Trash talking and creating a stem cell community

imilce2

Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.

Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.

The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.

One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.

Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.

Unlocking the secrets of premature aging

Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.

Creating a Community

ssscr

Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it’s 4th annual conference and the theme was “Culturing a Stem Cell Community.”

The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.

What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.

Bridging the divide

But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.

All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.

 

Circular RNAs: the Mind-Boggling Dark Matter of the Human Genome

We were just a few hours into the 2016 annual meeting of the International Society for Stem Cell Research (ISSCR) yesterday afternoon and my mind was already blown away. Pier Paolo Pandolfi of the Beth Israel Deaconess Medical Center at Harvard, spoke during the first plenary session about circular RNAs, which he dubbed, “the mind-boggling dark matter of the human genome” because their existence wasn’t confirmed until just four years ago.

To introduce the topic, Pandolfi compared human DNA to that of bacteria. Both species contain stretches of DNA sequence called genes that contain the instructions for making proteins which collectively form our bodies. Each gene is first transcribed into messenger RNA (mRNA) which in turn is translated into a protein.

Iceberg

Our DNA contains 20,000 genes. But that genetic material is just the tip of the iceberg.

But with the ability to sequence all the mRNA transcripts of an organism, or its transcriptome, came a startling fact about how differently our genetic structure is organized compared to bacteria. It turns out that 88% of DNA sequence in bacteria make up genes that code for proteins but only 2% of human DNA sequence directly codes for proteins. So what’s going with the other 98%? Scientist typically call this 98% chunk of the genome “regulatory DNA” because it contains sequences that act as control switches for turning genes on or off. But Pandolfi explained that more recent studies suggest that a whopping 70% of our genome (maybe even 95%) is transcribed into RNA but those RNA molecules just don’t get translated into protein.

 

One type of this “non-coding” RNA which we’ve blogged about plenty of times is called microRNA (miRNA). So far, about 5,000 human miRNAs have been identified compared to the 20,000 messenger RNAs that code for proteins. But by far the most abundant non-coding RNA in our transcriptome is the mysterious circular RNA (circRNA) with at least 100,000 different transcripts. circRNA was first observed as cellular structures in the 1980’s via electronic microscope images. Then in the 1990’s a scientist published DNA sequencing data suggesting the existence of circRNA. But the science community at that time panned the results, discrediting it as merely background noise of the experiments.

Pandolfi_2

Pier Paolo Pandolfi
Image: Beth Israel Deaconess Medical Center

But four years ago, the circRNAs were directly sequenced and their existence confirmed. The circRNAs are formed when messenger RNA goes through a well-described trimming process of its sequence. Some of the excised pieces of RNA form into the circular RNAs. It would seem that these circRNAs are just throw away debris but Pandolfi’s lab has found evidence that they directly play a role in cellular functions and even cancer.

His team studies a gene called Pokemon which, when genetically “knocked out” or removed from a mouse’s genome, leads to cancer. Now, it turns out this knockout not only removes the Pokemon protein but also a Pokemon circRNA (circPok). When the lab added back just the Pokemon gene, as you might expect, it acted to suppress cancer in the mice. But when just the circPok was added back, stunningly, it increased the formation of cancer in the mice. Given that genetic knockouts are one of the most pervasive techniques in biomedical science, a closer look at circRNAs that may have been overlooked in all of those results is clearly warranted.

Though this finding is somewhat scary in the fact that it’s a whole aspect of our genome that we’ve been unaware of, one fortunate aspect of circRNA is that they all carry a particular sequence which could be used as a target for a new class of drugs.

This data may extend to stem cells as well. We know that microRNAs have critical roles in regulating the maturation of stem cells into specialized cell types. Since circRNAs are thought to act by competing microRNA, it may not be long before we learn about circRNA’s role in stem cell function.

The other speakers at the first plenary session of the ISSCR annual meeting all gave high caliber talks. Luckily, Paul Knoepfler live blogged on two of those presentations. Here are the links:

 

Brave new world or dark threatening future: a clear-eyed look at genome editing and what it means for humanity

Frankenstein

   Is this the face of the future?

“Have you ever wished that there were something different about yourself? Maybe you imagined yourself taller, thinner or stronger? Smarter? More attractive? Healthier?”

That’s the question posed by UC Davis stem cell researcher (and CIRM grantee) Paul Knoepfler at the start of his intriguing new book ‘GMO Sapiens: The Life-Changing Science of Designer Babies’.

51rmGzXqfwL._SX336_BO1,204,203,200_

You can find GMO Sapiens on Amazon.com

The book is a fascinating, and highly readable, and takes a unique look at the dramatic advances in technology that allow us to edit the human genome in ways that could allow us to do more than just create “designer babies”, it could ultimately help us change the definition of what it means to be human.

Paul begins by looking at the temptation to use technologies like CRISPR (we have blogged about this here), to genetically edit or alter human embryos so that the resulting child is enhanced in some ways. It could be that the editing is used to remove a genetic mutation that could cause a deadly disease (such as the BRCA1 gene that puts women at increased risk of breast and ovarian cancer) or it could be that the technique is used to give a baby blue eyes, to make it taller, more athletic, or to simply eliminate male pattern baldness later in life.

Paul says those latter examples are not as ridiculous as they sound:

Paul Knoepfler

Paul Knoepfler

“If you think these ideas sound far-fetched, consider that Americans alone spend tens of billions of dollars each year on plastic surgery procedures and creams to try to achieve these kinds of goals. Some of the time elective cosmetic surgery is done on children. In the future, we might have “cosmetic genetic surgeons” who do “surgery” on our family’s genes for cosmetic reasons. In other countries the sensibilities and cultural expectations could lead to other kinds of genetic modifications of humans for “enhancements”.

While the technology that enables us to do this is new, the ideas behind why we would want to do this are far from new. Paul delves into those ideas including a look at the growth of the eugenics movement in the late 19th and early 20th century advocating the improvement of human genetic traits through higher reproductive rates for people considered “superior”. And there was a darker side to the movement:

“Indiana had instituted the first law for sterilization of “inferior” people in the world in 1907. Astonishingly this state law and then similar laws (the original was revoked, but a new law was passed later) stayed on the books in that state until 1974.

This led to approximately 2,500 governmentally forced sterilizations. The poor, uneducated, people of color, Native Americans, and people with disabilities were disproportionately targeted.”

Paul explores the ethical and moral implications of changing our genetic code, changes that can then be passed on to future generations. While he understands the desire to use these technologies to create positive changes, he is also very clear in his concerns that we don’t yet have enough knowledge to be able to use them in a safe manner.

“CRISPR can literally re-write the genomic book inside of us. However, it remains unknown how often it might go to the wrong page or paragraph, so to speak, or stay on the right page, but make an undesired edit there.”

Tiny errors in editing the genome, particularly at such an early stage in an embryo’s development, could have profound and unintended consequences years down the road, resulting in physical or developmental problems we can’t anticipate or predict. For example, you might remove the susceptibility to one disease only to create an even larger problem, one that is now embedded in that person’s DNA and ready to be passed on to subsequent generations.

The book includes interviews with key figures in the field – scientists, bioethicists etc. – and covers a wide range of views of what we should do. For example, the Director of the US National Institutes of Health (NIH), Francis Collins, said that designer babies “make good Hollywood — and bad science,” while the Center for Genetics and Society has advocated for a moratorium on human genetic modification in the US.

In contrast, scientists such as Harvard professor George Church and CRISPR pioneer Jennifer Doudna of UC Berkeley, say we need to carefully explore how to harness the potential for these technologies.

For Church it is a matter of choice:

“The new technology enables parents to make choices about their children just as they might with Ritalin or cleft palate surgery to ‘improve’ behavior or appearance.”

For Doudna it’s acknowledging the fact that you can’t put the genie back in the bottle:

“There’s no way to unlearn what is learned. We can’t put this technology to bed. If a person has basic knowledge of molecular biology they can do it. It’s not realistic to think we can block it…We want to put out there the information that people would need to make an informed decision, to encourage appropriate research and discourage forging ahead with clinical applications that could be dangerous or raise ethical issues.”

The power of Paul’s book is that while it does not offer any easy answers, it does raise many important questions.

It’s a wonderfully well-written book that anyone can read, even someone like me who doesn’t have a science background. He does a good job of leading the reader through the development of these technologies (from the basic idea of genetically altering plants to make them disease resistant) to the portrayal of these concepts in literature (Frankenstein and Brave New World) to movies (Gattaca – 4 stars on Rotten Tomatoes  a great film if you haven’t already seen it).

It’s clear where Paul stands on the issue; he believes there should be a moratorium on human genetic modification until we have a much deeper understanding of the science behind it, and the ethics and morality underpinning it:

“This is a very exciting time to be alive and we should be open to embracing change, but not blindly or in a rush. Armed with information and passion, we can have a major, positive impact on how this biotech revolution unfolds and impacts humanity.”

By the way, Paul also has one of the most widely read blogs about stem cells, where you can read more about his thoughts on CRISPR and other topics.