‘STARS’ Help Scientists Control Genetic On/Off Switch

All life on Earth relies, ultimately, on the delicate coordination of switches. During development, these switches turn genes on—or keep them off—at precise intervals, controlling the complex processes that guide the growth of the embryo, cell by cell, as it matures from a collection of stem cells into a living, breathing organism.

Scientists have found a new way to control genetic switches.

Scientists have found a new way to control genetic switches.

If you control the switch, you could theoretically control some of life’s most fundamental processes.

Which is precisely what scientists at Cornell University are attempting to do.

Reporting in today’s issue of Nature Chemical Biology, synthetic biologists have developed a new method of directing these switches—a feat that could revolutionize the field of genetic engineering.

At the heart of the team’s discovery is a tiny molecule called RNA. A more simplified version of its cousin, DNA, RNA normally serves as a liaison—translating the genetic information housed in DNA into the proteins that together make up each and every cell in the body.

In nature, RNA does not have the ability to ‘turn on’ a gene at will. So the Cornell team, led by Julius Lucks, made a new kind of RNA that did.

They engineered a new type of RNA that they are calling Small Transcription Activating RNAs, or STARS, that can serve as a kind of artificial switch. In laboratory experiments, Lucks and his team showed that they could control how and when a gene was switched on by physically placing the STARS system in front of it. As Lucks explained in a news release:

“RNA is like a molecular puzzle, a crazy Rubik’s cube that has to be unlocked in order to do different things. We’ve figured out how to design another RNA that unlocks part of that puzzle. The STAR is the key to that lock.”

RNA is an attractive molecule to manipulate because it is so simple, says Lucks, much simpler than proteins. Many efforts aimed at protein manipulation have failed, due to the sheer complexity of these molecules. But by downshifting into the simpler, more manageable RNA molecules, Lucks argues that greater strides can be made in the field of synthetic biology and genetic engineering.

“This is going to open up a whole set of possibilities for us, because RNA molecules make decisions and compute information really well, and they detect things really well,” said Lucks.

In the future, Lucks envisions a system based solely on RNA that has the capability to manipulate genetic switches to better understand fundamental processes that guide the healthy development of a cell—and provide clues to what happens when those processes go awry.

Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

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.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.

Getting the right tools for the right job

Imagine a device that sits outside the body and works like a form of dialysis for a damaged liver, filtering out the toxins and giving the liver a chance to regenerate, and the patient a chance to avoid the need for a transplant.

Or imagine a method of enhancing the number of stem cells we can harvest or generate from umbilical cord blood, enabling us to use those stem cells and offer life-saving bone marrow transplants to all the patients who don’t have a matched donor.

Well, you may not have to imagine for too long. Yesterday, our governing Board approved almost $30 million in funding for our Tools and Technology Awards and two of the successful applications are for researchers hoping to turn those two ideas into reality.

The Tools n Tech awards may not have the glamor or cache of the big money awards that are developing treatments heading towards clinical trials, but they are nonetheless an essential part of what we do.

As our Board Chair Jonathan Thomas said in a news release they focus on developing new approaches or creating new ways of overcoming some of the biggest obstacles in stem cell research.

“Sometimes even the most promising therapy can be derailed by a tiny problem. These awards are designed to help find ways to overcome those problems, to bridge the gaps in our knowledge and ensure that the best research is able to keep progressing and move out of the lab and into clinical trials in patients.”

Altogether 20 awards were funded for a wide variety of different ideas and projects. Some focus on improving our ability to manufacture the kinds of cells we need for transplanting into patients. Another one plans to use a new class of genetic engineering tools to re-engineer the kind of stem cells found in bone marrow, making them resistant to HIV/AIDS. They also hope this method could ultimately be used to directly target the stem cells while they are inside the body, rather than taking the cells out and performing the same procedure in a lab and later transplanting them back.

Dr. Kent Leach, UC Davis School of Engineering

Dr. Kent Leach, UC Davis School of Engineering

One of the winners was Dr. Kent Leach from the University of California, Davis School of Engineering. He’s looking to make a new kind of imaging probe, one that uses light and sound to measure the strength and durability of bone and cartilage created by stem cells. This could eliminate the need for biopsies to make the same measurements, which is good news for patients and might also help reduce healthcare costs.

We featured Dr. Leach in one of our Spotlight videos where he talks about using stem cells to help repair broken bones that no longer respond to traditional methods.

Extending the Lease: Stanford Scientists Turn Back Clock on Aging Cells

In the end, all living things—even the cells in our bodies—must die. But what if we could delay the inevitable, even just for a bit? What new scientific advances could come as a result?

Stanford scientists have found a way to temporarily extend the life of an aging cell.

Stanford scientists have found a way to temporarily extend the life of an aging cell.

In research published this week in the FASEB Journal, scientists at the Stanford University School of Medicine have devised a new method that gives aging DNA a molecular facelift.

The procedure, developed by Stanford Stem Cell Scientist Helen Blau and her team at the Baxter Laboratory for Stem Cell Biology, physically lengthens the telomeres—the caps on the ends of chromosomes that protect the cell from the effects of aging.

When born, all cells contain chromosomes capped with telomeres. But during each round of cell division, those telomeres shrink. Eventually, the telomeres shorten to such an extent that the chromosomes can no longer replicate at the rate they once could. For the cell, this is the beginning of the end.

The link between telomeres and cellular aging has been an intense focus in recent years, including the subject of the 2009 Nobel Prize in Physiology or Medicine. Extending the lifespan of cells by preventing—or reversing— the shortening of telomeres can not only boost cell division during laboratory studies, but can also lead to new therapeutic strategies to treat age-related diseases.

“Now we have found a way to lengthen human telomeres… turning back the internal clock in these cells by the equivalent of many years of human life,” explained Blau in a press release. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

The method Blau and her team describe involves the use of a modified bit of RNA that boosts the production of the protein telomerase. Telomerase is normally present in high levels in stem cells, but drops off once the cells mature. Blau’s modified RNA gives the aging cells a shot of telomerase, after which they begin behaving like cells half their age. But only for about 48 hours, after which they begin to degrade again.

The temporary nature of this change, say the researchers, offers significant advantages. On the biological level, it means that the treated cells won’t begin dividing out of control indefinitely, minimizing the risk of tumor formation. The study’s first author John Ramunas offers up some additional pluses to their method:

“Existing methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”

Indeed, the genetic disease Duchenne muscular dystrophy is in part characterized by abnormally short telomeres. Blau reasons that their discovery could lead to better treatments for this disease. Their immediate future steps involve testing their method in a variety of cell types. Said Blau:

“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally successful.”

Hear more about stem cells and muscular dystrophy in our recent Spotlight on Disease featuring Helen Blau:

Scientists Develop Colorful Cell-Imaging Technique

Proteins are the helmsmen of the cell. They drive the essential processes that keep cells alive, keep them healthy and keep them functioning. And in recent years scientists have discovered that proteins rarely act alone.

In fact, so-called ‘protein-protein interactions’ are now known to drive the vast majority of cellular functions. But figuring out exactly how they do so has proven difficult.

Luckily, scientists now have a way to see these interactions—in a dazzling array of Technicolor.

As described in today’s issue of Nature Methods, Robert Campbell and his team at the University of Alberta have announced a new way to visualize protein-protein interactions, by converting these interactions into changes in color. This technique could be employed across a variety of disciplines, helping scientists understand normal processes in the cell—and observe the molecular changes that occur when those processes go awry.

“With this development,” explained Campbell in a news release, “we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

Called FPX, Campbell’s method links a change in a protein-protein interaction to a color. As seen in the video below, every time the interaction changes, a color change—from red to green, and back to red again—is visible.

The FPX method is based on previously published work by Campbell and others, which found that green and red fluorescent proteins could both be inserted into a single cell so that the protein could be red or green—but not both at the same time. So, the team was able to construct biosensors that changed color in response to changes in protein-protein interactions.

In this study, the researchers have essentially given scientists a powerful tool to help them understand how even the smallest molecular changes can lead to significant changes in the health of the cell.

According to Campbell:

“It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes and cancer.”

Scientists Send Rodents to Space; Test New Therapy to Prevent Bone Loss

In just a few months, 40 very special rodents will embark upon the journey of a lifetime.

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Today UCLA scientists are announcing the start of a project that will test a new therapy that has the potential to slow, halt or even reverse bone loss due to disease or injury.

With grant funding from the Center for the Advancement of Science in Space (CASIS), a team of stem cell scientists led by UCLA professor of orthopedic surgery Chia Soo will send 40 rodents to the International Space Station (ISS). Living under microgravity conditions for two months, these rodents will begin to undergo bone loss—thus closely mimicking the conditions of bone loss, known as osteoporosis, seen in humans back on Earth.

At that point, the rodents will be injected with a molecule called NELL-1. Discovered by Soo’s UCLA colleague Kang Ting, this molecule has been shown in early tests to spur bone growth. In this new set of experiments on the ISS, the researchers hope to test the ability of NELL-1 to spur bone growth in the rodents.

The team is optimistic that NELL-1 could really be key to transforming how doctors treat bone loss. Said Ting in a news release:

“NELL-1 holds tremendous hope, not only for preventing bone loss but one day even restoring healthy bone. For patients who are bed-bound and suffering from bone loss, it could be life-changing.”

“Besides testing the limits of NELL-1’s robust bone-producing efforts, this mission will provide new insights about bone biology and could uncover important clues for curing diseases such as osteoporosis,” added Ben Wu, a UCLA bioengineer responsible for initially modifying NELL-1 to make it useful for treating bone loss.

The UCLA team will oversee ground operations while the experiments will be performed by NASA scientists on the ISS and coordinated by CASIS.

These experiments are important not only for developing new therapies to treat gradual bone loss, such as osteoporosis, which normally affects the elderly, but also those who have bone loss due to trauma or injury—including bone loss due to extended microgravity conditions, a persistent problem for astronauts living on the ISS. Said Soo:

“This research has enormous translational application for astronauts in space flight and for patients on Earth who have osteoporosis or other bone-loss problems from disease, illness or trauma.”

UC Davis Surgeons Begin Clinical Trial that Tests New Way to Deliver Stem Cells; Heal Bone Fractures

Each year, approximately 8.9 million people worldwide will suffer a bone fracture. Many of these fractures heal with the help of traditional methods, but for some, the road to recovery is far more difficult.

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After exhausting traditional treatments—such as surgically implanted pins or plates, bed rest and injections to spur bone growth—these patients can undergo a special type of stem cell transplant that directs stem cells extracted from the bone marrow to the fracture site to speed healing.

This procedure has its drawbacks, however. For example, the act of extracting cells from one’s own bone marrow and then injecting them into the fracture site requires two very painful surgical procedures: one to extract the cells, and another to implant them. Recovery times for each procedure, especially in older patients, can be significant.

Enter a team of surgeons at UC Davis. Who last week announced a ‘proof-of-concept’ clinical trial to test a device that can extract and isolate stem cells far more efficiently than before—and allow surgeons to implant the cells into the fracture in just a single surgery.

As described in HealthCanal, he procedure makes use of a reamer-irrigator-aspirator system, or RIA, that normally processes wastewater during bone drilling surgery. As its name implies, this wastewater was thought to be useless. But recent research has revealed that it is chock-full of stem cells.

The problem was that the stem cells were so diluted within the wastewater that they couldn’t be used. Luckily, a device recently developed by Sacramento-based SynGen, Inc., was able to quickly and efficiently extract the cells in high-enough concentrations to then be implanted into the patient. Instead of having to undergo two procedures—the patient now only has to undergo one.

“The device’s small size and rapid capabilities allow autologous stem cell transplantation to take place during a single operation in the operation room rather than requiring two procedures separated over a period of weeks,” said UC Davis surgeon Mark Lee, who is leading the clinical trial. “This is a dramatic difference that promises to make a real impact on healing and patient recovery.”

Hear more from Lee about how stem cells can be used to heal bone fractures in our 2012 Spotlight on Disease.

In living color: new imaging technique tracks traveling stem cells

Before blood stem cells can mature, before they can grow and multiply into the red blood cells that feed our organs, or the white blood cells that protect us from pathogens, they must go on a journey.

A blood stem cell en route to taking root in a zebrafish. [Credit: Boston Children's Hospital]

A blood stem cell en route to taking root in a zebrafish. [Credit:
Boston Children’s Hospital]

This journey, which takes place in the developing embryo, moves blood stem cells from their place of origin to where they will take root to grow and mature. That this journey happened was well known to scientists, but precisely how it happened remained shrouded in darkness.

But now, for the first time, scientists at Boston Children’s Hospital have literally shone a light on the entire process. In so doing, they have opened the door to improving surgical procedures that also rely on the movement of blood cells—such as bone marrow transplants, which are in essence stem cell transplants.

Reporting in today’s issue of the journal Cell, Boston Children’s senior investigator Leonard Zon and his team developed a way to visually track the trip that blood stem cells take in the developing embryo. As described in today’s news release, the same process that guides blood stem cells to the right place also occurs during a bone marrow transplant. The similarities between the two, therefore, could lead to more successful bone marrow transplants. According to the study’s co-first author Owen Tamplin:

“Stem cell and bone marrow transplants are still very much a black box—cells are introduced into a patient and later on we can measure recovery of the blood system, but what happens in between can’t be seen. Now we have a system where we can actually watch that middle step.”

And in the following video, Zon describes exactly how they did it:

As outlined in the above video, Zon and his team developed a transparent version of the zebrafish, a tiny model organism that is often used by scientists to study embryonic development. They then labeled blood stem cells in this transparent fish with a special fluorescent dye, so that the cells glowed green. And finally, with the help of both confocal and electron microscopy, they sat back and watched the blood stem cell take root in what’s called its niche—in beautiful Technicolor.

“Nobody’s ever visualized live how a stem cell interacts with its niche,” explained Zon. “This is the first time we get a very high-resolution view of the process.”

Further experiments found that the process in zebrafish closely resembled the process in mice—an indication that the same basic system could exist for humans.

With that possibility in mind, Zon and his team already have a lead on a way to improve the success of human bone marrow transplants. In chemical screening experiments, the team identified a chemical compound called lycorine that boosts the interaction between the zebrafish blood stem cell and its niche—thus promoting the number of blood stem cells as the embryo matures.

Does the lycorine compound (or an equivalent) exist to boost blood stem cells in mice? Or even in humans? That remains to be seen. But with the help of the imaging technology used by Zon and the Boston Children’s team—they have a good chance of being able to see it.

Strong ARMing regenerative medicine; bold thoughts on a bright future

It’s a time-honored tradition for the President of the United States to begin his State of the Union speech by saying “The state of our union is strong.” Well, Ed Lanphier, the incoming Chairman of the Alliance for Regenerative Medicine (ARM) – the industry trade group – took a leaf out of that book in kicking off the annual “State of the Industry Briefing” in San Francisco yesterday. He said the state of the industry is not just strong, but getting stronger all the time.

ARM_State_of_the_Industry_Briefing_2015_And he had the facts to back him up. In monetary terms alone he said the regenerative medicine field raised $6.3 billion in 2014, compared to $2.3 billion in 2013.

He pointed to the growing number of partnerships and alliances between big pharmaceutical businesses and smaller biotech and cell therapy companies as a sign that deep pocket investors recognize the potential in the field, saying “Big Pharma sees the value of these outcomes and the maturation of these pipelines.”

Lanphier also highlighted the more than 375 clinical trials that were underway last year, and the fact that more than 60 regenerative medicine products have been approved.

But he also pointed out that the field as a whole faces some big challenges in the coming years. One of the most pressing could be pricing. He cited criticisms that exploded over medicines like Gilead’s hepatitis C treatment Sovaldi because of its $1,000-a-day price tag. Lanphier warned that regenerative medicine could face similar criticisms when some of its therapies are finally approved, because they are likely to be very expensive (at least to start with). He said we need to start thinking now how to talk to patients and the public in general about this, so they understand why these treatments are so expensive, but may be cheaper in the long run if they cure rather than just treat disease.

As if to reinforce that message the first panel discussion in the briefing focused on the gene therapy and genome-editing field. Panel members talked about the high expectations for this field in the 1990’s but that it took decades of work before we finally started to see those early hopes turn into reality.

Jeffrey Walsh, the COO of bluebird bio talked about: “The excitement about gene therapy in the early days… and then having to survive the 15-20 years after that in the very challenging days for gene therapy.”

Katrine Bosley, the CEO of Editas Medicine, says those challenges have not gone away and that the field will have to address some big issues in the future. Among those are working with regulatory agencies such as the Food and Drug Administration (FDA) to win approval for completely new ways of treating disease. Another is anticipating the kinds of ethical issues they will have to address in using these techniques to alter genes.

Questions about the regulatory process also popped up in the second panel, which focused more on advanced therapy and drug development. Paul Laikind of ViaCyte (whose clinical trial in type 1 diabetes we are funding) highlighted those challenges saying: “Making the cells the way you want is not rocket science; but doing it in a way that meets regulatory requirements is rocket science.”

Paul Wotton, the President and CEO of Ocata Therapeutics (formerly called ACT) echoed those sentiments:

“We are pioneering things here and it’s the pioneers who often end up with arrows in their back, so you really have to spend a lot of time working with the FDA and other regulatory bodies to make sure you are having all the right conversations ahead of time.”

But while everyone freely acknowledged there are challenging times ahead, the mood was still very positive, perhaps best summed up by C. Randal Mills, the President of CEO of CIRM and moderator of the panel, when he said:

“I find it remarkable where we are in this space today – with this number of cutting edge companies in clinical trials. Stem cell therapy is becoming a reality, it’s no longer a place where only a foolish few dare to go in; it’s a reality. There is a change in the practice of medicine that is coming and we are all fortunate to be a part of it.”