Victor Ambros, UMass Chan Medical School

The 2024 Nobel Prize in physiology or medicine goes to Victor Ambros and Gary Ruvkun for their discovery of microRNA, tiny biological molecules that tell the cells in your body what kind of cell to be by turning on and off certain genes.

The Conversation Weekly podcast caught up with Victor Ambros from his lab at the UMass Chan Medical School to learn more about the Nobel-winning research and what comes next. Below are edited excerpts from the podcast.

How did you start thinking about this fundamental question at the heart of the discovery of microRNA, about how cells get the instructions to do what they do?

The paper that described this discovery was published in 1993. In the late 1980s, we were working in the field of developmental biology, studying C. elegans as a model organism for animal development. We were using genetic approaches, where mutations that caused developmental abnormalities were then followed up to try to understand what the gene was that was mutated and what the gene product was.

It was well understood that proteins could mediate changes in gene expression as cells differentiate, divide.

We were not looking for the involvement of any sort of unexpected kind of molecular mechanisms. The fact that the microRNA was the product of this gene that was regulating this other gene in this context was a complete surprise.

There was no reason to postulate that there should be such regulators of gene expression. This is one of those examples where the expectations are that you’re going to find out about more complexity and nuance about mechanisms that we already know about.

But sometimes surprises emerge, and in fact, surprises emerge perhaps surprisingly often.

These C. elegans worms, nematodes, is there something about them that allows you to work with their genetic material more easily? Why are they so key to this type of science?

C. elegans was developed as an experimental organism that people could use easily to, first, identify mutants and then study the development.

It only has about a thousand cells, and all those cells can be seen easily through a microscope in the living animal. But still it has all the various parts that are important to all animals: intestine, skin, muscles, a brain, sensory systems and complex behavior. So it’s quite an amazing system to study developmental processes and mechanisms really on the level of individual cells and what those cells do as they divide and differentiate during development.

Listen to Victor Ambros on The Conversation Weekly podcast.

You were looking at this lin-4 gene. What was your surprising discovery that led to this Nobel Prize?

In our lab, Rosalind Lee and Rhonda Feinbaum were working on this project for several years. This is a very labor intensive process, trying to track down a gene.

And all we had to go by was a mutation to guide us as we gradually homed in on the DNA sequence that contained the gene. The surprises started to emerge when we found that the pieces of DNA that were sufficient to confer the function of this gene and rescue a mutant were really small, only 800 base pairs.

And so that suggested, well, the gene is small, so the product of this gene is going to be pretty small. And then Rosalind worked to pare down the sequence more and to mutate potential protein coding sequences in that little piece of DNA. By a process of elimination, she finally showed that there was no protein that could be expressed from this gene.

And at the same time, we identified this very, very small transcript of only 22 nucleotides. So I would say there was probably a period of a week or two there where these realizations came to the fore and we knew we had something new.

You mentioned Rosalind, she’s your wife.

Yeah, we’ve been together since 1976. And we started to work together in the mid-’80s. And so we’re still working together today.

And she was the first author on that paper.

That’s right. It’s hard to express how wonderful it is to receive such validation of this work that we did together. That is just priceless.

Like it’s a Nobel Prize for her too?

Yes, every Nobel Prize has this obvious limitation of the number of people that they give it to. But, of course, behind that are the folks who worked in the lab – the teams that are actually behind the discoveries are surprisingly large sometimes. In this case, two people in my lab and several people in Gary Ruvkun’s lab.

In a way they’re really the heroes behind this. Our job – mine and Gary’s – is to stand in as representatives of this whole enterprise of science, which is so, so dependent upon teams, collaborations, brainstorming amongst multiple people, communications of ideas and crucial data, you know, all this is part of the process that underlies successful science.

That first week of the discoveries, did you anticipate at that point that this could be such a huge step for our understanding of genes?

Until other examples are found of something new, it’s very hard to know how peculiar that particular phenomenon might be.

We’re always mindful that evolution is amazingly innovative. And so it could have been that this particular small RNA base-pairing to this mRNA of lin-14 gene and turning off production of the protein from lin-14 messenger RNA, that could be a peculiar evolutionary innovation.

The second microRNA was identified in Gary Ruvkun’s lab in 1999, so it was a good six years before the second one was found, also in C. elegans. Really, the watershed discovery was when Ruvkun showed that let-7, the other microRNA, was actually conserved perfectly in sequence amongst all the bilaterian animals. So that meant that let-7 microRNA had been around for, what, 500 million years?

And so it was immediately obvious to the field that there had to be other microRNAs – this was not just a C. elegans thing. There must be others, and that quickly emerged to be the case.

You and Gary Ruvkun had been postdoctoral fellows at the same time at MIT, but by the time you made your respective discoveries, you’d both set up your own labs. Would you call them rival labs, in the same town?

No, I would certainly not call it rival labs. We were working together as postdocs basically on this problem of developmental timing in Bob Horvitz’s lab.

We just basically informally divided up the work. The understanding was, OK, Ambros lab will focus on lin-4 gene, and Ruvkun lab will focus on lin-14, and we anticipated that there would be a point that we would get together and share information about what we’ve learned and see if we could come to a synthesis.

That was the informal plan. It was not really a collaboration. It was certainly not a rivalry. The expectation was that we would divide up the work and then communicate when the time came. There was an expectation in this community of C. elegans researchers that you should share data freely.

Your lab still works on microRNA. What are you investigating? What questions do you still have?

One I find very interesting is a project where we collaborated with a clinician, a geneticist who studies intellectual disability. She had discovered that her patients, children with intellectual disabilities, in certain families carried a mutation that neither of their parents had – a spontaneous mutation – in the protein that is associated with microRNAs in humans called the Argonaute protein.

Each of our genomes contains four genes for Argonautes that are the partners of microRNAs. In fact, this is the effector protein that is guided by the microRNA to its target messenger RNAs. This Argonaute is what carries out the regulatory processes that happen once it finds its target.

These so-called Argonaute syndromes were discovered, where there are mutations in Argonautes, point mutations where only one amino acid changes to another amino acid. They have this very profound and extensive effect on the development of the individual.

And so working with these geneticists, our lab and other labs took those mutations, that were essentially gifted to us by the patient. And then we put those mutations into our system, in our case into C. elegans‘ Argonaute.

I’m excited by the very organized, active partnership between the Argonaute Alliance of families with Argonaute syndromes and the basic scientists studying Argonaute.

How does this collaboration potentially help those patients?

What we’ve learned is that the mutant protein is sort of a rogue Argonaute. It’s basically screwing up the normal process that these four Argonautes usually do in the body. And so this rogue Argonaute, in principle, could be removed from the system by trying to employ some of the technology that folks are developing for gene knockout or RNA interference of genes.

This is promising, and I’m hopeful that the payoff for the patients will come in the years ahead.

Victor Ambros, Professor of Molecular Medicine, UMass Chan Medical School

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

Kory London, Thomas Jefferson University

Unimaginable pain and restlessness. Vomiting so frequent and forceful that it can perforate the esophagus. Blood pressure and heart rate so high that they damage the heart. Sweating that drenches clothing and sheets. Nerve sensitivity that makes even the softest touch agonizing. A prolonged panic attack that is provoked and worsened by even mundane activities and conversations.

The withdrawal symptoms from “tranq dope” – the combination of the synthetic opioid fentanyl and the animal tranquilizer xylazine that dominates Philadelphia’s street opioids supply – tend to be far worse than those experienced by even the most severe heroin users of the past.

So it’s no surprise that people will do whatever they can to forestall them. That includes walking out of the hospital before their care is complete.

I’m an associate professor of emergency medicine who has spent a decade as an emergency physician working in Center City and South Philadelphia. I’ve spent most of that time directing projects to improve care for people who use drugs.

Beginning in 2022, our team – a group of emergency and addiction physicians – began experimenting with new approaches to treating tranq dope withdrawal.

We were able to reduce the likelihood of these patients leaving the hospital before treatment was complete by more than half – from 10% to just under 4%.

We also reduced the severity of their suffering, lowering their withdrawal scores – or how they rate their pain and other symptoms – by more than half.

Traditional treatments don’t work

Before tranq dope, treating opioid withdrawal in the emergency department was relatively straightforward, with well-studied, conventional protocols.

For patients without chronic pain, health care providers started buprenorphine, known by its brand name Suboxone, when patients showed signs of withdrawal.

Buprenorphine works by partially, rather than fully, stimulating opioid receptors in the body. This subtle difference relieves symptoms of withdrawal but reduces the risk of overdose if patients continue to use other opioids. It quite literally saves lives.

Tranq dope, however, created a much larger set of challenges.

Fentanyl and other synthetic opioids are dozens to hundreds of times more powerful than heroin. Xylazine, meanwhile, adds symptoms of sedative withdrawal to the mix: restlessness, adrenaline activation and agitation.

As synthetic opioids became pervasive in Philadelphia’s drug supply over the past decade, overdose deaths in the city tripled. Those numbers are beginning to decline, for reasons that remain unclear.

Meanwhile, tranq users started to share buprenorphine horror stories. They refused the medication due to a phenomenon called “precipitated withdrawal.” Precipitated withdrawal is a condition in which taking buprenorphine paradoxically makes withdrawal symptoms worse, rather than improving them. Due to the severity of their symptoms, some patients who precipitate severely even require treatment in the intensive care unit.

Furthermore, when patients did accept buprenorphine, their withdrawal symptoms were no longer being effectively controlled, even with very high doses. We were adrift.

Patients demand discharge

When people with severe substance use disorders are hospitalized, even compassionate staff members sometimes lose patience.

Being confined to a stretcher in a loud, chaotic environment, in withdrawal, with prior traumatic health care experiences, can lead patients to act out. They might repeatedly hit call bells, use inappropriate language, make impulsive decisions or sneak drugs into the hospital.

This creates a lot of stress for nurses and staff, and distracts from the care of others.

So when patients demand to leave before treatments are complete, exhausted care teams often quickly acquiesce. Traditionally, this was termed leaving “against medical advice,” but is now called “patient-directed discharge.”

Patient-directed discharge is associated with higher rates of mortality, permanent disability and rehospitalization.

Rates of patient-directed discharge can be 10 to 50 times higher in people with an opioid use disorder compared with the general public.

A cycle of mistrust can also form, where the expectation that a patient may leave again leads to a less engaged care team, which in turn can make patients more likely to leave.

At staff meetings, some compared the challenges of caring for these individuals to those experienced in the hardest parts of the COVID-19 pandemic.

New approach needed

Many physicians have been reticent to consider other options for treating opioid withdrawal. I believe there are two key reasons for this. One is the lack of Food and Drug Administration approval for alternative treatments. The other is that federal regulations consider addiction a behavioral rather than medical condition, effectively separating most doctors from the addiction care of these individuals.

As fentanyl and xylazine became ubiquitous in Philadelphia’s street dope, local hospitals reported astronomical rates of patient-directed discharge among these patients. This was happening despite the best efforts of hospital staffs that are deeply experienced in conventional opioid withdrawal treatment.

In 2021, an editorial in the Annals of Internal Medicine journal advocated for the use of short-acting opioids for some patients’ opioid withdrawal – which is already common practice in Canada. Short-acting opioids are medications doctors traditionally use to treat acute pain.

Philadelphia hospitals started experimenting with using these previously verboten medications. That included our team at Jefferson Health.

Oxycodone, hydromorphone and ketamine

By using short-acting opioids such as oxycodone or hydromorphone, combined with a low-dose version of buprenorphine, we prevented precipitated withdrawal and treated opioid withdrawal and pain in our patients.

The low-dose bupenorphine can be increased over time to steady doses. This shows patients that the medication is safe and provides them a bridge to long-term treatment.

The short-acting opioids replace the opioids that their bodies are frantically searching for. They reduce their pain and misery, and are decreased when their symptoms are controlled.

Patients with opioid use disorder will often do whatever they can to stay out of the hospital due to fear of withdrawal. Asking how withdrawal symptoms are managed, therefore, is often their first priority when hospitalized. We see this even when they have conditions that require complicated and time-sensitive treatments.

Owing to the vast amounts of opioids many of our patients use, we also give them additional strong medications, or “adjunctive therapies,” to supplement the effects of the short-acting opioids and low-dose buprenorphine. One is ketamine, an anesthetic that affects nerve impulses and is increasingly being used to treat depression, post-traumatic stress discorder and substance use disorders.

Ketamine is also an effective pain medication that can extend the effects of opioids and reduce the number of doses needed.

We additionally add muscle relaxants – which work similarly to xylazine – along with nausea medications and IV fluids, to help give patients a chance at healing.

Side effects and future problems

In patients who received our medications, the risks of serious side effects were minimal. The few patients who suffered serious adverse effects had other acute medical problems that could have contributed to the side effects. Almost all the side effects we saw were mild and resolved on their own.

As powerful synthetic opioids and other contaminants become pervasive in more U.S. cities, more emergency departments will need to figure out how to care for patients in withdrawal so that they don’t leave treatment.

It is our hope that this work will inspire others to do a better job of providing relief to patients suffering from this complicated and severe condition.

Kory London, Associate Professor of Emergency Medicine, Thomas Jefferson University

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

Shaoyu Yuan, Rutgers University – Newark and Jun Xiang, Rutgers University – Newark

It may sound far-fetched, but the future of global technology supremacy could hinge on a video game.

Black Myth: Wukong, China’s latest blockbuster, isn’t just breaking gaming records – it could be driving a critical shift in the global balance of technological power. What seems like just another action-packed video game is, in reality, a vital component in Beijing’s larger strategy to challenge Western dominance in the tech industry.

The game, released by Chinese company Game Science on Aug. 19, 2024, is based on the legendary 16th century Chinese novel “Journey to the West.” The novel tells the story of a monk, Xuanzang, who journeys to India in search of Buddhist scrolls. The monkey Sun Wukong protects the monk by confronting and battling various demons and spirits.

Black Myth: Wukong has captivated millions with its stunning visuals and storytelling. It quickly became a cultural sensation in China and abroad, attracting widespread attention and praise for its graphic fidelity and technological sophistication.

As global affairs scholars, we see that the game’s success goes beyond the number of downloads or accolades. It’s what this success is driving within China’s technology sector that has far-reaching consequences.

Video games and global power

For years, China has been playing catch-up in the tech race, particularly in the production of semiconductors – the tiny microchips that power everything from smartphones to advanced artificial intelligence systems. The United States has maintained its dominance in this field by limiting China’s access to the most advanced chip-making technology.

As of 2024, China has shifted away from its aggressive “wolf warrior” diplomacy to a more cooperative approach in order to rebuild international ties. The government has also issued mandates for companies like Huawei to develop domestic chips. However, China’s success in boosting semiconductor development and production using these approaches has been limited.

Historically, video games have played a significant role in driving technological innovation in the semiconductor industry. From the early days of the 8-bit Nintendo Entertainment System to the modern PlayStation 5, gaming has always pushed chipmakers to develop faster, more efficient processors and graphics processing units, or GPUs. The intense graphical requirements of modern games – high resolutions, faster frame rates and real-time rendering – demand the most advanced semiconductor technology. The development of advanced GPUs by companies like NVIDIA was directly influenced by the gaming industry’s needs.

Gamers require advanced processors to enjoy Black Myth: Wukong’s high-end visual and gameplay experience. Built using the state-of-the-art Unreal Engine 5 video game development tool, the game is a visual spectacle featuring lifelike graphics, seamless open-world environments and complex combat systems. The game is available for PlayStation 5 and PCs, and Game Science plans to release an Xbox version.

As Black Myth: Wukong sweeps across gaming platforms, it not only puts pressure on China’s semiconductor makers to build more and better chips, but it also reveals the vast market potential for high-performance hardware, especially for gaming PCs equipped with powerful GPUs. The game’s success showcases just how big the demand is.

Market analysts expect the Chinese video game industry to reach revenues of US$66.13 billion in 2024, compared with $78.01 billion in the U.S. Analysts predict the game will have annual sales of 30 million to 40 million copies in 2024.

China’s gaming industry has surged into a global powerhouse, yet it remains dependent on foreign-made chips. Coupled with the West‘s restrictions on chip exports, Wukong has become a key catalyst for China’s semiconductor development, and domestic companies now face growing pressure to innovate.

This pressure aligns with Beijing’s broader technological ambitions. The government’s “Made in China 2025” plan calls for technological self-reliance, particularly in sectors like semiconductors, where China lags behind. And advanced GPUs haven’t been confined to the entertainment industry. They have become integral to advances in AI, including deep learning and autonomous systems.

Flexing China’s cultural muscle

While it might seem strange to link video games with geopolitics, Black Myth: Wukong is more than just entertainment. It’s a tool in China’s soft power arsenal. Soft power is nations influencing each other through cultural exports. For decades, the West, particularly the U.S., dominated global culture through Hollywood, music and video games.

Now, China is flexing its cultural muscle. The success of Black Myth: Wukong abroad, where it has been hailed as a game-changing title, is part of Beijing’s strategy to export its culture and technological prowess. Millions of gamers around the world are now being exposed to Chinese mythology, art and storytelling through a highly sophisticated digital medium.

But Black Myth: Wukong isn’t just a cultural triumph for China; it’s a warning shot. The country is taking advantage of its booming gaming industry to drive advances in a field that will define the future of technology. This game not only exports Chinese culture but also strengthens its tech base by accelerating the demand for domestic semiconductors.

While Black Myth: Wukong entertains millions, it also shows China’s growing influence in the digital realm. In the future, we might not look back at Black Myth: Wukong as just a successful video game, but as a catalyst that helped China close the technological gap with the West. Beijing is playing a long game, and video games like Black Myth: Wukong are turning out to be effective weapons.

Shaoyu Yuan, Dean’s Fellow at the Division of Global Affairs, Rutgers University – Newark and Jun Xiang, Professor of Economics and Global Affairs, Rutgers University – Newark

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