Author: cirmweb

Key stem cell gene controlled from afar, Canadian scientists discover

/ cirmweb / 1 Comment

Embryonic stem cells can, by definition, mature into any cell type in the body. They are able to maintain this state of so-called pluripotency with the help of a gene called Sox2. And now, researchers at the University of Toronto (U of T) have discovered the unseen force that controls it. These findings, reported in the latest issue of Genes & Development, offer much-needed understanding of the steps a cell must take as it grows up.

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Led by U of T Professor Jennifer Mitchell, the research team were, for the first time, able to identify the specific molecular regulator that switched the Sox2 gene on and off at specific times during an embryonic cell’s lifetime. As Mitchell explained:

“We studied how the Sox2 gene is turned on in mice, and found the region of the genome that is needed to turn the gene on in embryonic stem cells. Like the gene itself, this region of the genome enables these stem cells to maintain their ability to become any type of cell.”

The team named this region the Sox2 control region, or SCR.

For the last decade scientists have been using knowledge gleaned from the Human Genome Project to map how and when genes are switched on and off. Interestingly, the regions that control the gene in question aren’t always located close by.

This was the case with Sox2, said Mitchell. Early on, researchers had argued that Sox2 was regulated from nearby. But in this study, the team found the SCR, which controls Sox2, to be located more than 100,000 DNA base pairs away. According to Mitchell, the process by which the SCR activates Sox2 is fascinating:

“To contact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embryonic stem cells… It is possible that the formation of the loop needed to make contact with the Sox2 gene is an important final step in the process by which researchers practicing regenerative medicine can generate pluripotent cells from adult cells.”

Indeed, despite a flurry of research breakthroughs and a promising number of clinical trials moving forward, there are still some fundamental aspects of stem cell biology that remain unknown. This discovery, argues Mitchell, is an important step towards reaching toward improving the way in which scientists manipulate stem cells to treat disease.

A time to kill, a time to heal: cells linked to aging also help heal wounds

/ cirmweb / Leave a comment

Senescent cells, so called because of the role they play in the aging process, have acquired a bit of a bad reputation.

Yet new research from the Buck Institute suggests that these cells may not be so bad after all.

Buck Institute faculty Judith Campisi and Postdoc Marco Demaria. [Credit: The Buck Institute]

Buck Institute Professor Judith Campisi and Postdoc Marco Demaria. [Credit: The Buck Institute]

Reporting in today’s issue of Developmental Cell, Buck Institute scientists have found that, while senescent cells do indeed contribute to cellular aging and age-related diseases, they also play an important role in healing wounds. Furthermore, the team has identified the specific molecule in senescent cells that does the healing—pointing to a new therapy that could harness the good aspects of senescent cells, while flushing out the bad.

As we age, so do our cells. During cellular senescence, cells begin to lose their ability to grow and divide. The number of so-called senescent cells accumulates over time, releasing molecules thought to contribute to aging and age-related diseases such as arthritis and some forms of cancer.

But experiments led by Buck Institute Professor Judith Campisi and postdoctoral fellow Marco Demaria revealed that following a skin wound, cells that produce collagen and that line the blood vessels become senescent, and lose the ability to divide. Instead, they accelerate wound healing by secreting a growth factor called PDGF-AA. And once the wound was healed, the cells lost their senescence and shifted back into their normal state.

Because cellular senescence has long been linked to aging and age-related diseases, some research has been focused on finding ways to flush out senescent cells entirely. But the findings by the Buck Institute team throw a wrench in that idea, by revealing that these cells do in fact serve an important purpose.

According to Campisi, there is still a lot to learn:

“It is essential that we understand the full impact of senescence. The possibility of eliminating senescent cells holds great promise and is one of the most exciting avenues currently being explored in efforts to extend healthspan. This study shows that we can likely harness the positive aspects of senescence to ensure that future treatments truly do no harm.”

December ICOC Board Meeting to Begin Soon

/ cirmweb / Leave a comment

The December ICOC Board Meeting begins this morning in Berkeley, CA.

The complete agenda can be found here. Dude to inclement weather our Spotlight on Disease has been canceled.

For those not able to attend, you are welcome to dial in:

To join the event as an attendee
——————————————————-
1. Go to https://cirm.webex.com/mw0307l/mywebex/default.do?nomenu=true&siteurl=cirm&service=6&rnd=0.3004049356896069&main_url=https%3A%2F%2Fcirm.webex.com%2Fec0606l%2Feventcenter%2Fevent%2FeventAction.do%3FtheAction%3Dlandingfrommail%26confViewID%3D2023263422%26%26EMK%3D4832534b0000000206e16422b6688520d75b860933effb35ce2c41b56594ba5351fdb8c0a969dd92%26email%3Dacheung%2540cirm.ca.gov%26encryptTicket%3Daee20fe734ccdae68884f9fe07b3197e%26%26siteurl%3Dcirm

2. Click “Join Now”.

——————————————————-
To join the teleconference only
——————————————————-
Dial in: (800) 398-9389

Confirmation Number: 346314

To access the live event or archive, use this URL:
https://im.csgsystems.com/cgi-bin/confCast

Enter Conference ID# 346314

[Members of the Public will be invited to provide testimony before or during consideration of each item. Makers of public comments are asked to limit their testimony to three (3) minutes.]

Finding the Sweet Spot: shifting metabolism keeps stem cells in suspended animation

/ cirmweb / Leave a comment

The future is bright for a stem cell: it has the potential to become almost anything. This potential is one of its two defining characteristics. The second is that it can create copies of itself over and over again.

Researchers are announcing a new breakthrough on how best to keep embryonic stem cells (above) in a state of suspended animation.

Researchers are announcing a new breakthrough on how best to keep embryonic stem cells (above) in a state of suspended animation.

This second characteristic, known as the ability to self-renew, is of particular importance to researchers. After all, if they are to use stem cell technology to heal injury and treat disease, they must figure out how to keep them suspended in this embryonic state, so that large quantities can be grown in order to manufacture enough treatments for all who need them.

Unfortunately, that is easier said than done. But scientists have made extraordinary progress, developing a specific, nutrient-rich environment—a ‘medium’ called 2i—that can keep cells in a suspended, animation-like state.

The only problem was that they didn’t know why it worked.

Enter a joint team of scientists from The Rockefeller University and Memorial Sloan Kettering Cancer Center in New York, who today announce in the journal Nature that they may have cracked the case. According to team leader C. David Allis, it all comes down to the cell’s metabolism.

A cell’s metabolism is not unlike our body’s metabolism, though on a much smaller scale. Cellular metabolism refers to the process by which chemical reactions transform food into energy and other cellular products through something called the Citric Acid Cycle. The faster the cells’ metabolism, the faster the cycle produces energy, and vice versa.

Previously, scientists had observed a connection between the Citric Acid Cycle and the way in which a cell’s DNA was bundled into what is known as chromatin.

Embryonic stem cells (ES cells) have a different chromatin structure than mature, differentiated cells. This allows for heightened gene expression. [Credit: stembook.org]

Embryonic stem cells (ES cells) have a different chromatin structure than mature, differentiated cells. This allows for heightened gene expression. [Credit: stembook.org]

Chromatin is made by winding DNA strands around proteins called histones, much like winding strands of yarn around a tennis ball. The pattern in which DNA is organized into the chromatin structure is crucial: it affects which genes are switched on and off, and when.

For genes to become activated, or ‘expressed,’ they must be physically accessible within the chromatin structure. Postdoctoral researcher and co-first author Bryce Carey hypothesized that speeding up or slowing down a cell’s metabolism was responsible for which genes were accessible, and could therefore become activated. As he explained in a news release:

“What if, in stem cells, the changes to chromatin reflect a unique metabolism that helps to drive reactions that help to keep chromatin accessible? This connection would explain how embryonic stem cells are uniquely poised to activate so much of their genomes.”

To pinpoint the exact connection between metabolism and gene expression, Carey and co-first author Lydia Finley compared the metabolic functions of embryonic stem cells grown in the 2i medium and compared them to cells grown in a traditional medium made from bovine serum.

When study authors Bryce Carey (left) and Lydia Finley (right) exposed mouse embryonic stem cells to the metabolite alpha-ketoglutarate, those cells became more likely to renew themselves, appearing as pink colonies on the screen. This is one of the first demonstrations that a metabolite can influence the fate of stem cells. [Credit: Zach Veilleux / The Rockefeller University]

When study authors Bryce Carey (left) and Lydia Finley (right) exposed mouse embryonic stem cells to the metabolite alpha-ketoglutarate, those cells became more likely to renew themselves, appearing as pink colonies on the screen. This is one of the first demonstrations that a metabolite can influence the fate of stem cells. [Credit: Zach Veilleux / The Rockefeller University]

Surprisingly, the team found that the 2i cells were producing energy at staggering levels—through a molecular shortcut that cut out an entire step of the Citric Acid Cycle. This shortcut boosted the production of a protein called alpha-ketoglutarate, which in turn spurred more efficient energy production. It was as if the 2i medium instilled these embryonic stem cells with super powers.

Alpha-ketoglutarate appeared to be the key to shifting cells’ metabolism so that the right genes are expressed—thus keeping the cell in an embryonic state. Even cells growing in the traditional, bovine serum medium became supercharged when given a healthy dose of alpha-ketoglutarate.

These results not only solve a long-standing mystery of why the 2i medium was so superior for growing stem cells, they also pinpoint the particular protein—alpha-ketoglutarate—that is at the heart of this difference. This discovery, according to Allis, moves us closer to developing stem cell-based treatments in the clinic:

“This newly established link between metabolism and stem cell fate improves our understanding of development and regeneration, which may, in turn, bring us a little closer to harnessing stem cells’ ability to generate new tissue as a way to, for example, heal spinal cord injuries or cure Type 1 diabetes. It may also add a new dimension to our understanding of cancer, in which differentiated cells erroneously take on stem-cell like properties.”

Stem Cell Stories that Caught our Eye: Stem Cell Summit Roundup, Spinal Cords in a Dish and Stem Cell Tourism in the NFL

/ cirmweb / Leave a comment

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.

Success at the World Stem Cell Summit. This week some of the biggest names in regenerative medicine descended upon San Antonio, Texas for the annual summit. Along with researchers from the world’s top universities, institutions and companies were members of CIRM, including CIRM President and CEO C. Randall Mills.

We’ve been publishing top highlights from the Summit all week here on the Stem Cellar. There’s also been detailed coverage in the local San Antonio press, including the local ABC station. And if you’d like to find out more about this year’s conference, be sure to visit @WSCSummit and #WSC14 on Twitter.

Scientists have found a way to grow spinal cords from embryonic stem cells in a petri dish. [Credit: Abigail Tucker/ MRC Centre for Developmental Neurobiology/ Wellcome Images.]

Scientists have found a way to grow spinal cords from embryonic stem cells in a petri dish. [Credit: Abigail Tucker/ MRC Centre for Developmental Neurobiology/ Wellcome Images.]

Growing Spinal Cords in the Lab. Tissue engineering, the process of using stem cells to build new tissues and organs, has been the Holy Grail for regenerative medicine. And while there has been some progress with engineering some organs, others—especially the spinal cord—have proven far more difficult. This is because the biodegradable scaffolding cannot be made correctly to grow complex and intricately connected nerve cells.

But now, a research team in Germany has grown complete spinal cords in the lab, pointing to a new strategy for treating those with irreparable spinal cord injuries.

As reported in The Guardian this week, Andrea Meinhardt of the Dresden University of Technology and her colleagues worked around the problem of scaffolding by employing a new method called self-directed morphogenesis, first developed by the late Yoshiki Sasai. According to The Guardian‘s Mo Costandi:

“Self-directed morphogenesis is a method for growing embryonic stem cells in a three-dimensional suspension. Cells grown in this way can, when fed the right combination of signaling molecules, go through the motions of development and organize themselves to form complex tissues such as eyes, glands and bits of brain.”

While preliminary, this research offers immense promise towards the ultimate goal: reversing the devastating effects of spinal cord injuries.

Stem Cells and the NFL. Despite the best efforts of experts, stem cell tourism continues to proliferate. A new study published this week in 2014 World Stem Cell Report (a special supplement to Stem Cells and Development) describes the latest example of people seeking unproven stem cell treatments: this time in the NFL.

New research from Rice University is suggesting that some NFL players are seeking out unproven stem cell treatments—oftentimes traveling abroad without fully understanding the risks. This poses serious problems not only for players but also for the NFL as a whole. As Co-lead author Kirsten Matthews elaborated in a news release:

“With the rise of new and unproven stem cell treatments, the NFL faces a daunting task of trying to better understand and regulate the use of these therapies in order to protect the health of its players.”

Specifically, 12 NFL players are known to have received unproven treatments at some point during the last five years, including star quarterback Peyton Manning who we’ve blogged about before The authors caution that high-profile players broadcasting that they are receiving these unproven therapies could influence regular patients who are also desperate for cures.

In order to fix this growing problem, the authors recommend the NFL review and investigate these unproven stem cell treatments with the help of an independent committee of medical professionals. Finally, they suggest that the NFL could support stem cell research here in the United States—so that proven, effective stem cell-based treatments could more quickly enter the clinic.

Searching for a Cure for HIV/AIDS: Stem Cells and World AIDS Day

/ cirmweb / Leave a comment

World-AIDS-Day

It’s been 26 years since the first World AIDS Day was held in 1988—and the progress that the international scientific community has made towards eradicating the disease has been unparalleled. But there is much more work to be done.

One of the most promising areas of HIV/AIDS research has been in the field of regenerative medicine. As you observe World AIDS Day today, we invite you to take a look at some recent advances from CIRM-funded scientists and programs that are well on their way to finding ways to slow, halt and prevent the spread of HIV/AIDS:

Calimmune’s stem cell gene modification study continues to enroll patients, show promise:
Calimmune Approved to Treat Second Group in HIV Stem Cell Gene Modification Study

Is a cure for HIV/AIDS possible? Last year’s public forum discusses the latest on HIV cure research:


Town Hall: HIV Cure Research

The Stem Cell Agency’s HIV/AIDS Fact Sheet summarizes the latest advances in regenerative medicine to slow the spread of the disease.

And for more on World AIDS Day, follow #WorldAIDSDay on Twitter and visit WorldAIDSDay.org.

Speak Friend and Enter: How Cells Let the Right Travelers through their Doors

/ cirmweb / 1 Comment

For decades, it’s been a molecular mystery that scientists were seemingly unable to solve: how do large molecules pass through the cell and into the nucleus, while others half their size remain stranded outside?

These are nuclear pores imaged by atomic force microscopy, appearing as a craterlike landscape in which each crater corresponds to a pore of ~100 nm diameter. [Credit: UCL]

Nuclear pores imaged by atomic force microscopy, appearing as a crater-like landscape in which each crater corresponds to a pore of ~100 nm diameter. [Credit: UCL]

But as reported in the latest issue of Nature Nanotechnology, researchers now believe they may have cracked the case. By shedding light on this strange anomaly, University College London (UCL) scientists have opened the door for one day delivering gene therapies directly into the nucleus. With numerous research teams working on ways to merge stem cell therapy and gene therapy, this could be extremely valuable to our field.

Scientists already knew that the membrane that surrounds the cell’s nucleus is ‘punctured’ with millions of tiny holes, known as nuclear pores. Co-lead author Bart Hoogenboom likened the pores to a strange kind of sieve:

“The pores have been to known to act like a sieve that could hold back sugar while letting grains of rice fall through at the same time, but it was not clear how they were able to do that.”

In this study—which used cells taken from frog eggs—Hoogenboom, along with co-lead author Ariberto Fassati, harnessed atomic force microscopy (AFM) to give them a new understanding of how these pores work. Like a blind person moving their fingers to read braille, AFM uses a tiny needle to pass over the nuclear pores in order to measure their shape and structure.

“AFM can reveal far smaller structures than optical microscopes,” said Hoogenboom, “but it’s feeling more than seeing. The trick is to press hard enough to feel the shape and the hardness of the sample, but not so hard that you break it. [In this study], we used it to successfully probe the membrane…to reveal the structure of the pores.”

And what they found, adds Fassati, offered an explanation for how these pores worked:

“We found that the proteins in the center of the pores tangle together just tightly enough to form a barrier—like a clump of spaghetti. Large molecules can only pass through [the pores] when accompanied by chaperone molecules. These chaperones, called nuclear transport receptors, have the property of lubricating the [spaghetti] strands and relaxing the barrier, letting the larger molecules through.”

Astoundingly, Fassati said that this process happens upwards of several thousand times per second.

These results are exciting not only for solving a long-standing mystery, but also for pointing to new ways of delivering gene therapies.

As evidenced by recent clinical advances in conditions such as sickle cell disease and SCID (‘bubble baby’ disease), gene therapy represents a promising way to treat—and even cure—patients. Hoogenboom and Fassati are optimistic that their team’s discovery could lead further refinements to gene therapy techniques.

Said Fassati, “It may be possible to improve the design of current mechanisms for delivering gene therapy to better cross the nuclear pores and deliver their therapeutic genes into the nucleus.”

Shape-Shifting Cells Drive Bone Healing; Point to New Method of Correcting Bone Deformities

/ cirmweb / 1 Comment

There’s a time to grow and a time to heal—and the cells that make up our bone and cartilage have impeccable timing. During childhood and adolescence, these cells work to grow the bones longer and stronger. Once we’ve reached adulthood, they shift focus to repair and healing.

New research may help doctors treat craniofacial abnormalities while the patient is still growing—rather than having to wait until adulthood.

New research may help doctors treat craniofacial abnormalities while the patient is still growing—rather than having to wait until adulthood.

This is part of why children with bone deformities are often forced to wait until adulthood—until their bones stop growing—before their condition can be corrected.

Another part of the reason behind the agonizing wait is that scientists still don’t know exactly how this transition in bone cells, from a focus on growing to a focus on healing, even happens.

But new research out of the University of Michigan (UM) is well on its way to changing that.

In findings published today in Nature Cell Biology, Noriaki Ono (a UM assistant professor of dentistry) and his team announce the discovery of a subset of cartilage-making cells that take on new duties during the transition from adolescence into adulthood.

Previously, scientists had thought that these cartilage-making cells, known as chondrocytes, die once the bones stopped growing. But these new findings by Ono and his team showed that is not the case—not all chondrocytes bite the dust. Instead, they literally transform themselves from growing bone, to healing it.

The fact that some chondrocytes persist through to adulthood may mean that they can be selectively targeted to correct bone deformities in younger patients. As Ono explained in more detail:

“Up until now, the cells that drive this bone growth have not been understood very well. As an orthodontist myself, I have special interest in this aspect, especially for finding a cure for severe bone deformities in the faces of children. If we can find a way to make bones that continue to grow alongside the child, maybe we should be able to put these pieces of growing bones back into children and make their faces look much better than they do.”

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

/ cirmweb / Leave a comment

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

Entrepreneurship and Education

/ cirmweb / 1 Comment

Guest author Neil Littman is CIRM’s Business Development Officer.

CIRM works closely with UCSF on a number of initiatives, from providing funding to academic investigators to jointly hosting events such as the recent CIRM Showcase with J-Labs held at the Mission Bay campus.

Beyond our joint initiatives, UCSF also provides many other valuable resources and educational opportunities to the life sciences community in the Bay Area. For instance, I was a mentor in UCSF’s “Idea to IPO” class which focused on helping students translate concepts into a commercializable product and viable business.

Another opportunity that may be of interest to all you budding entrepreneurs is UCSF’s Lean LaunchPad course, which kicks off in January (application deadline is Nov 19th). The course teaches…

“scientists and clinicians how to assess whether the idea or technology they have can serve as the basis of a business. The focus is on the marketplace where you must validate that your idea has value in order to move into the commercial world.”

See more at: Lean Launchpad for Life Sciences & Healthcare.

The course is being run out of the Entrepreneurship Center at UCSF, which is a division of the UCSF Office of Innovation, Technology & Alliances (ITA).