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Events, Genetics, Patient Care, Pediatrics, Research, Stanford News, Stem Cells

“It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy

“It’s not just science fiction anymore": Childx speakers talk stem cell and gene therapy

childx PorteusAt the Childx conference last week there was a great deal of optimism that stem cell and genetic therapies are about to have a huge impact on many childhood diseases. “It’s not just science fiction anymore,” Matthew Porteus, MD, PhD, told the audience. “We can correct mutations that cause childhood disease.”

The session was hosted by Stanford professor Maria Grazia Roncarolo, MD, who until recently was head of the Italy’s Telethon Institute for Cell and Gene Therapy at the San Raffaele Scientific Institute in Milan. Roncarolo pointed out that there are more than 10,000 human diseases that are caused by a single gene defect. “Stem cell and gene therapies can be used to treat cancer and other diseases,” Roncarolo said.

Two such diseases are sickle cell disease and severe combined immune deficiency. In both cases, a single nucleotide change in DNA becomes a deadly defect for children with the bad luck to have them. Porteus is working on very new genome editing technologies that allow clinicians to go in and fix those DNA typos and cure diseases.

Stanford dermatology researcher Anthony Oro, MD, PhD is working to do something similar with skin cells for a painful blistering disease called epidermolysis bullosa. Children with EB lack a functional gene for one of the proteins that anchors the layers of skin together. Oro and Stanford Institute for Stem Cell Biology and Regenerative Medicine scientist Marius Wernig, MD, PhD, are taking defective skin cells from patients, transforming them into embryonic-like stem cells, fixing the gene defect, and then growing them back into skin stem cells and then layers of skin ready for transplantation. Oro says that they have shown that they can do this in a scalable way in mice, and they hope to start a clinical trial in humans soon.

One of the challenges to genetic therapy is that it often requires putting the gene into blood stem cells to deliver it to the body, but the high dose chemotherapy or radiation that is necessary to remove the bodies own blood stem cells and make way for the transplanted cells is very dangerous in itself. Researchers like Stanford researcher Hiromitsu Nakuchi, MD, PhD, are exploring gentler ways to make space in the body for the transplanted cells. He has discovered that simply by feeding mice a diet deficient in a particular amino acid, blood stem cells begin to die. Other cells in the body don’t seem to be as strongly affected. A dietary solution may eventually allow clinicians to avoid using the highly toxic treatments that have traditionally been used for blood stem cell transplant.

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Research, Science, Stanford News, Stem Cells

Bridging the stem-cell gap: Stanford researchers identify unique transition state

Bridging the stem-cell gap: Stanford researchers identify unique transition state

474026463_87cca6b272_zIn 2006, Shinya Yamanaka, MD, PhD, turned the stem-cell world upside down when he showed it was possible to take mature, specialized cells such as those found in skin and convert them to a pluripotent state simply by exposing them to a few key proteins. The discovery earned Yamanaka the Nobel Prize in Physiology or Medicine in 2012 and sparked an explosion of stem-cell science.

Although the exact steps of the reprogramming process are unknown, scientists have thought it proceeded mostly as a two-step pathway that essentially rewinds the march to specialization that normally occurs during development. Now Marius Wernig, MD, and his colleagues at the Stanford Institute for Stem Cell Biology and Regenerative Medicine have uncovered an intermediary state through which the cells must pass to successfully acquire pluripotency (a term that describes a cell’s ability to become nearly any cell type in the body). The researchers published their findings in today’s  Nature.

As Wernig described in my article on the research:

This [finding] was completely unexpected. It’s always been assumed that reprogramming is simply a matter of pushing mature cells backward along the developmental pathway. These cells would undergo two major changes: they’d turn off genes corresponding to their original identity, and begin to express pluripotency genes. Now we know there’s an intermediary state we’d never imagined before.

Cells in this “bridge” state express cell surface markers that are distinct from those found on fibroblasts (the starting cell type) and on successfully reprogrammed iPS cells. They also express specific transcription factors that likely contribute to the cells’ progression through the reprogramming process.

The researchers believe it may be possible to increase the efficiency of reprogramming in cells that typically resist the process (these cell types include highly specialized cells or cancer cells). But they’re more excited about peeking into the inner workings of a transformation that’s been both revolutionary and mysterious.

“We’re learning more and more about how cells accomplish this really unbelievable task of reverting to pluripotency,” Wernig told me. “Now we know that the cell biology of this process is novel, and this intermediary state is unique.”

Previously: Congratulations to Marius Wernig, named Outstanding Young Investigator by stem cell society, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Human neurons from skin cells without pluripotency?
Photo by Alexis R

Genetics, Pediatrics, Podcasts, Research, Stem Cells

Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

RoncaroloNext month’s inaugural Childx conference will bring a diverse group of experts to Stanford to discuss big challenges in infant, child and maternal health. Today, in a new 1:2:1 podcast interview, stem cell and gene therapy expert Maria Grazia Roncarolo, MD, provides an interesting preview of a once-controversial area of research that will be featured at the conference.

Roncarolo talks about the history and future of stem cell and gene therapy treatments, which have recovered from tragic setbacks such as the 1999 death of 18-year-old Jesse Gelsinger in an early gene therapy trial. The early problems forced researchers to reevaluate what they were doing, with the result that the entire field has reemerged stronger, she explains:

I would say that there were major problems, that we underestimated the complexity that it takes to manipulate the genome, and to introduce a healthy gene to fix a genetic disease. However, from these mistakes and from these tragedies, we learned a lot. We were really forced as doctors, and more importantly, as scientists, to go back to the bench and develop better technologies and to understand more of what was required. … [Today] we use better vectors — which are the carriers to introduce the healthy gene — we know much more about what we have to do to prepare the patient to receive the gene therapy, and we also learned that we need to do a very careful monitoring of the patients to really understand where the gene lands in the genome.

At the Childx conference, Roncarolo will moderate a panel on “Definitive Stem Cell and Gene Therapy for Child Health,” hosting such guests as GlaxoSmithKline’s senior vice president of rare diseases, Martin Andrews, and Nadia Rosenthal, PhD, founding director of the Australian Regenerative Medicine Institute.

Information about registration for Childx, being held here April 2–3, is available on the conference website.

Previously: Stanford hosts inaugural Childx conference this spring and Stanford researchers receive $40 million from state stem cell agency
Photo by Norbert von der Groeben

Cancer, Stanford News, Stem Cells, Videos

A look at stem cells and “chemobrain”

A look at stem cells and "chemobrain"

As many as 75 percent of cancer patients experience memory and attention problems during or after their treatment, and up to 3.9 million are afflicted by long-term cognitive dysfunction. This foggy mental state, often referred to as “chemobrain,” can also affect cancer survivors’ fine motor skills, information processing speed, concentration and ability to calculate.

In this recently posted California Institute for Regenerative Medicine video, Stanford physician-scientist Michelle Monje, MD, PhD, explains the role that damage to stem cells in the brain plays in the condition, outlines some of the interventions that can mitigate patients’ symptoms, and highlights efforts to develop effective regenerative therapies.

Previously: Stanford brain tumor research featured on “Bay Area Proud”, Emmy nod for film about Stanford brain tumor research – and the little boy who made it possible and Stanford study shows effects of chemotherapy and breast cancer on brain function

Events, Research, Science, Stanford News, Stem Cells

Live tweeting Stanford speakers at AAAS meeting

Live tweeting Stanford speakers at AAAS meeting

Whether you plan to spend the weekend wallowing in work, or canoodling on the couch (Happy Valentine’s Day!), you can follow Stanford Medicine researchers at the AAAS Annual Meeting, a gathering of thousands of scientists that will be held this weekend in San Jose.

Kicking off Friday (the conference officially began today), we’ll be live tweeting from the panel discussion “Informatics and Bioimaging: New Ways to Better Medicines,” featuring Stanford bioengineer Russ Altman, MD, PhD, from 10 to 11:30 `a.m.

Take a break for lunch, then check in to hear Steve Goodman, MD, PhD, Stanford’s associate dean of clinical and translational research, discussing “Responsible Data-Sharing for Clinical Trials” from 3 to 4:30 p.m.

Early Saturday, join Christopher Scott, PhD, director of the Stanford University Program on Stem Cells in in Society, as he addresses “Challenges in Communicating about Stem Cells” from 8 to 9:30 a.m.

Finally on Sunday, we’ll be tweeting as John Ioannidis, MD, DSc, director of the Stanford Prevention Research Center, discusses the “Reproducibility of Science: A Roadmap Forward” from 1 to 2:30 p.m.

We’ll sprinkle in other tweets throughout the weekend, and we’ll follow-up with a series of blog posts about the various talks. You can follow the tweets on the @StanfordMed feed or by using the hashtag #AAASmtg.

Previously: Live tweeting sessions at Stanford’s Med School 101, Live tweeting Jack Andraka’s Medicine X keynote and Live tweeting Big Data in Biomedicine

Biomed Bites, In the News, Research, Stem Cells, Technology, Videos

“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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