sick, twisted and politically incorrect” makes an interesting observation about stem cell research. But then, The Family Guy is not a typical TV show. It describes itself a show about how “a dysfunctional Rhode Island family strive to cope with everyday life as they are thrown from one crazy scenario to another.”

So what does that have to do with stem cells? Well, in a recent episode the “crazy scenario” in question had to do with the lead character, Peter Griffin, suffering a horrible disfiguring medical emergency, stumbling into a stem cell clinic and walking out five minutes later perfectly normal. Or as normal as you can be in a cartoon sitcom.

As he walks out he asks the guard outside the clinic “how long was I in there?” “5 minutes” the guard says, to which Peter replies “Why are we not funding this?”

Here is a link to the scene.

He’s referring, of course, to funding of stem cell research, which has been a matter of some political debate and one recent lawsuit (which we blogged about here). Federal agencies can fund stem cell research, including research with certain embryonic stem cell lines derived from left over embryos from in vitro fertilization, but cannot fund the creation of new stem cell lines.

Here in California, not only do we fund all types of stem cell research, but we also have an entire round of funding dedicated to creating new lines. According to a survey last year, those lines are being used by researchers working toward new therapies.

Perhaps we’re not quite as far along as The Family Guy shows – it is a cartoon after all – and none of our grantees have yet found a way of reversing horribly disfiguring emergencies in five minutes, but we are certainly making important strides on a number of different fronts like heart disease, diabetes and HIV/AIDS.

Recent research – and some of our recent blogs – have highlighted advances being made in using stem cells to restore damaged muscles in injured soldiers, to repair spinal cord injuries in rats, and to restore hearing in gerbils. We clearly still have a long way to go but, in California at least, we are heading in the right direction.

It’s good to know that we have some fictional cartoon characters supporting our work and our mission. Now if only we could get Homer Simpson on board we’d really be making progress.

K.M.

CIRM stem cell research interns: the high school musical

As summer winds down and school starts back up, some of the students are returning with high-tech stories about what they did this summer. Nine institutions in California hosted high school students to carry out stem cell research for the summer. (We blogged recently about an end-of-program meeting for those students.)

We’re really excited about the program because it teaches young people how fun it can be to work in the lab and encourages students to pursue stem cell research careers. The program also has a focus on students from diverse backgrounds, which is a nice way of making sure that we are reaching out to people of all backgrounds in the state. After all, the best minds are not confined to a few zip codes.

I recently learned of two very different videos about the program. One, from UC Davis, quotes Sheldon High School senior Laura Kay:

By giving students the ability to come and intern, that opens their eyes and expands their knowledge on the different careers that this world has to offer, which is brilliant.

Meanwhile in southern California, the students of the City of Hope Creativity program got creative and musical with their video. Here I reveal my lack of hipness when I admit that I don’t know any of the songs, but the students lip-synching while at a microscope certainly look like they’d spent time learning to use the gear.

Despite the hours of fun they must have had making the video, the City of Hope interns clearly got a realistic experience of lab work. Their lyrics included many references to being busy, being in the lab long hours and waiting many days for results. In a nutshell, that’s how new discoveries come about.

I was rather fond of the closing, where all the students leapt from a scenic fountain yelling “Go CIRM!”.

To which we say, Go students! As Gerhard Bauer, a stem cell scientist at UC Davis, says at the end of their video, these students are the ones who will be developing the next generation of stem cell therapies. We’re glad they worked hard, got a great experience and if the City of Hope video is representative, also had fun.

A.A.

New intestines for babies, new muscles for soldiers

Over the past three days the New York Times has been running a fascinating series of stories on regenerative medicine and the use of stem cells to treat a number of serious medical conditions from a cancerous windpipe to a leg shattered by a Taliban bomb. It’s a interesting glimpse into the hope and promise of regenerative medicine, and to the tremendous progress that has already been made.

In one story, the focus is on Dr. Tracy Grikscheit, a CIRM-funded pediatric surgeon at Children’s Hospital Los Angeles, and the work she does in helping treat children who are born with a disorder that causes their intestinal tissue to die. Much of her work is done surgically, trying to conserve as much of the intestine as possible so that the child can lead as normal a life as possible.

But surgery can only do so much so Dr. Grikscheit spends a lot of time in the lab, working with stem cells to try and find a way to make replacement intestines for infants. As she points out in the story:

Not much new intestine would be required. “You only need to engineer an organ up to the point where you fix the missing function,” Dr. Grikscheit said. Even a couple of inches might be enough. “That will tip them back over into having enough absorptive function to get off of I.V. nutrition and live a full life.”

This is clearly important work and we are helping her do it. Dr. Grikscheit is a recipient of a CIRM New Faculty Award. She got almost $2.4 million to help support her and fund the research she is doing. Grants like this are particularly important for researchers who are doing innovative work and who are at an early point in their career where finding funding can be difficult.

Dr. Grikscheit has already had some success in her work, and although she knows it may be many years before the techniques she is developing are ready to be tested in people she says in the New York Times article that she is optimistic she’ll get there:

“The really fascinating thing is how to put something together that came out wrong and make it as right as possible.”

If you want to hear more about Grikscheit’s work, listen to her explanation in this video we shot. She was at a tissue engineering workshop we hosted last year, which brought together some of the leading researchers who are combing stem cells and engineering to help generate new intestines, windpipes, bones and a range of other therapies.

K.M

Liver transplant saves girl’s life, but not everyone can get one: stem cell-derived liver cells to the rescue?

Vanessa Lupian and her Mother Veronica discuss Vanessa’s liver transplant

Imagine browsing a restaurant menu and all you see is a list of toxins that can cause constant vomiting, hallucinations, emergency dialysis treatment, brain damage, and even death. That was the predicament of 13 year old Vanessa Lupian who spoke, along with her mother Veronica, to the governing board of California’s Stem Cell Agency during the September 6th Spotlight on Liver Disease seminar (watch the Spotlight videos here).

Vanessa has maple syrup urine disease (MSUD), a metabolic liver disease caused by a genetic mutation. This inherited disorder leads to the lack of an enzyme responsible for digesting specific amino acids in foods like milk, meat, and eggs. The build up of amino acids can lead to the symptoms that haunted Vanessa. Her mother described Vanessa’s episodes:

When she would get sick we’d start seeing the side effects of her just not wanting to eat, the constant throwing up, and at times she’d even start hallucinating, not knowing who we were. All those points are very scary… From birth to 10 years, she was in the hospital one or two times a year. Three or four times we were close to losing her.

Fortunately, Vanessa received a liver transplant in 2010. It wasn’t a cakewalk since she needed two transplants and four major surgeries over a 3-month period. But she is now doing well, going to school full time, and enjoys eating normal foods including her favorite: french fries. She was even able to donate her own liver to a child whose disease was not caused by MSUD. Still, Vanessa’s UCSF doctor, clinical fellow Andrew Grimm, pointed out to the board that:

The important thing to remember is that the therapies that we have for these [metabolic liver] diseases is pretty primitive. We understand the metabolic defects that are involved and so we can approach those from a biochemical perspective and can limit [certain foods]…but many children still have irreversible injury from metabolic [failure] so there’s a potential for cell therapies to be able to provide an alternative, less invasive, less dangerous method of treatment.

The liver transplant helped Vanessa, but not everyone is as lucky. There are too few donated livers for all the people who need them, and organ transplants come at significant risk of rejection. With those limitations in mind, UCSF researcher Holger Willenbring has been trying to use stem cell-derived liver cells, or hepatocytes, as the tissue source for treating liver disease.

Willenbring spoke to the board about progress he’s making toward generating stem cell-derived liver cells for transplantation through collaborations with UC Davis and Shanghai Institute of Biological Sciences which are supported by CIRM Early Translation II and Early Translation III grants, respectively. He also points to his earlier CIRM SEED award as an important factor in helping him reach this point in his research:

I came to UCSF at the end of 2005, I was working on adult stem cells…I definitely didn’t have exposure to embryonic stem cells. And the CIRM SEED grant was definitely geared towards…people like me with a certain expertise with a certain desire to develop treatments to maybe consider…using and getting to know embryonic stem cells. I have since become a fan and a real believer of pluripotent stem cells and we have very little adult stem cell work going on in our lab. I’m not saying it’s not working or it’s not worth pursuing but … just simply because of the reason [that]…the [human] liver has 250 billion hepatocytes. It’s just a numbers game. It’s just about efficiency and just about making enough cells and I don’t know any adult stem that can pull it off. I’m grateful that I have an opportunity within my career to see this come to fruition and being applied in patients.

You can bet that future patients like Vanessa who are suffering with liver disease and without many options will also be grateful.

This page shows all CIRM funding for liver disease

T.D.

stem cells partially repair spinal cord injuries in rats

Mark Tuszynski

I have friends who are paralyzed so I admit to being biased when I read about promising research to repair the spinal cord. I’d like to see my friends walk, or, at least have more movement. The ability to simply hug their kids would be life-changing.

Today, there’s a new paper published by a CIRM grantee at the University of California San Diego that describes a big advance. Mark Tuszynski, co-author of the study and director of the UC San Diego Center for Neural Repair, was able to coerce neural stem cells implanted into the damaged region of the spine to grow past the injury, reconnecting the brain with the parts of the spinal cord below the injury.

The work was in rats, so all the usual caveats apply. Rats have been cured of many things in the lab that did not end up working in people. But still, those rats regained some movement.

The work Tuszynski describes in this paper formed the basis of a $4.7 million Early Translational award that will take the research from rats toward human trials.

A San Diego Union Tribune story quotes CIRM president Alan Trounson talking about the work:

“I’ve been in the business a long time and have never seen this degree of regeneration in rats. This is very significant work.”

That story went on to quote Susan Howley, executive vice president, research at the Christopher & Dana Reeve Foundation talking about CIRM’s role in funding this research:

“At a time when money for research is so jeopardized across many funding sources, it’s particularly noteworthy that CIRM has the capacity to support this promising work and take it to the next level, particularly for individuals living with spinal cord injury.”

Our spinal cord injury fact sheet has more information about CIRM’s funding for the condition.

A.A.

Stem cells repair nerves damaged in hearing loss

Ear hair cell derived from embryonic stem cells | Stefan Heller, Stanford University School of Medicine

This week researchers at the University of Sheffield in England used cells derived from embryonic stem cells to help restore hearing in gerbils. One note: the scientists weren’t driven by a concern for gerbil hearing. It just so happens that the rodents hear in roughly the same sound range as us humans and so their ears are a good model for human hearing.

This work, which was published in this week’s advanced online edition of Nature, differens from some other stem cell-related hearing projects in that it focused on the nerves that carry sound sensation from the ear to the brain. Most people with hearing loss have damage to the hair cells within the ear that first detect sound. This kind of damage can be aided in some cases by cochlear implants. But if the nerves that transmit signals from the cochlear implant to the brain are damaged then the person still can’t hear. That’s where this new technology would fit in.

A story in the Technology Review says:

The stem-cell treatment could eventually be combined with cochlear implants to give more deaf patients the ability to hear. But much more work would be required to bring this idea to fruition.

The story goes on to quote Stefan Hellar from Stanford University, who has a CIRM-funded project to generate the hair cells that first detect sound (those are his embryonic stem cell-derived ear hair cells above). Technology Review goes on:

While the study shows the potential of stem cells to replace auditory nerve fibers, says Stefan Heller, who studies hair-cell function and regeneration at the Stanford School of Medicine, the results will be difficult to translate to patients. “It is virtually impossible to diagnose a reduction of auditory nerve fibers in hearing-loss patients.”

Our hearing loss fact sheet has more information about stem cell research into hearing loss, including a few videos about the work we fund.

A.A.