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MicroRNA is the master regulator of the genome − researchers are learning how to treat disease by harnessing the way it controls genes

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MicroRNA is the master regulator of the genome − researchers are learning how to treat disease by harnessing the way it controls genes

RNA is more than just a transitional state between DNA and protein.
Kateryna Kon/Science Photo Library via Getty Images

Andrea Kasinski, Purdue University

The Earth formed 4.5 billion years ago, and less than a billion years after that. Although life as we know it is dependent on four major macromolecules – DNA, RNA, proteins and lipids – only one is thought to have been present at the beginning of life: RNA.

It is no surprise that RNA likely came first. It is the only one of those major macromolecules that can both replicate itself and catalyze chemical reactions, both of which are essential for life. Like DNA, RNA is made from individual nucleotides linked into chains. Scientists initially understood that genetic information flows in one direction: DNA is transcribed into RNA, and RNA is translated into proteins. That principle is called the central dogma of molecular biology. But there are many deviations.

One major example of an exception to the central dogma is that some RNAs are never translated or coded into proteins. This fascinating diversion from the central dogma is what led me to dedicate my scientific career to understanding how it works. Indeed, research on RNA has lagged behind the other macromolecules. Although there are multiple classes of these so-called noncoding RNAs, researchers like myself have started to focus a great deal of attention on short stretches of genetic material called microRNAs and their potential to treat various diseases, cancer.

MicroRNAs play a key role in regulating gene expression.

MicroRNAs and disease

Scientists regard microRNAs as master regulators of the genome due to their ability to bind to and alter the expression of many protein-coding RNAs. Indeed, a single microRNA can regulate anywhere from 10 to 100 protein-coding RNAs. Rather than translating DNA to proteins, they instead can bind to protein-coding RNAs to silence genes.

The reason microRNAs can regulate such a diverse pool of RNAs stems from their ability to bind to target RNAs they don’t perfectly match up with. This means a single microRNA can often regulate a pool of targets that are all involved in similar processes in the cell, leading to an enhanced response.

Because a single microRNA can regulate multiple genes, many microRNAs can contribute to disease when they become dysfunctional.

In 2002, researchers first identified the role dysfunctional microRNAs play in disease through with a type of blood and bone marrow cancer called chronic lymphocytic leukemia. This cancer results from the loss of two microRNAs normally involved in blocking tumor cell growth. Since then, scientists have identified over 2,000 microRNAs in people, many of which are altered in various diseases.

The field has also developed a fairly solid understanding of how microRNA dysfunction contributes to disease. Changing one microRNA can change several other genes, resulting in a plethora of alterations that can collectively reshape the cell’s physiology. For example, over half of all cancers have significantly reduced activity in a microRNA called miR-34a. Because miR-34a regulates many genes involved in preventing the growth and migration of cancer cells, losing miR-34a can increase the risk of developing cancer.

Researchers are looking into using microRNAs as for cancer, heart disease, neurodegenerative disease and others. While results in the laboratory have been promising, bringing microRNA treatments into the clinic has met multiple challenges. Many are related to inefficient delivery into target cells and poor stability, which limit their effectiveness.

Diagram showing a loop of microRNA binding to a strand of mRNA as it's being translated from DNA
MicroRNA can silence genes by binding to mRNA.
Kajsa Mollersen/Wikimedia Commons, CC BY-SA

Delivering microRNA to cells

One reason why delivering microRNA treatments into cells is difficult is because microRNA treatments need to be delivered specifically to diseased cells while avoiding healthy cells. Unlike mRNA COVID-19 vaccines that are taken up by scavenging immune cells whose job is to detect foreign materials, microRNA treatments need to fool the body into thinking they aren’t foreign in order to avoid immune attack and get to their intended cells.

Scientists are studying various ways to deliver microRNA treatments to their specific target cells. One method garnering a great deal of attention relies on directly linking the microRNA to a ligand, a kind of small molecule that binds to specific proteins on the surface of cells. Compared with healthy cells, diseased cells can have a disproportionate number of some surface proteins, or receptors. So, ligands can help microRNAs home specifically to diseased cells while avoiding healthy cells. The first ligand approved by the U.S. Food and Drug Administration to deliver small RNAs like microRNAs, N-acetylgalactosamine, or GalNAc, preferentially delivers RNAs to liver cells.

Identifying ligands that can deliver small RNAs to other cells requires finding receptors expressed at high enough levels on the surface of target cells. Typically, over one million copies per cell are needed in order to achieve sufficient delivery of the drug.

One ligand that stands out is folate, also referred to as vitamin B9, a small molecule critical during periods of rapid cell growth such as fetal development. Because some tumor cells have over one million folate receptors, this ligand provides sufficient to deliver enough of a therapeutic RNA to target different types of cancer. For example, my laboratory developed a new molecule called FolamiR-34a – folate linked to miR-34a – that reduced the size of breast and lung cancer tumors in mice.

Microscopy image juxtaposing endothelial cells sprouting extensions to form new blood vessels and a cell bathed in microRNA unable to sprout
Tumors can exploit healthy cells to grow blood vessels that them nutrients, as seen in the endothelial cells to the left sprouting extensions. Exposing these cells to certain microRNAs, however, can disable that growth, as seen in the cell to the right.
Dudley Lab, University of Virginia School of Medicine/NIH via Flickr, CC BY-NC

Making microRNAs more stable

One of the other challenges with using small RNAs is their poor stability, which to their rapid degradation. As such, RNA-based treatments are generally short-lived in the body and require frequent doses to maintain a therapeutic effect.

To overcome this , researchers are modifying small RNAs in various ways. While each RNA requires a specific modification pattern, successful changes can significantly increase their stability. This reduces the need for frequent dosing, subsequently decreasing treatment burden and cost.

For example, modified GalNAc-siRNAs, another form of small RNAs, reduces dosing from every few days to once every six months in nondividing cells. My team developed folate ligands linked to modified microRNAs for cancer treatment that reduced dosing from once every other day to once a . For diseases like cancer where cells are rapidly dividing and quickly diluting the delivered microRNA, this increase in activity is a significant advancement in the field. We anticipate this accomplishment will facilitate further development of this folate-linked microRNA as a cancer treatment in the years to .

While there is still considerable work to be done to overcome the hurdles associated with microRNA treatments, it’s clear that RNA shows promise as a therapeutic for many diseases.The Conversation

Andrea Kasinski, Associate Professor of Biological Sciences, Purdue University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Cells have more mini ‘organs’ than researchers thought − unbound by membranes, these rogue organelles challenge biology’s fundamentals

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theconversation.com – Allan Albig, Associate Professor of Biological Sciences, Boise – 2024-11-05 07:44:00

Specialized compartments within cells carry out specific functions.
Christoph Burgstedt/Science Photo Library via Getty Images

Allan Albig, Boise State University

Think back to that basic biology class you took in high school. You probably learned about organelles, those little “organs” inside cells that form compartments with individual functions. For example, mitochondria produce energy, lysosomes recycle waste and the nucleus stores DNA. Although each organelle has a different function, they are similar in that every one is wrapped up in a membrane.

Membrane-bound organelles were the textbook standard of how scientists thought cells were organized until they realized in the mid-2000s that some organelles don’t need to be wrapped in a membrane. Since then, researchers have discovered many additional membraneless organelles that have significantly changed how biologists think about the chemistry and origins of .

I was introduced to membraneless organelles, formally called biomolecular condensates, a years ago when in my lab observed some unusual blobs in a cell nucleus. Unbeknownst to me, we had actually been studying biomolecular condensates for years. What I finally saw in those blobs opened my eyes to a whole new world of cell biology.

Like a lava lamp

To get a sense of what a biomolecular condensate looks like, imagine a lava lamp as the blobs of wax inside fuse together, break apart and fuse again. Condensates form in much the same way, though they are not made of wax. Instead, a cluster of proteins and genetic material, specifically RNA molecules, in a cell condenses into gel-like droplets.

Some proteins and RNAs do this because they preferentially interact with each other instead of their surrounding , very much like how wax blobs in a lava lamp mix with each other but not the surrounding liquid. These condensates create a new microenvironment that attracts additional proteins and RNA molecules, thus forming a unique biochemical compartment within cells.

Biomolecular condensates behave like liquids.

As of 2022, researchers have found about 30 kinds of these membraneless biomolecular condensates. In comparison, there are around a dozen known traditional membrane-bound organelles.

Although easy to identify once you know what you are looking for, it’s difficult to figure out what biomolecular condensates exactly do. Some have well-defined roles, such as forming reproductive cells, stress granules and protein-making ribosomes. However, many others don’t have clear functions.

Nonmembrane-bound organelles could have more numerous and diverse functions than their membrane-bound counterparts. Learning about these unknown functions is affecting scientists’ fundamental understanding of how cells work.

Protein structure and function

Biomolecular condensates are breaking some long-held beliefs about protein chemistry.

Ever since scientists first got a good look at the structure of the protein myoglobin in the 1950s, it was clear that its structure is important for its ability to shuttle oxygen in muscles. Since then, the mantra for biochemists has been that protein structure equals protein function. Basically, proteins have certain shapes that allow them to perform their .

The proteins that form biomolecular condensates at least partially break this rule since they contain regions that are disordered, meaning they do not have defined shapes. When researchers discovered these so-called intrinsically disordered proteins, or IDPs, in the early 1980s, they were initially confounded by how these proteins could lack a strong structure but still perform specific functions.

Later, they found that IDPs tend to form condensates. As is so often the case in science, this finding solved one mystery about the roles these unstructured rogue proteins play in the cell only to open another deeper question about what biomolecular condensates really are.

Bacterial cells

Researchers have also detected biomolecular condensates in prokaryotic, or bacterial, cells, which traditionally were defined as not containing organelles. This finding could have profound effects on how scientists understand the biology of prokaryotic cells.

Only about 6% of bacterial proteins have disordered regions lacking structure, with 30% to 40% of eukaryotic, or nonbacterial, proteins. But scientists have found several biomolecular condensates in prokaryotic cells that are involved a variety of cellular functions, including making and breaking down RNAs.

The presence of biomolecular condensates in bacterial cells means that these microbes aren’t simple bags of proteins and nucleic acids but are actually more complex than previously recognized.

Microscopy image of round lavender blobs with round magenta blobs within them
Inclusion bodies, stained magenta in this micrograph of herpesvirus 6, are aggregates of proteins that form a type of biomolecular condensate.
National Cancer Institute/National Institutes of Health via Wikimedia Commons

Origins of life

Biomolecular condensates are also changing how scientists think about the origins of life on Earth.

There is ample evidence that nucleotides, the building blocks of RNA and DNA, can very plausibly be made from common chemicals, like hydrogen cyanide and , in the presence of common energy sources, like ultraviolet light or high temperatures, on universally common minerals, like silica and iron clay.

There is also evidence that individual nucleotides can spontaneously assemble into chains to make RNA. This is a crucial step in the RNA world hypothesis, which postulates that the first “lifeforms” on Earth were strands of RNAs.

A major question is how these RNA molecules might have evolved mechanisms to replicate themselves and organize into a protocell. Because all known life is enclosed in membranes, researchers studying the origin of life have mostly assumed that membranes would also need to encapsulate these RNAs. This would require synthesizing the lipids, or fats, that make up membranes. However, the materials needed to make lipids likely weren’t present on early Earth.

With the discovery that RNAs can spontaneously form biomolecular condensates, lipids wouldn’t be needed to form protocells. If RNAs were able to aggregate into biomolecular condensates on their own, it becomes even more plausible that living molecules arose from nonliving chemicals on Earth.

New treatments

For me and other scientists studying biomolecular condensates, it is exciting to dream of how these rule-breaking entities will change our perspective on how biology works. Condensates are already changing how we think about human diseases like Alzheimer’s, Huntington’s and Lou Gehrig’s.

To this end, researchers are developing several new approaches to manipulate condensates for medical purposes like new that can promote or dissolve condensates. Whether this new approach to treating disease will bear fruit remains to be determined.

In the long term, I wouldn’t be surprised if each biomolecular condensate is eventually assigned a particular function. If this happens, you can bet that high school biology students will have even more to learn – or complain – about in their introductory biology classes.The Conversation

Allan Albig, Associate Professor of Biological Sciences, Boise State University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Carl Sagan’s scientific legacy extends far beyond ‘Cosmos’

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theconversation.com – Jean-Luc Margot, Professor of Earth, Planetary, and Sciences, of California, Los Angeles – 2024-11-05 07:44:00

Carl Sagan at his Cornell University laboratory in Ithaca, N.Y., in 1974.
Santi Visalli, Inc./Archive Photos via Getty Images

Jean-Luc Margot, University of California, Los Angeles

On Nov. 9, 2024, the world will mark Carl Sagan’s 90th birthday – but sadly without Sagan, who died in 1996 at the age of 62.

Most people remember him as the co-creator and host of the 1980 “Cosmos” television series, watched worldwide by hundreds of millions of people. Others read “Contact,” his best-selling science fiction novel, or “The Dragons of Eden,” his Pulitzer Prize-winning nonfiction book. Millions more saw him popularize astronomy on “The Tonight Show.”

What most people don’t know about Sagan, and what has been somewhat obscured by his fame, is the far-reaching impact of his science, which resonates to this day. Sagan was an unequaled science communicator, astute advocate and prolific writer. But he was also an outstanding scientist.

Sagan propelled science forward in at least three important ways. He produced notable results and insights described in over 600 scientific papers. He enabled new scientific disciplines to flourish. And he inspired multiple generations of scientists. As a planetary astronomer, I believe such a combination of talents and accomplishments is rare and may occur only once in my lifetime.

Scientific accomplishments

Very little was known in the 1960s about Venus. Sagan investigated how the greenhouse effect in its carbon dioxide atmosphere might explain the unbearably high temperature on Venus – approximately 870 degrees Fahrenheit (465 degrees Celsius). His research remains a cautionary tale about the dangers of fossil fuel emissions here on Earth.

Carl Sagan poses before a backdrop that shows the stars and galaxies of space.
Carl Sagan hosted and co-wrote ‘Cosmos,’ a 13-part TV series that aired on PBS stations from 1980 to 1981.
Mickey Adair/Michael Ochs Archives/Hulton Archive via Getty Images

Sagan proposed a compelling explanation for seasonal changes in the brightness of Mars, which had been incorrectly attributed to vegetation or volcanic activity. Wind-blown dust was responsible for the mysterious variations, he explained.

Sagan and his studied how changes to the reflectivity of Earth’s surface and atmosphere affect our climate. They considered how the detonation of nuclear bombs could inject so much soot into the atmosphere that it would to a yearslong period of substantial cooling, a phenomenon known as nuclear winter.

With unusual breadth in astronomy, physics, chemistry and biology, Sagan pushed forward the nascent discipline of astrobiology – the study of life in the universe.
Together with the research scientist Bishun Khare at Cornell University, Sagan conducted pioneering laboratory experiments and showed that certain ingredients of prebiotic chemistry, called tholins, and certain building blocks of life, known as amino acids, form naturally in laboratory environments that mimic planetary settings.

A photograph of the golden record.
Carl Sagan proposed the ‘Golden Record,’ which features the sounds of Earth, greetings spoken in 55 languages.
NASA via Wikimedia Commons

He also modeled the delivery of prebiotic molecules to the early Earth by asteroids and comets, and he was deeply engaged in the biological experiments onboard the Mars Viking landers. Sagan also speculated about the possibility of balloon-shaped organisms floating in the atmospheres of Venus and Jupiter.

His passion for finding life elsewhere extended far beyond the solar system. He was a champion of the search for extraterrestrial intelligence, also known as SETI. He helped fund and participated in a systematic search for extraterrestrial radio beacons by scanning 70% of the sky with the physicist and electrical engineer Paul Horowitz.

He proposed and co-designed the plaques and the “Golden Records” now affixed to humanity’s most distant ambassadors, the Pioneer and Voyager spacecrafts. It is unlikely that extraterrestrials will ever find these artifacts, but Sagan wanted people to contemplate the possibility of communication with other civilizations.

Carl Sagan, offering his unique commentary in a scene from ‘Cosmos.’

Advocacy

Sagan’s scientific output repeatedly led him to become an eloquent advocate on issues of societal and scientific significance. He testified before about the dangers of climate change. He was an antinuclear activist and spoke out against the Strategic Defense Initiative, also known as “Star Wars.” He urged collaborations and a joint space mission with the Soviet Union, in an attempt to improve U.S.-Soviet relations. He spoke directly with members of Congress about the search for extraterrestrial intelligence and organized a petition signed by dozens of prominent scientists urging for the search.

But perhaps his most important gift to society was his promotion of truth-seeking and critical thinking. He encouraged people to muster the humility and discipline to confront their most cherished beliefs – and to rely on evidence to obtain a more accurate view of the world. His most cited book, “The Demon-Haunted World: Science as a Candle in the Dark,” is a precious resource for anyone to navigate this age of disinformation.

Impact

A scientist’s impact can sometimes be gauged by the number of times their scholarly work is cited by other scientists. According to Sagan’s Google Scholar page, his work continues to accumulate more than 1,000 citations per year.

Indeed, his current citation rate exceeds that of many members of the National Academy of Sciences, who are “elected by their peers for outstanding contributions to research,” according to the academy’s website, and is “one of the highest honors a scientist can .”

Sagan was nominated for election into the academy during the 1991-1992 cycle, but his nomination was challenged at the annual meeting; more than one-third of the members voted to keep him out, which doomed his admission. An observer at that meeting wrote to Sagan, “It is the worst of human frailties that keeps you out: jealousy.” This belief was affirmed by others in attendance. In my opinion, the academy’s failure to admit Sagan remains an enduring stain on the organization.

No amount of jealousy can diminish Sagan’s profound and wide-ranging legacy. In addition to his scientific accomplishments, Sagan has inspired generations of scientists and brought an appreciation of science to countless nonscientists. He has demonstrated what is possible in the realms of science, communication and advocacy. Those accomplishments required truth-seeking, hard work and self-improvement. On the 90th anniversary of Sagan’s birth, a renewed commitment to these values would honor his memory.The Conversation

Jean-Luc Margot, Professor of Earth, Planetary, and Space Sciences, University of California, Los Angeles

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The 27 Club isn’t true, but it is real − a sociologist explains why myths endure and how they shape reality

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theconversation.com – Zackary Okun Dunivin, Postdoctoral Fellow in Communication, of California, Davis – 2024-11-04 14:02:00

Many members of the 27 Club are outsize in their cultural influence.
Psychology Forever/Wikimedia Commons, CC BY-SA

Zackary Okun Dunivin, University of California, Davis

There’s a certain allure to the notion that some of the world’s brightest burn out at the age of 27. The so-called 27 Club has captivated the public imagination for half a century. Its members include legendary musicians Jimi Hendrix, Janis Joplin, Jim Morrison, Kurt Cobain and Amy Winehouse. The idea is as seductive as it is tragic: a convergence of talent, fame and untimely at a singular age.

But is there any truth to this phenomenon, or is it merely a story we tell ourselves and each other about fame and youth?

In our newly published research, my colleague Patrick Kaminski and I explore why the 27 Club persists in culture. We didn’t set out to debunk the myth. After all, there is no reason to think that 27 is an especially dangerous age beyond superstition.

Rather, we wanted to explore the 27 Club to understand how such a myth gains traction and affects people’s perception of reality.

Is the 27 Club real?

The origin of the 27 Club dates back to the early 1970s, following the deaths of Brian Jones, Jimi Hendrix, Janis Joplin and Jim Morrison – all at age 27, within a span of two years.

This uncanny coincidence left its mark on collective memory. It wasn’t just their age. It was the common thread of musical genius, countercultural influence and the tragic allure of lives cut short by a cocktail of fame, drug use and the struggle of being human. The narrative is not just compelling but almost mystical in its synchronicity.

Analyzing data from 344,156 notable deceased individuals listed on Wikipedia, we found that while there’s no increased risk of dying at 27, those who do die at that age receive significantly more public attention. Using Wikipedia page views as a proxy for fame, our study revealed that the legacies of these 27-year-olds are amplified, garnering more visibility than those who die at adjacent ages.

This increased visibility has a strange effect: People are more likely to encounter those who died at 27 than other young ages, even if they are not aware of the myth. This in turn creates the appearance of greater risk of mortality at 27. The myth of the 27 Club is a self-fulfilling prophecy: It became “real” because we believed it.

Why is the 27 Club a thing?

We believe this phenomenon can be understood through three interrelated concepts: path dependence, stigmergy and memetic reification.

Path dependence refers to how random can set a precedent that influences future outcomes. The initial cluster of high-profile deaths at age 27 was statistically improbable – we estimate that one in 100,000 timelines would have four such famous deaths at age 27 – but it established a narrative pathway that has persisted and shaped collective reality.

Stigmergy how traces of an or action left in the can indirectly coordinate future events or actions. In the digital age, platforms such as Wikipedia serve as repositories of collective memory. The existence of a dedicated 27 Club page, with links to its members’ pages, increases the visibility of those who die at 27. This creates a feedback loop: The more we click, the more prominent these figures become, and the more the myth is reinforced.

Finally, what we call memetic reification captures how beliefs can shape reality. We draw from a sociological concept called the Thomas theorem, which states that if you “define a situation as real, they are real in their consequences.” The 27 Club myth has tangible effects on cultural memory and fame. By imbuing significance into the age of 27, society elevates the legacies of those who die at that age, making the myth materially consequential.

Why do myths endure?

Why do such myths endure? At their core, myths are not about factual accuracy but about narratives that resonate with people. They thrive on mystery, tragedy and the human penchant for finding patterns even in randomness. The story of the 27 Club is poetic, encapsulating the fleeting nature of genius and the fragility of . It’s a story that begs to be told and retold, regardless of its veracity.

This isn’t an isolated phenomenon. Cultural patterns often arise from chance events that, through collective commitment and storytelling, become embedded in our understanding of the world.

Your social world shapes what you value and how you behave.

Consider the evolution of language – why do we call a dog a “dog”? There is nothing doggy about the word. Philosopher Ludwig Wittgenstein observed that nearly all symbols are arbitrary. Some countries on the left side of the road while others on the right. While the choice to adopt left- or right-side traffic is influenced by neighboring countries or car producers, ultimately these followed from an arbitrary resolution to the need to pick one side or the other. These conventions began as random occurrences that, over time, became standardized and meaningful through social reinforcement.

The 27 Club serves as a lens through which you can examine the power of mythmaking in shaping perceptions of history and reality. It highlights how collective beliefs can have real-world consequences, influencing who becomes immortalized in cultural memory. It’s a testament to the complex interplay between chance events, storytelling and the mechanisms by which myths are perpetuated.

Though we may appear to dispel the myth of the 27 Club, let’s not abandon the story. We’re myth trusters, not myth busters. In unraveling the myth, we’re acknowledging the profound ways in which narratives influence our collective consciousness. By understanding the processes behind myth formation, we can better appreciate the richness of culture and the stories people choose to tell.The Conversation

Zackary Okun Dunivin, Postdoctoral Fellow in Communication, University of California, Davis

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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