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“It gives me the chills just thinking about it”: Stanford researcher on the potential of stem cells

"It gives me the chills just thinking about it": Stanford researcher on the potential of stem cells

Welcome to the last Biomed Bites of 2014. We’ll be continuing this series next year — check each Thursday to meet more of Stanford’s most innovative biomedical researchers. 

If you watch this video and aren’t moved by the passion and conviction of Stanford biologist Margaret Fuller, PhD, then email me. Seriously, I’ll try to talk some sense into you. Because Fuller’s enthusiasm for biomedicine is downright contagious. This is a professor who you want to teach biology.

Fuller, a professor of developmental biology and of genetics, works with adult stem cells, and she’s palpably gleeful about their potential to improve the health of millions.

“I was really struck and inspired by a recent article in the New York Times,” Fuller says in the video above. She’s talking about “Human Muscle Regenerated with Animal Help,” a 2012 piece that told the story of Sgt. Ron Strang, a Marine who lost part of his quadriceps in Afghanistan. Yet here is Strang, walking, thanks to the donation of a extracellular matrix from a pig. This paper-like sheet secreted signals instructing his stem cells to come to the rescue and build new muscle. “It was amazing,” Strang told the Times reporter. “Right off the bat I could do a full stride, I could bend my knee, kick it out a little bit…”

“This is really amazing,” Fuller agrees. “It gives me the chills just thinking about it. This is the kind of knowledge and advances of the basic work that I do… The hope is that understanding those underlying mechanisms will allow people to design small molecules and other strategies that can be used to induce our own adult stem cells to be called into action for repair.”

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Center for Reproductive and Stem Cell Biology receives NIH boost, Why the competition isn’t adult vs. embryonic stem cells and Induced pluripotent stem cell mysteries explored by Stanford researchers

Biomed Bites, Genetics, Research, Stem Cells, Videos

Working on a gene therapy for muscular dystrophy

Working on a gene therapy for muscular dystrophy

Here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of biomedical disciplines. 

The most common form of muscular dystrophy, Duchenne muscular dystrophy, is genetic, resulting from a defective gene on the X chromosome, so it affects primarily boys. That makes it a prime target for genetic therapy – currently the goal of Stanford geneticist Michele Calos, PhD.

Calos started out as a basic scientist, examining the nature of DNA and the controls of genes; they developed techniques used to insert new genes into existing cells and ensure they are turned on.

Now, Calos has found applications for her earlier research. Capitalizing on the work that won the 2012 Nobel Prize in Medicine, Calos and her team have set their sights on developing healthy muscle cells that can restore function for muscular dystrophy patients. Here’s Carlos in the video above:

We’re repairing the mutation in the patients’ cells… then putting back the correct copy of the gene, differentiating them into muscle precursors and injecting them into muscles where they can form healthy muscle fibers.

Calos said she and her team are currently perfecting the technique in mice, before it can be used in human patients. “Our dream really is to develop a therapy in the lab that would be translatable to clinical use in the future,” she said.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Elderly muscle stem cells from mice rejuvenated by Stanford scientists, New mouse model for muscular dystrophy provides clues to cardiac failure and Visible symptoms: Muscular-dystrophy mouse model’s muscles glow like fireflies as they break down

Aging, Men's Health, Research, Science, Stanford News, Stem Cells

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

6111053153_5b14f4570d_zOk, so it may *appear* that this post is just an excuse to post a cute hedgehog picture. After all, who could resist that little face? But this is really meant to be a quick shout-out to Stanford developmental biologist Philip Beachy, PhD, who has shown yet again that the signalling protein called hedgehog is critically important during many aspects of development.

In Beachy’s latest work, published earlier this week in Nature Cell Biology, he and his colleagues show that the precise control of when and where the hedgehog protein is made dictates the branching of tubules in the adult prostate (you may remember other recent work from Beachy’s lab about the role that hedgehog plays in bladder cancer, and what that could mean for patients). The findings of the current research suggest that aberrant hedgehog signalling could play a role in the prostatic hyperplasia, or non-cancerous enlargement of the prostate, which often happens as men age.

Previously: Drug may prevent bladder cancer progression, say Stanford researchers, Cellular culprit identified for invasive bladder cancer, according to Stanford study and Bladder infections – How does your body repair the damage?
Photo by Tiffany Bailey

Dermatology, Research, Science, Stanford News, Stem Cells

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

Many stem cells live a life of monotony, biding their time until they’re needed to repair tissue damage or propel the growth of a developing embryo. But when the time is right, they must spring into action without hesitation. Like Clark Kent in a phone booth, they fling aside their former identity to become the needed skin, muscle, bone or other cell types.

Now researchers at Stanford, Harvard and the University of California-Los Angeles have learned that embryonic stem cells in mice and humans chemically tag RNA messages encoding key stem-cell genes. The tags tell the cell not to let the messages linger, but to degrade them quickly. Getting rid of those messages allows the cells to respond more nimbly to their new marching orders. As dermatology professor Howard Chang, MD, PhD, explained to me in an email:

Until now, we’ve not fully understood how RNA messages within the cell dissipate. In many cases, it was thought to be somewhat random. This research shows that embryonic stem cells actively tag RNA messages that they may later need to forget. In the absence of this mechanism, the stem cells are never able to forget they are stem cells. They are stuck and cannot become brain, heart or gut, for example.

Chang, who is a Howard Hughes Medical Institute investigator and a member of the Stanford Cancer Institute, is a co-senior author of a paper describing the research, which was published today in Cell Stem Cell. He shares senior authorship with Yi Xing, PhD, an associate professor of microbiology, immunology and molecular genetics at UCLA, and Cosmas Giallourakis, MD, an assistant professor of medicine at Harvard. Lead authorship is shared by postdoctoral scholars Pedro Batista, PhD, of Stanford, and Jinkai Wang, PhD, of UCLA; and by senior research fellow Benoit Molinie, PhD, of Harvard.

Messenger RNAs are used to convey information from the genes in a cell’s nucleus to protein-making factories in the cytoplasm. They carry the instructions necessary to assemble the hundreds of thousands of individual proteins that do the work of the cell. When, where and how long each protein is made is a carefully orchestrated process that controls the fate of the cell. For example, embryonic stem cells, which can become any cell in the body, maintain their “stemness” through the ongoing production of proteins known to confer pluripotency, a term used to describe how these cells can become any cell in the body.

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Cancer, Clinical Trials, Research, Science, Stanford News, Stem Cells

Drug may prevent bladder cancer progression, say Stanford researchers

Drug may prevent bladder cancer progression, say Stanford researchers

Bladder cancer is an insidious foe. About 70 percent of the time the condition is diagnosed while still confined to the bladder lining (in these cases, it’s known as a “carcinoma in situ,” or CIS). However, a subset of these localized cancers will go on to invade tissue surrounding the bladder and become much more deadly.

Now, developmental biologist Philip Beachy, PhD, a Howard Hughes Medical Institute investigator, and his colleagues have found that low doses of a drug called FK506 currently used to prevent the rejection of transplanted organs can prevent the progression of CIS into invasive bladder cancer in mice. Beachy collaborated with collaborated with urologist Joseph Liao, MD, and pulmonary specialist Edda Spiekerkoetter, MD, to conduct the research, which was published today in Cancer Cell. As Beachy explains in our release:

This could be a boon to the management of bladder cancer patients. Bladder cancer is the most expensive cancer to treat per patient because most patients require continual monitoring. The effective prevention of progression to invasive carcinoma would be a major advance in the treatment of this disease.

Beachy and Liao are members of the Stanford Cancer Institute. Together they’re hoping to initiate clinical trials of FK506 in people with CIS to learn whether the drug can also prevent progression to invasive cancer in humans.

The findings of the current study build upon previous research into the disease in Beachy’s laboratory and a long-time interest by Beachy in a molecular signaling pathway governed by a protein called sonic hedgehog. Beachy identified the first hedgehog protein in 1992; the protein (and the hedgehog pathway) have since been shown to play a vital role in embryonic developments and many types of cancers. Sonic hedgehog, Beachy has found, is produced by specialized stem cells in the bladder as a way to communicate with neighboring cells. They learned it’s required for the formation of CIS, but that it must also be lost in order for the cancer cells to invade other tissues. As Beachy explained in our release:

This was a very provocative finding. It was clear that these [sonic-hedgehog-expressing] bladder stem cells were the source of the intermediate cancers, or carcinomas in situ, that remain confined to the bladder lining. However, it was equally clear that sonic hedgehog expression must then be lost in order for those cancer cells to be able to invade surrounding tissue. We wondered whether the loss of this expression leads to increased tumor cell growth.

The researchers found that sonic hedgehog expression works in a loop with another class of proteins called BMPs. (You can read more about this in our release.) FK506 works by activating the BMP portion of the pathway in the absence of sonic hedgehog. Ten out of ten mice with CIS who received a low dose of the drug (low enough not to cause immunosuppression) were protected from developing invasive bladder cancer after five months of exposure to the carcinogen. In contrast, seven of nine mice receiving a placebo did develop the invasive form of the disease within the same time period.

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Cardiovascular Medicine, Genetics, Research, Science, Stanford News, Stem Cells

Stem cell study explains how mutation common in Asians affects heart health

Stem cell study explains how mutation common in Asians affects heart health

10011881004_d5ab6d7cd9_zMany Asians carry a mutation that causes their faces to flush when they drink alcohol. The affected gene is called ALDH2, and it also plays a role in cardiovascular health. Carriers are more susceptible to coronary artery disease and tend to recover more poorly than non-carriers from the damage caused by a heart attack. Now Stanford cardiologist Joseph Wu, MD, PhD, and postdoctoral scholar Antje Ebert, PhD, have learned why.

The researchers used a type of stem cell called an induced pluripotent stem cell, or iPS cell, to conduct the study. The stem cells are made from easily obtained tissue like skin, and they can be coaxed in the laboratory to become other types of tissue, like heart muscle cells. It’s one of the first times iPS cells have been used to examine ethnic-specific differences among populations. The research was published yesterday in Science Translational Medicine.

From our release:

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It is the first time ALDH2, which is involved in many common metabolic processes in cells of all types, has been shown to play a role in cell survival. In particular, ALDH2 activity, or the lack of it, influences whether a cell enters a state of programmed cell death called apoptosis in response to stressful growing conditions. […]

The use of heart muscle cells derived from iPS cells has opened important doors for scientists because tissue samples can be easily obtained and maintained in the laboratory for study. Until recently, researchers had to confine their studies to genetically engineered mice or to human heart cells obtained through a heart biopsy, an invasive procedure that yields cells which are difficult to keep alive long term in the laboratory.

You’ve likely read about Wu’s previous work with heart muscle cells derived from iPS cells. Now he’s shown iPS cells are also a good way to compare the effect of genetic differences among populations, and he has big plans. More details about his plans from our release:

Wu is working to start a biobank at the Stanford Cardiovascular Institute of iPS cells from about 1,000 people of many different ethnic backgrounds and health histories. “This is one of my main priorities,” he said. “For example, in California, we boast one of the most diverse populations on Earth. We’d like to include male and female patients of major representative ethnicities, age ranges and cardiovascular histories. This will allow us to conduct ‘clinical trials in a dish’ on these cells, a very powerful new approach, to learn which therapies work best for each group. This would help physicians to understand for the first time disease process at a population level through observing these cells as surrogates.”

Previously: Induced pluripotent stem cell mysteries explored by Stanford researchers, A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists

Photo by Nicholas Raymond

Neuroscience, Research, Stanford News, Stem Cells

Cellular padding could help stem cells repair injuries

Cellular padding could help stem cells repair injuries

The idea of using stem cells to heal injuries seems so obvious. If you have a spinal cord injury, why not inject some new cells that can replace the ones that are lost?

Unfortunately, the very act of injecting those cells is rife with trouble. The scraping as they move through the needle damages the cells and can even kill them. Then, once in the site of the injury, the cells can easily ooze away into other tissue, or die from the onslaught of chemicals in the injury.

Material scientists Sarah Heilshorn, PhD, is trying to help these cells with a type of gel that can protect and support them, allowing them to live long enough to possibly repair the injury. A grant from Stanford Bio-X, the pioneering interdisciplinary life sciences institute, is now helping Heilshorn and her colleagues, neurosurgeon Giles Plant, PhD, and chemical engineer Andrew Spakowitz, PhD, get the project off the ground.

In a story I wrote about the work, Heilshorn equates the gel to ketchup:

It’s pretty thick, but when you bang on the bottle the sauce flows smoothly through the neck, then firms back up on the plate – a process she calls self-healing. “We want our polymers to self-heal better than ketchup,” she said. “It flows a bit across the plate.”

Her goal is to develop a polymer that supports the cells when they are loaded in a syringe, but then flows freely through the needle, padding and protecting the cells, then firming up quickly when it reaches the site of injury. “We don’t want the cells to flow away,” she says.

These Seed grants from Bio-X have been credited as part of what has made the institute so successful in bringing together people from diverse disciplines to solve biomedical problems. “The seed grants are the special Bio-X glue that brings teams of faculty from all over the university to tackle complex problems in human health using new approaches,” said Carla Shatz, PhD, who directs Bio-X.

We’ll be writing about a few of the most exciting projects being funded with the recently announced 2014 Bio-X Seed grants over the next few weeks.

Previously: They said “Yes”: The attitude that defines Stanford Bio-X

Research, Science, Stanford News, Stem Cells

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cell mysteries explored by Stanford researchers

Induced pluripotent stem cells, also called iPS cells, made from easily accessible skin or other adult cells, are ideal for disease modeling, drug discovery and, possibly, cell therapy. That’s because they can be generated in large numbers and grown indefinitely in the laboratory. They also reflect the genetic background of the person from whom they were generated. However, some fundamental questions still remain before they’re ready for the full glare of the clinical limelight. Does it matter what type of starting cells scientists use to create the pluripotent stem cells? And what’s the best control to use when studying the effect of a particular, patient-specific mutation?

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have addressed and answered these questions. Their work was published yesterday in two back-to-back papers in the Journal of the American College of Cardiology. (Each paper is also accompanied by an editorial.) As Wu explained in an e-mail to me:

If your goal is to generate healthy iPS cell derivatives for regenerative therapy, it’s important to know whether the starting material makes a difference. For example, if I’m treating Alzheimer’s disease, is there a benefit to using iPS cell-derived brain cells made from brain cells? Likewise, if I’m treating a skin disorder, is there a benefit to using iPS cell-derived skin cells made from skin cells? As cardiologists, we are asked this quite often and each time, I had to say “I don’t know.” So we decided to do a study comparing the differentiation and functional ability of iPS cell-derived cardiomyocytes generated from two different sources: skin and heart. We also wanted to devise more efficient ways for researchers to quickly and easily create their own “designer” iPS cell lines to study particular mutations.

To answer the first question, the researchers created iPS cells from two types of starter cells: human fetal skin cells and cardiac progenitor cells. Not surprisingly, only the cardiac progenitor cells expressed genes known to be expressed in heart tissue. Wu and his colleagues then exposed the newly created pluripotent stem cells to growing conditions that favor the development of heart muscle cells called cardiomyocytes. They found that, although iPS cells derived from cardiac progenitor cells were more efficient at becoming cardiomyocytes, both types of starting material produced heart muscle cells that functioned similarly after a period of growth in the laboratory. As Wu explained:

These two populations of cells are essentially no different from one another over time. It appears that they lost the memory of their starting material (this memory is stored in the form of chemical tags on the cells’ DNA in a phenomena known as epigenetic marking). This suggests that I could take my own skin cells, make iPS cells and then create specialized brain, heart, liver or kidney cells for cell therapy. This is much easier than biopsying each tissue, and could be a good way to create universal iPS cell lines for research or cell therapy.

In the second paper, Wu and his colleagues devised a way to introduce specific mutations into iPS cells before transforming them into particular tissues. The approach relies on the use of what’s known as “dominant negative” mutations that exert their disruptive effect even when the unmutated gene is still present. This is important because it’s much easier and quicker than previous similar efforts, which required a complicated, time-consuming procedure to snip out and then replace individual genes. The technique also allows researchers to generate two cell lines that are identical except for the mutation under study. That way researchers can be confident that differences between the cell lines are due only to that mutation, which is particularly important when the lines are used to test the effect of therapeutic drugs. Again, from Wu:

Investigators can make their own designer iPS cell lines to study particular mutations with genetically identical controls to use in their experiments. We won’t have to make new iPS cells from each patient, which is laborious and time consuming. Instead we can create standardized lines to study many different mutations alone and in combination. This has the potential to revolutionize the field of disease modeling and drug discovery.

The two papers describe ongoing research in the Wu lab designed to optimize iPS cells for a variety of applications. The group, including graduate student Arun Sharma, recently published research using human iPS cell-derived cardiomyocytes to investigate the effect of various antiviral drugs againse coxsackievirus, a leading cause of an infection of the middle layer of the heart wall in children and the elderly. The research is the first time that iPS cell-derived heart muscle has been used to investigate the mechanisms behind an acquired viral disease.

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells, “Clinical trail in a dish” may make common medicines safer, say Stanford scientists and Lab-made heart cells mimic common cardiac disease in Stanford study

Cancer, Research, Science, Stanford News, Stem Cells

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Localized radiation therapy for breast cancer kills cancer cells at the tumor site. But, in a cruel irony, Stanford radiation oncologist Edward Graves, PhD, and research associate Marta Vilalta, PhD, have found that the dying cells in the breast may send out a signal that recruits other cancer cells back to the site of the initial tumor. Their work was published today in Cell Reports. As Graves explained in an e-mail to me:

Cancer spreads by shedding tumor cells into the circulation, where they can travel to distant organs and form secondary lesions.  We’ve demonstrated with this study that cancer radiation therapy may actually attract these circulating tumor cells, or CTCs, back to the primary tumor, which may lead to the regrowth of the tumor after radiation therapy.

The researchers studied mouse and human breast cancer cells growing in a laboratory dish, as well as human breast cancer cells implanted into mice. They found that irradiated cells secreted a molecule called granulocyte macrophage colony stimulating factor, or GM-CSF. Blocking the expression of GM-CSF by the cells inhibited (but didn’t completely block) their ability to recruit other cells to the cancer site. The finding is particularly interesting, since physicians sometimes give cancer patients injections of GM-CSF to enhance the growth of infection-fighting white blood cells that can be damaged during chemotherapy. As Graves explained, “This work has important implications for clinical radiotherapy, and for the use of GM-CSF in treating neutropenia in cancer patients during therapy.”

The researchers say, however, that cancer patients shouldn’t eschew radiation therapy. Rather, the finding may help clinicians devise better ways to fight the disease – perhaps by blocking GM-CSF signaling. Graves concluded:

It should be emphasized that radiation therapy remains one of the most effective treatments for cancer. Our findings will help us to further optimize patient outcomes following this already potent therapy.

Previously: Using 3-D technology to screen for breast cancer, Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers and Common drug class targets breast cancer stem cells, may benefit more patients, says study

Research, Science, Stanford News, Stem Cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

Ford assembly lineIn the early 1900s, Henry Ford was lauded for his use of the assembly line, which allowed the rapid, reliable and uniform production of over 15 million Model T automobiles. By codifying each step of production and using identical, interchangeable parts, he brought car ownership within reach of the average American and changed the face of our country.

Now Stanford cardiologist Joseph Wu, MD, PhD, and instructor Paul Burridge, PhD, have done something similar with stem cells. They’ve devised a way to create large numbers of heart muscle cells called cardiomyocytes from stem cells without using human or animal-derived products, which can vary in composition and concentration among batches. Their technique was published Sunday in Nature Methods. Wu, who is the director of the Stanford Cardiovascular Institute explained to me in an e-mail:

This technique solves an important hurdle for the use of iPS-derived heart cells. In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost. Due to their chemically defined nature, this system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes matching a specific patient’s heart phenotype.

Chemically defined cell culture means that scientists know exactly what (and how much) is in the liquid in which the cells are grown. In contrast, many common cell culture methods involve the use of nutrient-rich broth derived from animal or human sources. These liquids are teaming with proteins, some known and some unknown, that can promote stem cell growth. They get the job done, but their components can vary among batches and the outcome isn’t always reproducible.

In the new method, Wu and his colleagues collected cells from the skin or blood of an individual. They used a virus called the Sendai virus encoding four reprogramming genes to create induced pluripotent stem cells. These cells were then grown in a liquid in which everything needed for growth was precisely defined. As Wu explained, “This approach gives us an opportunity to fully understand the molecular and macromolecular requirements for cardiac differentiation and eliminates any animal-derived components that were previously used.”

The researchers found they were able to produce about 100 cardiomyocytes for every one stem cell by following a systematic series of steps and using a growing medium that contained just three well-defined components. They showed the technique worked on 11 different batches of induced pluripotent stem cells. The cardiomyocytes were more than 95 percent pure, making it easier to get large numbers of cells to study disease processes or to test the effects of compounds during drug development. According to Wu:

We can use this approach to assess the effect of a particular medication on a specific patient’s heart cells, to discover new drugs, to better understand the process of heart development and to generate cardiomyocytes for use in regenerative medicine approaches, such as for injection into the heart to aid recovery after a heart attack. The system also serves as a platform to study cardiomyocyte subtype specification and maturation.

Of course, stem cells are nothing like automobiles, and regular people aren’t lining up clamoring for a fresh vial of heart muscle cells. But it’s possible that the ability to reliably generate large numbers of cardiomyocytes for study and therapy could be as transformative to cardiac medicine as the Model T was to our grandparents and great grandparents.

Previously: Oh grow up! “Specialized” stem cells tolerated by the immune system, say Stanford researchers, Stem cell medicine for hearts? Yes, please, says one amazing family and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists
Photo by Kyle Harris

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