RNA

Stem cell stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

/ Kevin McCormack / 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.

zika

Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

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Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”

 

The key to unlocking stem cell’s potential and blocking a deadly threat

/ Kevin McCormack / Leave a comment
A small slice of who you are - brain cells made from embryonic stem cells.

A small slice of who you are – brain cells made from embryonic stem cells.

Our bodies are amazingly complex systems. By some estimates there are more than 37 trillion cells in our bodies.  That’s trillion with a “t”. Each of those cells engages in some form of communication and signaling with other cells which makes our bodies one heck of a busy place to be.

Yet all this activity may owe much of its splendor and complexity to a relatively small number of starting materials. Key among those may be one protein which seems to act like a “master switch” and can determine if a cell changes and multiplies, or just stays the same.

Starting out

But let’s begin at the beginning. We all start out as a single fertilized egg that develops into embryonic stem cells, which in turn become adult stem cells, which then give rise to all the different cells and tissues and structures in our body – such as our bones and brains and blood.

But how do those cells know when to change, what to change into, and when to stop? Change too little and something is undeveloped. Change too much and you risk the kind of explosive uncontrolled multiplication of cells that you see in cancer.

So, clearly, knowing what controls those changes in stem cells, and learning how to use it, could have an enormous impact on our ability to use stem cells to treat a wide range of diseases.

What’s in a name, or a number

Now researchers at Mount Sinai have identified a single protein that appears to play a major role in this control process. The protein is called zinc finger protein 217 (ZFP217) and it controls the actions of genes that in turn control whether a cell changes into another kind of cell and how often it keeps dividing and multiplying.

The study is published in Cell Stem Cell  and there is some pretty complex science involved but ultimately what it boils down to is that ZFP217 has an impact on m6A (scientists really need to start coming up with more imaginative names) which is a protein that helps determine if a gene is turned on or off. If turned on the gene performs one function. If turned off it doesn’t.

By, in effect, blocking the action of m6A, ZFP217 is able to stop the process that would allow stem cells to differentiate, or change, into other cells and also ends their ability to keep renewing themselves.

But wait, there’s more!

One other important role that ZFP217 plays is in helping spur the growth of cancerous tumors. Too much of the protein allows these cells to multiply in an unlimited and uncontrolled fashion, typical of the kind of growth we see in tumors.

The study was done in mice but in a news release  the lead study author, Martin Walsh, PhD, talked about the possible significance of the findings for people:

“The hope is that ZFP217 could be used to maintain supplies of therapeutic stem cells. At the same time, as the human ZPF217 is associated with poor survival in a variety of cancers, understanding how this protein operates in physiological conditions may help to predict cancer risk, achieve earlier diagnosis and provide novel therapeutic approaches.”

Having a deeper understanding of what makes some stem cells multiply and change into other cells could enable researchers to better use stem cells to develop new approaches to treating some of the most intractable diseases of our time.

If that happens then ZFP217 might be a name to remember after all.

‘STARS’ Help Scientists Control Genetic On/Off Switch

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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.

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

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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: