Stem cell Stories that caught our eye: perspectives on cloning, alligator teeth, power of patient advocates

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.

Putting cloning into perspective. There has been much written the past few days about the first ever creation of embryonic stem cells from a cloned embryo. Perhaps too much. One of the best pieces I have seen comparing these new stem cells to other types of stem cells was written by one of my colleagues here. There has been much gnashing of teeth about this research being just one step away from cloning a human baby. It’s not even close. Another colleague discusses that issue here. USA Today had one of the best lay level discussions of the work. And if you want a little more science detail, the news section of Nature did a nice job here.

Let’s duplicate feat of alligator teeth. Alligators can regrow their 80 teeth as many as 50 times during their lifetime. If we can figure out how their bodies accomplish this trick, we could save a lot of human patients considerable pain and money compared to much restorative dentistry today. A team at the University of Southern California has made significant strides in understanding the wily critter’s dental prowess. While CIRM funds considerable work at USC, this project moved forward with federal funding.

It’s location, location, location. So, what does this old real estate adage have to do with stem cells. We are increasingly finding out that in order to drive stem cells to become the desired adult cell we have to pay close attention to the location where we ask them to grow, divide and mature. Stem cells take cues from the environment to decide what they are going to be when they grow up. Now a team at Harvard affiliated Brigham and Women’s Hospital has shown that they can get stem cells to consistently mature into bone if they embed them in a silica matrix similar to clay. (I wonder if the diner in the Brigham across from my old office at the med school still serves those wonderfully unhealthy burgers that felt a little like clay after about an hour in the stomach?)

Patient advocates’ role in research. We at CIRM work closely with the patient advocate community, spending considerable time listening to them, to their hopes and expectations, and to their perceptions of risk in potential therapies. An unexpected outlet, Chemical and Engineering News, posted a very thoughtful and detailed account of families that do more than just fund raise through walks. It focuses on Jill Wood, her son Jonah, and her work to jump start research into his rare condition, Sanfilippo Syndrome. My second job after college was down the hall from C&EN, starting one of the first consumer science magazines in the country SciQuest, which got swallowed by Discover, after three years. C&EN was not stepping out of its comfort zone like this back then. Glad they are covering this powerful trend.

Picture tells sad funding story. If a picture is worth a thousand words, and if you believe in the importance of research funding to the future of the American economy and our society, then this is one sad picture. We do not look good compared to our global competitors.

Science as art. As the instrumentation that powers science gets increasingly sophisticated one added benefit is we often get images that are quite lovely pieces of art. After the downer on funding, I have to end with these stunning images, which you can see here.

And if you want to see some beautiful stem-cell specific images visit our Flickr site or our new Pinterest board.
DG

bluebird bio files for IPO, advancing B-thalassemia program

Neil Littman is the Business Development Officer at CIRM where he is responsible for facilitating opportunities for outside investment in stem cell research in California for both CIRM-funded and non CIRM-funded programs by biopharma companies and venture capital investors.

A CIRM-funded company, bluebird bio Inc., today filed an S-1 registration statement with the SEC for an Initial Public Offering (“IPO”) to raise up to $86.3 million. For those unfamiliar with the IPO process, an IPO is a public offering where shares of a company’s stock are sold to institutional investors and the general public for the first time. It is through the IPO process that a private company becomes a publicly listed company in which shares can be freely bought and sold on a listed exchange (in this case The Nasdaq Global Market). By “going public,” bluebird bio is seeking to raise additional capital, expand their shareholder base and offer liquidity to existing investors.

In October 2012, CIRM awarded bluebird bio a $9.3 million grant through our Strategic Partnership Award to fund the company’s ß-thalassemia program, which is expected to be initiated in the U.S. in 2013. The award is to support a Phase 1/2 study to evaluate the safety and efficacy of LentiGlobin, which works by introducing a fully functional human beta-globin gene into the patient's own blood-forming stem cells. The goal is for these corrected stem cells to ultimately produce fully functioning red blood cells.

A portion of the proceeds from the IPO will be used to fund the ß-thalassemia program. These funds, in conjunction with the company’s $60 million Series D financing in July of 2012, will supplement CIRM's funding of the project. One of our strategic goals at CIRM, as outlined in our Industry Engagement and Commercialization Plan, is to help companies we fund get these types of additional funding sources to ensure that their projects are ultimately successful.

There's more about CIRM-funded projects headed toward or starting clinical trials and about our strategies to help those programs succeed on our website.

N.L.

Galileo and reproductive cloning both fall victim to dogma

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

Yesterday the news broke that scientists led by Shoukhrat Mitalipov at Oregon Health and Science University derived human embryonic stem cells through a process called nuclear transfer (more about that here). The report is an important step forward for the development of stem cell-based therapies because it will allow the comparison of different methods for obtaining embryonic-like stem cells, including human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and now hESCs derived by nuclear transfer (SCNT).

This development is particularly important at time when hESC- and iPSC-based treatments are entering clinical trials. In these early clinical stages, it is critical to evaluate different approaches to understand the best pathway to safe and effective therapies. As George Daley of Harvard University says in a story in The Scientist:

“We are now left to analyze the detailed molecular nature of SCNT-ES cells to determine how closely they resemble embryo-derived ES cells and whether they have any advantages over iPS cells.”

One might think advocates for iPS cell-based therapies would be particularly enthusiastic about the Mitalipov report because it enables comparison of different reprogramming methods. In the world of therapy development, more information is always the better.

However, there are groups of people who take it as dogma that if SCNT succeeds for generating new stem cell lines, reproductive cloning must surely follow. Bernard Siegel, executive director of the Genetics Policy Institute in Palm Beach, Florida is quoted in a story in Nature saying that the response has been “cloning hysteria.”

For instance, one headline from The Business Journals read, “Family Research Council Condemns Human Cloning in Oregon.” Another on the Center for Bioethics and Culture Network web page reads "Human Cloning is Here!" In another piece titled Scientists Clone and Kill Human Embryos for Dubious Research, David Prentice, Senior Fellow for Life Sciences at Family Research Council writes:

“It is a grave concern that some scientists are still pursuing human cloning, a technology that will open the door to human engineering and a brave, but highly dangerous, new world.”

Josephine Quintavalle, amplified this hysteria in a story in The Daily Mail, where she questioned the fundamental motivation of the research saying,

"The suspicion has to be that the real interest is not stem cell therapy per se, given that other uncontroversial approaches are already so successful. Let’s hope that the goal is not out and out reproductive cloning."

This fixation on human cloning persists despite repeated and ongoing efforts to advance socially responsible research under high ethical standards. First, and foremost, the research community supports a ban on human cloning such as the one in California.

Cloning hysteria disparages the accomplishments of scientists who work to ensure responsible application of research. For example, in a press release about the work, Mitalipov emphasized that group does not intend the work to be used for reproductive cloning:

"While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning."

It is unfortunate that a breakthrough designed to enable the development of stem cell therapies from any source is subject to unsubstantiated attacks. It is particularly disturbing to see underlying motivations of scientists distorted despite clear statements to the contrary.

Scientists should be recognized for their contributions and not demonized because of prevailing dogma. Galileo was persecuted because his theory that the earth rotated around the sun challenged Church dogma. Let's hope Mitalipov's work doesn't suffer a similar fate by who claim it will lead to cloning.

G.L.

New technique could prevent the immune system from rejecting transplanted cells or organs

Mark Anderson, MD, PhD, left, and Matthias Hebrok, PhD

In what could be a critical step for developing cell transplantation therapies, CIRM grantees at UCSF have managed to turn embryonic stem cells into functioning tissue from what might be the smallest and most easily forgotten organ of your body -- the thymus.

Although the thymus is small, it plays a big role in our immune system, helping produce the white blood cells our body needs to fight off infections and prevent autoimmune reactions.

In this study, published online in the May 16 issue of Cell Stem Cell the CIRM-funded researchers took some human embryonic stem cells and, using what they describe as “a unique combination of growth factors,” managed to engineer them into becoming thymus tissue. One of the lead authors on the paper, Mark Anderson, carried out the work with a Transplantation Immunology award from CIRM. This round of awards was specifically intended to find new ways of overcoming immune rejection of stem cell-transplantation therapies.

In a news release from UCSF about the work, the researchers said:

“The achievement marks a significant step toward potential new treatments based on stem-cell and organ transplantation, as well as new therapies for type-1 diabetes and other autoimmune diseases, and for immunodeficiency diseases.”

In organ transplants for example the immune system often attacks the new organ, requiring patients to take powerful anti-rejection medications that can have difficult side effects. If researchers can coax stem cells down two different paths, at the same time, one group could become thymus tissue and the other could form a replacement organ. If both the thymus tissue and organ were then transplanted into a patient the thymus tissue could help modify the immune system, prevent it attacking the new organ so the patient would not need immunosuppression medication.

That’s a long way down the road of course and so far this work has only been done in mice, and the researchers caution that even there only about 15 percent of the cells were successfully converted to thymus tissue. Nonetheless they remain optimistic that their findings. The UCSF release quotes Anderson as saying:

“We have now developed a tool that allows us to modulate the immune system in a manner that we never had before”

K.M.

Caffeine held the key to creating embryonic stem cells from cloned embryos

A colony of human embryonic stem cells, courtesy of Julie Baker at the Stanford University School of Medicine

Scientists at Oregon Health & Science University have achieved what many scientists have been working toward for decades: they’ve created embryonic stem cells from cloned human embryos.

These cells, like the embryonic stem cells that come from embryos donated after in vitro fertilization (IVF) and from reprogrammed skin cells, have the ability to form all the cell types of the body. This is also called being pluripotent (pluri= “many”, potent= “potential”). So, now there are three ways of generating pluripotent stem cells.

There are some subtle differences between the pluripotent stem cells from those different sources, and so far nobody knows what those differences mean in terms of their therapeutic potential. We do know that reprogrammed skin cells (known as iPS cells) have some changes to their DNA compared to normal embryonic stem cells and they also seem to age more quickly. Whether these differences matter when it comes to using the cells in therapies is still not known.

Like iPS cells, this new source of embryonic stem cells would be genetically identical to the patient. That means they are less likely to be rejected by the patient if the cells are used as a therapy, for example transplanted into the brain to treat Parkinson’s disease. But unlike iPS cells, the new source is relatively quick to make – on the order of weeks rather than the months it can take to reprogram skin or other tissues into iPS cells.

A story in Reuters quotes CIRM’s Natalie DeWitt discussing this increased speed:

"If you have a patient who needs [stem-cell-derived tissue], that can be an important difference.”

The story goes on to point out some potential drawbacks to the approach:

On the other hand, the human eggs needed for the Dolly technique are in short supply and hard to obtain, notes MIT's Jaenisch. (The Oregon team paid the women who donated eggs for their time and "discomfort.") Although the Oregon team coaxed stem cells out of every egg they collected from one of the women, other labs might not be so efficient.

The process

Many incremental steps have led to this recent advance, which the team published today in the journal Cell. In 2011, a group in New York also created embryonic stem cells through this technique, also called SCNT (somatic cell nuclear transfer) but their cells had three copies of each chromosome, limiting their usefulness. Normal cells have two copies of each chromosome, one from the mother and one from the father. We blogged about that work here.

SCNT is a reprogramming method that involves creating an embryo as a first step. In this case, the scientists first removed the nucleus, containing all the cell’s DNA, from a human egg. They then took DNA from a human skin cell and placed it in the egg, which they then stimulated to form a 5-6 day old embryo. Those embryos are like the 5-6 day old embryos donated through IVF clinics that are normally used to generate embryonic stem cells. Scientists remove cells from those embryos and place them in a lab dish where they go on to form embryonic stem cells.

That same paragraph would have described attempts to create SCNT-derived stem cells a decade ago, so what took so long? There aren’t that many steps. The scientists spent their time making minute tweaks to the cocktail of chemicals bathing the egg to stimulate it to start dividing and forming an embryo. Normally, the egg begins to divide when fertilized by a sperm, but with no sperm involved scientists had to figure out what chemicals could mimic fertilization. It turns out, the key was coffee. Or rather caffeine.

The fact that SCNT-derived stem cell lines have so much in common with other forms of pluripotent stem cells has some opponents of the research asking why bother? Here’s why. CIRM held a conference in June 2010 to discuss the value of pursuing SCNT and posted a report on the findings in November, 2010 (a report from that workshop is here).

That report suggests three areas where embryonic stem cell lines generated through SCNT would clearly be valuable:

• Understanding how you reprogram any cell to become pluripotent could help us optimize the creation of iPS cells, which are so far inefficient to create in addition to being incompletely reprogrammed.
• Understanding and treating the rare diseases that are passed on from those few genes that reside outside the nucleus in the cellular organ called the mitochondria.
• Studying the very early stages of human development, which are poorly understood now, and which is when some human diseases are thought to originate.

Ethics

This research brings up ethical concerns for many groups. First. SCNT requires woman to donate eggs. The Oregon team paid women for those eggs, which some oppose. In California, both CIRM regulations and state law prohibit any payment to women who donate eggs for research.

Also, there’s the issue of creating a cloned human embryo. In other animals, scientists can implant that embryo into a uterus and produce cloned animals such as Dolly the sheep. In California, that step—called reproductive cloning—is prohibited by a constitutional amendment. All significant research oversight groups oppose human reproductive cloning.

You can learn more about the different types of stem cells used in CIRM-funded research on our website. This table lists all awards, with filters on the left to see which grants use iPS, embryonic, adult, cancer or SCNT cells.

This video shows CIRM grantee Amander Clark from UCLA discussing the process of SCNT:



A.A.

Getting rid of a protein that promotes longer lifespan slows MS in mice

Neuron showing the protective sheath that is lost in people with multiple sclerosis

Our grantees at Stanford University have found a protein with an intriguing role in the development of multiple sclerosis. The work is still in mice, but points to a new pathway for developing drugs for the disease.

People with MS slowly lose the protective covering that surrounds their neurons. Over time, the damage leads to paralysis. There is currently no cure and no therapy that does more than just slow how quickly the disease progresses.

The group, led by Anne Brunet, was studying a protein called SIRT1, which has been dubbed the "skinny gene" because of it's role in helping animals burn fat. In animals, having high levels of SIRT1 seems to extend lifespan. In fact, if you search the web on SIRT1 or "skinny gene" you will find scores of companies offering to sell products or diet plans intended to help you mimic those animal studies.

So, SIRT1 seems to be something you'd want to have around. But Brunet's group found the opposite, at least when it came to MS. They were using a special group of mice that contained SIRT1 genes that the scientists could turn on and off. They then induced a form of MS in these mice and turned off the SIRT1 gene. Mice without SIRT1 were protected from the paralysis that struck their fellow mice with normal levels of SIRT1.

Stanford quoted Brunet in a press release about the work (myelin is that protective covering lost in MS):

“We are excited by the potential implications our study has on demyelinating diseases and injuries. It’s intriguing because activating SIRT1 is typically considered to be beneficial for metabolism and health, but in this case, inactivating SIRT1 can provide protection against a demyelinating injury.”

They went on to find other genes that are activated in mice lacking SIRT1. These genes appear to work by promoting neural stem cells to turn into the type of cells that form that protective sheath.

Brunet says finding drugs that manipulate these genes could be one step toward finding a therapy for the disease. The work was published online May 5 in Nature Cell Biology.

There's more information about CIRM's funding for multiple sclerosis research on our website, including a list of awards and descriptions of therapy development projects.

A.A.

Rafalski VA, Ho PP, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LM, Ibrahim A, Baker SJ, Barres BA, Steinman L, & Brunet A (2013). Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology PMID: 23644469

California a veritable hotbed of iPS cell patent activity, study finds

Frozen iPS cells courtesy of William Collins in the lab of Deepak Srivastava and Christopher Schlieve at the Gladstone Institutes.

It looks like California is a veritable hotbed of reprogrammed stem cell activity. (These are the iPS cells that are reprogrammed from adult tissues like skin.)

The publication Genetic Engineering News looked at new patents for iPS cell technology and found that world-wide, most of the activity was focused in California, Boston, Madison, Wisconsin, and Kyoto University.

They write:

California, the second most successful cluster, appears to reflect the “start up” cultures of the Bay Area and San Diego with strong academic support within the local universities. California is distinguished from Japan in that it also has a good number of smaller players in industry and multiple academic institutions trying to establish a foothold in the area.

One of CIRM's goals is to promote more biotech industry in the state working toward new stem cell-based therapies so it's nice to see that happening in the iPS cell field.

As the story says, we'll be posting the raw data used in this analysis on our website for others to peruse. We also have this list of our funding for iPS cell work.

A.A.

Breast cancer advocate Barbara Brenner dies of ALS

Ron Leuty of the San Francisco Business Times  wrote a nice obituary for breast cancer advocate Barbara Brenner, who founded the notoriously feisty Breast Cancer Action. The San Francisco-based organization took aim at Big Pharama, Big Biotech and what she called the "pinkwashing" of breast cancer awareness.

Brenner died of ALS, also known as Lou Gehrig's disease, at age 61. 

On their site, BCA referred to Brenner as, "Social justice activist. Corporate ass-kicker. Civil rights advocate. Profound changer of lives. Visionary."

Leuty wrote about the organization Brenner founded:

The nonprofit became the first breast cancer organization to refuse funding from any corporation that profits from cancer or contributes to cancer by polluting the environment.

BCA was one of a few breast cancer advocacy organizations to speak out in support of the Food and Drug Administration revoking its conditional approval of Genentech's blockbuster cancer drug Avastin for metastatic breast cancer. The drug's side effects, as the FDA eventually cited, outweighed its benefits for breast cancer patients overall.

I talked with Brenner back in 2007 when I was writing about what she referred to as "Pinkwashing" for a story in Stanford Medicine Magazine:

It irks BCA director Barbara Brenner that companies come off looking so good when they do so little. “Women are being encouraged to buy something rather than do something,” she says. In some cases the companies promoting breast cancer awareness might actually be doing harm. She points to BMW, which gives $1 per test drive during the month of October to breast cancer research. That same test drive spews toxins into the environment that, even if they don’t contribute directly to breast cancer, certainly aren’t a net health positive. Or there’s the bottle of Sutter Home white zinfandel that earns $1 for breast cancer research with each purchase. That’s despite the fact that alcohol increases breast cancer risk. 

Both breast cancer and ALS are diseases with active stem cell research programs in California and world-wide. CIRM funds research in solid tumors, including breast cancer. Here is a list of those awards. We've also committed more than $48 million to ALS research, including two teams that are working toward clinical trials testing stem cell-based therapies for the disease.

A.A.

Excercise induces new neurons to form in the brain via seratonin

Image by LittleDebbie11

Back in the late 1990s, CIRM grantee at Salk Institute for Biological Studies Fred Gage published what might be my favorite stem cell research ever: he found mice that exercise regularly have more new neurons forming in their brains and seemed to have better memories than their couch-potato labmates.

As a runner, that struck me as some very good news (more than a decade later, I'm doubting the memory part, however).

Now scientists in Germany have learned more about how exercise induces stem cells in the brain to form those new neurons. It turns out that the brain chemical serotonin – the same one that is linked to depression – is required for exercise to stimulate those new neurons to form.

The German group used two groups of mice, one that made serotonin and one that didn’t. The mice that didn’t make serotonin were able to form new neurons throughout their lives, as is normal, but didn’t make any extra after bouts of running on their wheels.

The mice with normal levels of serotonin, on the other hand, saw a profusion of new neurons forming from the brain’s stem cells after exercise.

Back in 2007, the New York Times ran an aptly named story “Lobes of Steel” about Gage’s work, in which he is quoted:

“We’ve always known that our brains control our behavior, but not that our behavior could control and change the structure of our brains.”

Now with the German work, we know more about how that behavior controls the brain.

Science Daily ran a story about the current work, which was published May 8 in the Journal of Neuroscience:

Deficiency in serotonin, popularly known as the "molecule of happiness," has been considered in the context of theories linking major depression to declining neurogenesis in the adult brain. "Our findings could potentially help to develop new approaches to prevent and treat depression as well as age-related decline in learning and memory," said Dr. Klempin and Dr. Alenina [authors on the study].

No word on the endorphin high experienced by either group of mice after exercise.

A.A.

Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N (2013). Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci. DOI: http://www.ncbi.nlm.nih.gov/pubmed/23658167

Stem cell Stories that caught our eye: getting therapies to market, creating new bone, healing skin ulcers

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.

Getting a therapy to market. Fierce Biotech published an insightful interview with Henry Termeer, former CEO of Genzyme, which was the first company to market a stem cell-derived product, one for cartilage repair. In the years he lead Genzyme the company gained a reputation for developing drugs for rare diseases, but also developing the reimbursement structures and markets that allowed them to become products for patients, not just research finding. Since he left the firm Henry has become a consultant to many small firms trying to travel that difficult path, including Verastem, which is developing drugs to rein in errant cancer stem cells. Henry sat on our advisory board during my years at Harvard Med School and I came to greatly respect his insights. This interview shares much of that learned wisdom from years in the field.

Bone as a living organ. While many teams have created bone cells from various types of stem cells, our friends at the New York Stem Cell Foundation have taken it one step further. They created bone tissue in three dimensions that contained the compartments for the blood vessels and nerves needed to make the bone a living organ. They started with stem cells created by reprogramming skin cells, so called iPS cells, which could come from a specific patient in the future making them compatible with the patient’s immune system. The work requires many more steps to become a therapy, but these structures with all the parts of functional bone move it significantly closer. Bio-Medicine wrote about the work, as did we.

Smart route to drug discovery. We have often written about the ability to make iPS cells from a patient with an inherited disease and model that disease in a dish. You can not only find out more about what is really causing the symptoms, but also test potential therapies. A CIRM-funded team at University of California, Los Angeles has use iPS cells to screen for potential drugs to treat a rare brain disease that is a form of ataxia. We blogged about that work here.

Budget cuts impact research. Many folks have written print and online commentaries on how the mandatory federal budget cuts known as the sequester will impact the pace of scientific research. This analysis starts with a formal report developed by the Federation of American Societies for Experimental Biology. The stories from some of the group’s members do make you wonder how much slower progress to therapies will become because of these cuts.

Healing wounds today. So much of stem cell science is so new, we most often write about potential therapies that are several years from reality, or just beginning clinical trials in people. It is easy to forget there are a few stem cell-based products already on the market. Organogenesis has one of those products. It speeds healing of difficult to heal skin ulcers. The firm’s product contains two types of cells on a scaffold to hold them in place. One is a type of skin cell that seems to secrete growth factors that accelerate healing according to data from nearly 1,500 patients presented at a recent meeting and described in this article. Geoff MacKay, the firm’s president is quoted discussing the fact that many of these patients had struggled for long periods with wounds that just would not heal. Geoff is also president of the Alliance for Regenerative Medicine. CIRM is a founding member of the Alliance and I had the privilege of chatting with Geoff at the group’s annual meeting in D.C. earlier this week. He is passionate about the field and its potential as a whole, while obviously proud that his company is able to make a difference in people’s lives today.

Silly and instructive. This video of an animated stem cell as an arrogant actor is quite fun. Predictably, the actor is proud of his ability to play any character. He boosts, “Working with me, it’s not easy. But frankly my dear I don’t give a damn.” Stem cells are not easy to work with, but their potential is so great, it is worth the effort.

D.G.