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Ethical Implications in the Development of AI

An AI researcher poses for the camera.

Published November 21, 2023

By Nick Fetty

Betty Li Hou, a Ph.D. student in computer science at the New York University Courant Institute of Mathematical Sciences, presented her lecture “AI Alignment Through a Societal Lens” on November 9 at The New York Academy of Sciences.

Seminar attendees included the 2023 cohort of the Academy’s AI and Society post-doctoral fellowship program (a collaboration with Arizona State University’s School for the Future of Innovation in Society), who asked questions and engaged in a dialog throughout the talk. Hou’s hour-long presentation examined the ethical impacts that AI systems can have on societies, and how machine learning, philosophy, sociology, and law should all come together in the development of these systems.

“AI doesn’t exist independently from these other disciplines and so AI research in many ways needs to consider these dimensions, otherwise we’re only looking at one piece of the picture,” said Hou.

Hou’s research aims to capture the broader societal dynamics and issues surrounding the so-called ‘alignment problem,’ a term coined by author and researcher Brian Christian in his 2020 book of the same name. The alignment problem aims to ensure that AI systems pursue goals that match human values and interests, while trying to avoid unintended or undesirable outcomes.

Developing Ethical AI Systems

As values and interests vary across (and even within) countries and cultures, researchers are nonetheless struggling to develop ethical AI systems that transcend these differences and serve societies in a beneficial way. When there isn’t a clear guide for developing ethical AI systems, one of the key questions from Hou’s research becomes apparent: What values are implicitly/explicitly encoded in products?

“I think there are a lot of problems and risks that we need to sort through before extracting benefits from AI,” said Hou. “But I also see so many ways AI provides potential benefits, anything from helping with environmental issues to detecting harmful content online to helping businesses operate more efficiently. Even using AI for complex medical tasks like radiology.”

Social media content moderation is one area where AI algorithms have shown potential for serving society in a positive way. For example, on YouTube, 90% of videos that are reviewed are initially flagged by AI algorithms seeking to spot copyrighted material or other content that violates YouTube’s terms of service.

Hou, whose current work is also supported by a DeepMind Ph.D. Scholarship and an NSF Graduate Research Fellowship, previously served as a Hackworth Fellow at the Markkula Center for Applied Ethics as an undergraduate studying computer science and engineering at Santa Clara University. She closed her recent lecture by reemphasizing the importance of interdisciplinary research and collaboration in the development of AI systems that adequately serve society going forward.

“Computer scientists need to look beyond their field when answering certain ethical and societal issues around AI,” Hou said. “Interdisciplinary collaboration is absolutely necessary.”

Ethics in Pediatric Research

Recent progress in the understanding of human disease has led to an explosion in the number of new medicines and therapeutics available for adults — however, significantly fewer drugs are developed and evaluated specifically for children due to complex ethical and logistical issues. Listen to this podcast addressing topics on how to provide children with evidence-based treatments while protecting them from inappropriate research. 

This podcast highlights discussions from the Ethical Considerations in Research for Pediatric Populations symposium presented by The New York Academy of Sciences and NYU Grossman School of Medicine and is made available thanks to funding provided by Johnson & Johnson. 

New Developments in Pain Research

Overview

Can we stop the pain? It may be the oldest question in medicine, and it remains one of the most important. But with chronic pain afflicting billions of people worldwide, and few effective treatments besides highly addictive opioids, researchers are still searching for better answers.

On May 3-4, the New York Academy of Sciences, in collaboration with Science Translational Medicine, convened the Advances in Pain conference. Across the meeting’s two keynote presentations, nine sessions of talks, and concluding panel discussion, leading experts in many branches of pain research discussed the field’s biggest challenges and latest developments.

Highlights

  • Specific ion channels on neurons, such as Nav1.7, are critical components of pain sensing and potential drug targets for new analgesics.
  • Several novel laboratory models are revealing new details of nociception, or pain sensing.
  • Large databases of genetic and clinical records are helping researchers link specific genes with common pain conditions.
  • Neuroimaging and sleep studies may offer objective ways to measure the severity of chronic pain.
  • New mechanistic data are pointing researchers toward novel strategies for analgesic drug development.
  • A subset of gut epithelial cells is critical for sensing visceral pain.
  • The immune system links tightly to pain sensation, through multiple mechanisms scientists are now beginning to uncover.
  • Data mining reveals subsets of neurons with distinct responses to nerve injury, including chronic pain.
  • Understanding sex and ethnic differences in pain perception requires new strategies in experimental design and data analysis.
  • Besides neurons, Schwann cells can also carry pain signals.
  • Novel drug discovery platforms and trial designs can accelerate the development of new analgesics.

Part 1

Speakers

David Bennett, MB, PhD
Oxford University, Nuffield Department of Clinical Neurosciences

Sarah E. Ross, PhD
University of Pittsburgh

Jing Wang, MD, PhD
NYU Langone Health

Tuning into the pain channel

A life free of pain may sound ideal, but as David Bennett explained in the meeting’s opening keynote presentation, individuals with defects in pain sensing often suffer tremendous difficulties. Describing one 26-year-old man with such a condition, Bennett explained that “he had pretty much fractured every long bone in his body, he is stunted because he’s destroyed all the growth plates … and had severe burns and mouth injuries.” The patient’s sister, who had the same condition, died of undiagnosed sepsis.

Genetic analysis revealed that the patient had a rare set of loss-of-function mutations in the gene for Nav1.7, a sodium ion channel expressed in nociceptors, or pain sensing neurons. Using a sophisticated cell culture system that mimics pain signaling through nociceptors, Bennett and his colleagues have characterized Nav1.7 in detail, and determined that it acts early in the pain signaling process, amplifying the electrical signal in the nociceptors to ensure that it’s relayed to the central nervous system.

Patients with gain-of-function mutations that make Nav1.7 overactive have the opposite problem: incurable chronic pain. Bennett’s team studied the Nav1.7 mutations in these patients, and discovered that the degree of the biochemical defect in a patient’s channel proteins correlates directly with the time of onset of their pain condition.

Based on his findings in patients with these rare, extreme pain disorders, Bennett hypothesized that Nav1.7 could also drive more common conditions. As rates of diabetes skyrocket globally, millions of people are developing diabetic neuropathy, which causes chronic pain only in a subset of patients. In an effort to determine what distinguishes painful from pain-free diabetic neuropathy, Bennett’s team looked at Nav1.7 gene sequences for patients with the condition.

“The rare variants in Nav1.7 seemed to cluster much more in the painful versus the painless diabetic neuropathy groups, so this is now acting as a risk factor, in the sense that these people did not experience [chronic] pain prior to developing diabetes,” Bennett says.

Some variants of Nav1.7 apparently predispose people to develop chronic pain, but the condition doesn’t manifest itself until a second event, such as diabetes, triggers it. A closer look at clinical testing results in these patients revealed that those with the rare variants were also more sensitive to certain stimuli, such as burning pain and pressure pain.

Nav1.7 isn’t the only ion channel involved in pain, though. The researchers have also identified strong associations between pain disorders and mutations in the related channel proteins Nav1.8 and Nav1.9, highlighting the diversity of channelopathies that can derail pain sensing. Indeed, an analysis of data from the UK Biobank, which has whole genome sequences and medical records for 100,000 Britons, revealed that voltage-gated sodium channels were the largest group of variants associated with neuropathic pain.

Based on his findings, Bennett advocates using both clinical testing data and gene sequencing to stratify patients according to which treatments are most likely to work for them. In particular, sodium channel blocking drugs appear to work much better in patients with variant channels predisposing them to pain.

Where does it hurt?

The meeting’s first regular session focused on efforts to dissect the central pain circuits in the nervous system. For Sarah Ross, the dissection is literal: she carefully removes a piece of a mouse spinal cord, along with the sensory nerves connected to a patch of skin from the animal’s hind paw, keeping all of the neuronal connections intact. Using luminescent probes, her team can then watch the activation of specific neurons in response to stimuli.

“We can see some neurons respond to heat, other neurons will respond to cool, other neurons will respond to mechanical stimuli,” said Ross.

Many neurons also respond to multiple stimuli, and mapping these responses reveals that distinct classes of neurons function as amplifiers, tuners, and integrators of pain signals.

Jing Wang studies what happens to pain signals in the cerebral cortex of the brain. Using optogenetics, which allows him to stimulate specific neurons in the brains of mice with light, he has identified subsets of neurons in the anterior cingulate cortex and prefrontal cortex that respond to pain.

In mice with experimentally induced chronic pain, low-intensity stimulation of the prefrontal cortex restores normal pain control. Wang’s lab is now studying ways to achieve similar responses with less invasive methods, including the drug ketamine and brain-machine interfaces.

“The cortex processes and regulates pain, but its normal endogenous function can be impaired by chronic pain, and [restoring cortical regulation] has the potential to transform pain treatment,” said Wang.

Part 2

Speakers

Aarno Palotie, MD, PhD
Institute for Molecular Medicine, Finland

Luda Diatchenko, MD, PhD
McGill University

Irene Tracey, MA (Oxon), DPhil, FRCA, FMedSci
University of Oxford

Alban Latremoliere, MSc, PhD
Johns Hopkins University

The pains of the father

Aarno Palotie began the meeting’s session on the genetics of pain by discussing his results from large-scale studies on migraine. With the exception of some rare, strictly inherited forms of the condition, these sporadic, debilitating headaches usually stem from variations in numerous common genes. To identify those genes, Palotie and a large team of collaborators scrutinized genetic and medical data from hundreds of thousands of migraine sufferers.

The effort revealed over 100 gene loci linked to migraine, mostly in regulatory regions associated with genes expressed in cardiovascular tissue and the central nervous system. Tracking those variants in another large data set revealed a cumulative effect.

“We can see that those with a high polygenic risk score, meaning a high load of common variants, they seem to have an earlier onset of migraine,” said Palotie.

Using data from the 500,000 participants in the UK Biobank, Luda Diatchenko and her colleagues have performed a similar analysis to identify genetic variants linked to chronic pain. The investigators subdivided chronic pain patients based on the type of pain they experienced, such as back pain, hip pain, knee pain, and multi-site pain.

Analyzing gene sequences for these sub-groups showed that multi-site pain had the highest correlation with specific gene variants. The gene most strongly linked to multi-site pain encodes a receptor protein involved in guiding nerve axons in development.

“This is one example of how [genome-wide association studies] can show us a new mechanism which contributes to human chronic pain conditions,” said Diatchenko.

On a scale of one to ten

The meeting’s third session focused on one of the biggest challenges in studying pain: measuring it. Clinical studies attempt to quantify pain severity with patient questionnaires, while animal experiments rely on behavioral responses, but both methods are notoriously unreliable.

Ilene Tracey hopes to solve that problem with neuroimaging, linking specific patterns of neuronal activation to painful stimuli.

“We’ve got now quite a good array of tools that are reasonably well developed and robust, that allow you to look at … ways that patients will experience their pain,” said Tracey.

By combining functional magnetic resonance imaging with electroencephalography, video analysis, and other sensing methods, this approach could allow researchers to quantify patient responses to pain treatment more reliably than current, fundamentally qualitative methods. Using machine learning, Tracey’s team can now measure pain and also distinguish different categories of it, such as physical versus emotional pain.

Sleep disturbances might also provide a pain gauge.

“The vast majority of patients with chronic pain suffer from poor sleep quality,” said Alban Latremoliere, who has been studying this connection as a potential pain biomarker.

By tracking electroencephalography and other measurements in sleeping mice, he and his colleagues have found that nerve injury, which causes chronic neuropathic pain, also changes the animals’ sleep architecture. Compared to uninjured animals, those with injured nerves suffer multiple brief interruptions in the non-REM phase of their sleep. When the injury heals, the normal sleep architecture returns; Latremoliere now hopes to use these patterns to quantify neuropathic pain severity and treatment efficacy in humans.

Part 3

Speakers

Greg Scherrer, PhD
University of North Carolina

Venetia Zachariou, PhD, MBBS, MMed, MS
Icahn School of Medicine at Mount Sinai

Rajesh Khanna, PhD
New York University

David J. Julius, PhD
University of California, San Francisco (UCSF)

The hurt blocker

As Greg Scherrer pointed out in the meeting’s fourth session, the real problem with pain isn’t that it exists, but that it’s unpleasant.

“If we were to understand how our brain collects this information from sensory neurons and the spinal cord to make pain unpleasant … maybe we’ll discover new ways to treat pain,” said Scherrer.

Indeed, a patient whose basolateral amygdala was removed to treat epilepsy could still sense painful stimuli, but didn’t label them as painful; the unpleasantness was gone. Examining mice with various alterations to the same brain region, Scherrer and his colleagues believe they have identified the amygdala cells responsible for connecting pain to unpleasantness. The investigators are now trying to identify receptors on those cells that would be good drug targets for new pain treatments.

Venetia Zachariou is also dissecting cellular signaling pathways to target in pain treatment, and her lab has uncovered several promising leads in recent years. When the COVID-19 pandemic derailed that work, though, the scientists quickly pivoted to apply their skills and techniques to study the new disease’s neuronal pathogenesis.

In a hamster model, they found that SARS-CoV-2, the virus that causes COVID-19, can acutely infect nerves in the dorsal root ganglia, which are also involved in pain sensing. Looking more closely at both the hamster model and a mouse model of SARS-CoV-2 infection, Zachariou has identified distinct changes in neurons’ gene expression patterns after virus infection, including a signature similar to that seen in models of neuropathic pain.

One of the most popular targets for researchers trying to develop new pain therapies is the sodium channel Nav1.7, a “pain amplifier” that several speakers at the meeting discussed. Rajesh Khanna is also interested in Nav1.7, but instead of targeting the protein directly, his team is trying to identify proteins that interact with it. That work led them to focus on collapsin response mediator protein 2 (Crmp2), which regulates Nav1.7 signaling.

Mice lacking Crmp2 are resistant to chronic pain, suggesting that drugs inhibiting its action would be good pain therapy candidates. After conducting extensive mechanistic studies, Khanna started a company to identify such inhibitors. So far, the company has optimized a lead compound that appears to stop chronic pain in animal models, without causing detectable side effects or tolerance.

You feel it in your gut

The meeting’s first day concluded with a keynote presentation by David Julius, who discussed his work on chronic visceral pain. This subtype of chronic pain, which can be caused by gut infection or non-infectious conditions such as inflammatory bowel disease, affects about 15% of the population. It’s three times more common in women than men, but nobody knows why.

“We’re interested in a particular aspect of visceral pain signaling, and that involves the interaction of sensory nerve fibers with the gut epithelium,” said Julius.

A subset of gut epithelial cells, called enterochromaffin cells, plays an outsize role in that interaction. Comprising only a fraction of a percentage of all gut epithelial cells, enterochromaffin cells make about 90% of the body’s serotonin, a potent neurotransmitter protein. They also fire electrical signals that could propagate to nearby neurons.

Julius wanted to analyze that process in live mice, but wasn’t happy with the standard mouse system for those types of experiments. That model involves putting irritants into a mouse’s gut to trigger a major inflammatory response, after which the animal remains hypersensitive to physical stimuli such as colon distention.

“Do we need to … put the mouse through all that, or can you have a model that’s simpler [and] does not require all the sequellae of an inflammatory episode?” asked Julius.

Instead, he and his colleagues first tried studying enterochromaffin cells in the context of cultured enteroids, pieces of intestinal epithelium that can mimic many aspects of gut biology in a petri dish. That system revealed that enterochromaffin cells respond to numerous compounds that fall into three general classes: ingested irritants, metabolites of common gut microbes, and endogenous regulatory hormones.

“So, we want to know how these cells integrate all this information, and what role this plays in maladaptive situations like [inflammatory bowel disease],” said Julius.

Based on those results, the researchers moved to a more complex system, an explanted piece of a mouse colon with its connecting nerves. Monitoring the electrical signals in the connected nerves reveals sensory signals from the explanted gut. In this setup, bathing the colon section with isovalerate, a bacterial metabolite that triggered a response from enterochromaffin cells in the enteroid experiment, makes it hypersensitive to subsequent physical or biochemical stimuli. This system also revealed different response patterns in guts from male and female mice.

Having demonstrated that isovalerate could induce gut hypersensitivity without the inflammatory response of harsher irritants, Julius’s team next tried looking at its effect in live mice. They used a small balloon in the colon, similar to an endoscope, as a stimulus, and monitored abdominal muscle contraction, a behavioral response to pain. Treating the mice with isovalerate increased the magnitude of subsequent pain responses potently in male mice, but less so in females, consistent with the explant results.

Subsequent experiments showed that enterochromaffin cells mediate these responses in live mice, apparently through both serotonin secretion and direct electrical signaling to neurons, and that these cells seem to respond differently in male and female mice.

Part 4

Speakers

Isaac Chiu, PhD
Harvard Medical School

Camila Svensson, MS, PhD
Karolinska Institutet

Alexander J. Davies, PhD
Nuffield Department of Clinical Neurosciences

Dana Orange, MD
Rockefeller University

Shrinivasan Raghuraman, PhD
University of Utah

Jeffrey S. Mogil, PhD
McGill University

Frank Porreca, PhD
University of Arizona

Roger Fillingim, PhD
University of Florida

Is antibody hurt?

Infections commonly cause pain, which researchers had long assumed was just a byproduct of the body’s inflammatory response. However, as Isaac Chiu explained in the meeting’s session on neuroimmune and autoimmune mechanisms in pain, infecting pathogens can also interact directly with nociceptors, or pain-sensing neurons. In one set of mouse experiments, for example, Chiu’s team found that nociceptors in the intestine can detect infection with Salmonella enterica, triggering a response that decreases the number of M cells, the specialized intestinal epithelial cells S. enterica preferentially infects.

“These neurons actually regulate cell numbers, [which] not only shuts down the number of gates for pathogen entry, it also helps a protective microbe … attach better on the surface of the epithelium,” said Chiu.

Camila Svensson discussed a pain condition that has baffled researchers and clinicians for decades: fibromyalgia. Characterized by pain hypersensitivity in soft tissues, sometimes coupled with neuropathic pain, the condition has long eluded efforts to uncover its etiology and underlying mechanisms.

After serendipitously discovering evidence for autoantibodies in fibromyalgia patients, Svensson has now developed human tissue and mouse models to characterize these antibodies in more detail. Transferring antibodies from fibromyalgia patients into mice causes pain hypersensitivity in the animals, and patients with higher levels of antibodies that react with human dorsal root ganglia cells have more severe disease.

“This suggests that there is an autoimmunity in subpopulations of fibromyalgia patients,” said Svensson, adding that besides suggesting a mechanism for the disease, autoantibody levels could help stratify patients in clinical trials.

The body’s own immune response is also a key contributor to chronic neuropathic pain, especially through neuroinflammation. Alexander Davies presented his work on another component of neuropathic pain: the cytotoxic cellular response.

Cytotoxic cells normally detect cancerous or virally-infected cells and target them for destruction, but they can also target injured neurons. Dissecting this response in an extensive series of experiments in mice, Davies and his colleagues have found that a specific receptor on cytotoxic cells allows them to target nociceptors after nerve injury, leading to degeneration of the damaged axons and resolution of pain hypersensitivity.

“So, our data suggest that intact sensory networks are a source of ongoing neuropathic hypersensitivity, and that by targeting those, we can help to resolve that,” said Davies.

Short, sharp shocks

Dana Orange gave the first of two short “data blitz” presentations, providing an overview of her group’s work on rheumatoid arthritis pain. Though inflammation of joints is a hallmark of this form of arthritis, Orange noticed an odd discrepancy.

“Patients who really don’t have a lot of inflammation were reporting a lot of pain,” she said.

Through a combination of human gene expression and mouse studies, she’s found that nerve development may play a bigger role than inflammation in driving rheumatoid arthritis pain.

Shrinivasan Raghuraman described his approach to characterizing chronic pain mechanisms, using a rat model. By collecting thousands of data points from individual rat neurons under different conditions, his lab has identified 19 different subsets of neurons with distinct responses to nerve injury. Raghuraman hopes that correlating the cells’ electrical responses with their gene transcription profiles will identify the underlying mechanisms driving chronic pain, and how different candidate drugs can influence it.

Sex and race

In the session on sex and ethnic differences in pain, Jeffrey Mogil began by pointing out a critical flaw in traditional pain research methods. Despite ample evidence that women experience more pain than men, “80 percent of preclinical studies use male rats or male mice only,” said Mogil.

That skew overlooks important differences in the biology of pain in males and females, though. In a mouse model of chronic neuropathic pain, for example, Mogil’s lab has linked chronic pain to premature shortening of chromosome ends, or telomeres – but only in male mice. Besides studying both sexes instead of just one, Mogil argued that researchers need to extend their animal studies to monitor chronic pain for longer time periods, to account for age-related phenomena such as telomere shortening.

Frank Porreca also looks at sex differences in pain, but focuses on the role of stress. Clinical data clearly show that stress exacerbates functional pain syndromes such as inflammatory bowel disease, migraine, and fibromyalgia, all of which are more prevalent in women than men.

To study such syndromes, Porreca’s team developed a mouse model in which they restrain the animals for a short time to induce stress, then treat them with a compound that causes headaches. These stress-primed mice develop allodynia, interpreting normally non-painful stimuli as painful, while controls that only got the headache-inducing compound didn’t.

While both male and female mice exhibited the same response, Porreca found that it operates through different biochemical mechanisms in the two sexes, underscoring the importance of studying both in preclinical research.

Unlike sex, race and ethnicity lack clear biological definitions.

“It’s important to keep in mind that race and ethnicity are not causal factors, but rather proxies for these many psychosocial and biopsychosocial factors, largely driven by systemic societal and environmental exposures,” said Roger Fillingim.

At the same time, the groups that suffer disproportionately from racial and ethnic health disparities are often the least-studied. That’s certainly the case in pain research and treatment. Indeed, experiments suggest that Black patients may experience more pain than white ones, but health data show they’re less likely to be treated for pain in hospitals and clinics.

Summarizing a large body of additional evidence for similar skews in various minoritized groups, Fillingim advocated more holistic approaches to pain research across and within sub-populations.

Part 5

Speakers

Alexander Chesler, PhD
National Center for Complementary and Integrative Health (NCCIH), NIH

Patrik Ernfors, PhD
Karolinska Institutet

Clifford Woolf, MD, PhD
Harvard Medical School

Bryan Roth, MD, PhD
University of North Carolina

Kelly Knopp, PhD
Eli Lilly

Get the sensation

The meeting’s penultimate session focused on how sensory signals such as pain propagate toward the central nervous system. Alexander Chesler started the session with a discussion of his work on peripheral sensory neurons.

To study these cells, Chesler and his colleagues initially developed an elegant system that allowed them to probe the responses of individual mouse cells in the trigenimal ganglion, a nerve cluster that receives sensory signals. That revealed a specific subset of neurons that responded only to a painful stimulus, while other subsets responded to gentle touches. By extending the system with gene expression profiling, and correlating responses in the mouse with those in a human patient who lacks a receptor critical for mechanical sensation, the scientists are now tracing pain-sensing pathways in unprecedented detail.

Neurons aren’t the only cells carrying pain signals, though, as Patrik Ernfors has discovered. In tracing sensory circuits, he and his colleagues discovered that Schwann cells, support cells closely associated with peripheral neurons, are also stem cells that form a sensory organ under the skin.

Using genetically modified mouse models that allowed them to selectively activate these Schwann cells, Ernfors and his colleagues discovered that both the Schwann cells and their associated neurons can initiate acute pain sensations. Further work revealed that the Schwann cells also appear to become sensitized during the development of arthritis.

“We believe that we have found the mechanosensory skin organ that is associated with [mechanical pain sensation],” said Ernfors, adding that these cells could contribute to allodynia in arthritis.

Something for the pain

Clifford Woolf began the meeting’s final session, on finding new ways to treat pain, with a summary of his team’s novel approach to drug discovery. Currently, most pharmaceutical companies focus on finding compounds that can target specific cellular molecules known to be involved in pain, then trying to develop them into drugs.

In 2010, Woolf advocated an alternative strategy, screening drugs to find those that inhibit stem cell-derived pain-sensing neurons, without worrying about their mechanisms of action.

“However, the question was how to execute on this,” he said.

After extensive effort, his team can now derive the correct neuron types from patients’ cells. Screening libraries of compounds against these cells has yielded several promising hits, which inhibit pain signaling in nociceptors without affecting other cell types.

Others hope to broaden the scope of target-based drug screening, which has focused on a large and diverse class of cell surface proteins called G-protein coupled receptors, or GPCRs.

“But … when we mapped the drugs onto the phylogeny of all the [GPCRs] in the genome, only a few targets actually came out as being targets of approved drugs,” said Bryan Roth, adding that “there are many, many other potential targets for treating pain and other serious conditions.”

To test those targets, Roth’s team developed an assay that allows them to test drugs against a library encompassing 90% of GPCRs encoded in the human genome. That has revealed several new targets, which the researchers are now testing with more specific screens, ultimately hoping to develop safer opioids.

Kelly Knopp began the meeting’s final talk with the grim statistics of chronic pain: affecting about one fourth of the global population, the direct and indirect costs of this condition add up to more than a trillion dollars.

“[Meanwhile,] the probability of technical success for pain [drugs] is worse than any other therapeutic area,” said Knopp.

To address that, she and her colleagues have focused on establishing standardized protocols for phase 2 proof-of-concept trials of pain treatments. Their approach uses sophisticated statistical techniques and uniform trial designs to enable testing of many more drug candidates, without exceeding available funding and medical trial capacity.

After the presentations, a panel of speakers from the meeting discussed several of the field’s biggest challenges. Chief among them are the immense burden of opioid addiction, and the difficulty of shifting real-world clinical treatment toward less addictive but possibly less effective therapies for chronic pain. Despite the difficulties, many researchers in the field remain optimistic.

As Ilene Tracey said in her presentation, “We’re often quite doom and gloom in the pain field, [but] we’ve actually got a lot of different tools at our disposal, [and] we should be more confident about where the field has got to and where it can go quite rapidly.”

9 Young Scientists Are Innovating to Transform Our World for a Better Future

Overview

The Blavatnik Awards for Young Scientists in the United Kingdom are the largest unrestricted prize available to early career scientists in the Life Sciences, Physical Sciences & Engineering, and Chemistry in the UK. The three 2021 Laureates each received £100,000, and two Finalists in each category received £30,000 per person. The honorees are recognized for their research, which pushes the boundaries of our current technology and understanding of the world. In this event, held at the historic Banqueting House in London, the UK Laureates and Finalists had a chance to explain their work and its ramifications to the public.

Victoria Gill, a Science and Environment Correspondent for the BBC, introduced and moderated the event. She noted that “Science has saved the world and will continue to do so,” and stressed how important it is for scientists to engage the public and share their discoveries at events like this. This theme arose over and over again over the course of the day.

Symposium Highlights

  • Single-cell analyses can reveal how multicellular animals develop and how our immune systems deal with different pathogens we encounter over the course of our lives.
  • Viruses that attack bacteria—bacteriophages—may help us fight antibiotic resistant bacterial pathogens.
  • Fossils offer us a glimpse into what life on Earth was like for the millennia in which it thrived before mammals took over.
  • Stacking layers of single-atom-thick sheets can make new materials with desired, customizable properties.
  • Memristors are electronic components that can remember a variety of memory states, and can be used to build quicker and more versatile computer chips than currently used.
  • The detection of the Higgs boson, which had been posited for decades by mathematical theory but was very difficult to detect, confirmed the Standard Model of Physics.
  • Single molecule magnets can be utilized for high density data storage—if they can retain their magnetism at high enough temperatures.
  • When examining how life first arose on Earth, we must consider all of its requisite components and reactions in aggregate rather than assigning primacy to any one of them.

Speakers

Stephen L. Brusatte
The University of Edinburgh

Sinéad Farrington
The University of Edinburgh

John Marioni
European Bioinformatics Institute and University of Cambridge

David P. Mills
The University of Manchester

Artem Mishchenko
The University of Manchester

Matthew Powner
University College London

Themis Prodromakis
University of Southampton

Edze Westra
University of Exeter

Innovating in Life Sciences

Speakers

John Marioni, PhD
European Bioinformatics Institute and University of Cambridge, 2021 Blavatnik Awards UK Life Sciences Finalist

Edze Westra, PhD
University of Exeter, 2021 Blavatnik Awards UK Life Sciences Finalist

Stephen Brusatte, PhD
The University of Edinburgh, 2021 Blavatnik Awards UK Life Sciences Laureate

How to Build an Animal

John Marioni, PhD, European Bioinformatics Institute and University of Cambridge, 2021 Blavatnik Awards UK Life Sciences Finalist

Animals grow from one single cell: a fertilized egg. During development, that cell splits into two, and then into four, and so on, creating an embryo that grows into the billions of cells comprising a whole animal. Along the way, the cells must differentiate into all of the different cell types necessary to create every aspect of that animal.

Each cell follows its own path to arrive at its eventual fate. Traditionally, the decisions each cell has to make along that path have been studied using large groups of cells or tissues; this is because scientific lab techniques have typically required a substantial amount of starting material to perform analyses. But now, thanks in large part to the discoveries of John Marioni and his lab group, we have the technology to track individual cells as they mature into different cell types.

Marioni has created analytical methods capable of observing patterns in all of the genes expressed by individual cells. Importantly, these computational and statistical methods can be used to analyze the enormous amounts of data generated from the gene expression patterns of many individual cells simultaneously. In addition to furthering our understanding of cell fate decisions in embryonic development, this area of research—single cell genomics—can also be applied to many other processes in the body.

One relevant application is to the immune system: single cell genomics can detect immune cell types that are activated by exposure to a particular pathogen. To illustrate this, Marioni showed many gorgeous, colorized images of individual cells, highlighting their unique morphology and function. Included in these images was histology showing profiles of different types of T cells elicited by infection with SARS-CoV-2 (the virus that causes COVID-19).

The cells were computationally grouped by genetic profile and graphed to show how the different cell types correlated with disease severity. There are many other clinical applications of his research into genomics. For instance, he said, if we know exactly which cell types in the body express the targets of specific drugs, we will be better able to predict that drug’s effects (and side effects).

In addition to his lab work, Marioni is involved in the Human Cell Atlas initiative, a global collaborative project whose goal it is to genetically map all of the cell types in healthy human adults. When a cell uses a particular gene, it is said to “transcribe” that gene to make a particular protein—thus, the catalog of all of the genes one cell uses is called its “transcriptome.” The Human Cell Atlas is using these single cell transcriptomes to create the whole genetic map.

This research is currently completely redefining how we think of cell types by transforming our definition of a “cell” from the way it looks to the genetic profile.

Bacteria and Their Viruses: A Microbial Arms Race

Edze Westra, PhD University of Exeter, 2021 Blavatnik Awards UK Life Sciences Finalist

All organisms have viruses that target them for infection; bacteria are no exception. The viruses that infect bacteria are called bacteriophages, or phages.

Edze Westra’s lab studies how bacteria evolve to defend themselves against infection by phage and, specifically, how elements of their environment drive the evolution of their immune systems. Like humans, bacteria have two main types of immune systems: an innate immune system and an adaptive immune system. The innate immune system works similarly in both bacteria and humans by modifying molecules on the cell surface so that the phage can’t gain entry to the cell.

In humans, the adaptive immune system is what creates antibodies. In bacteria, the adaptive immune system works a little bit differently—a gene editing system, called CRISPR-Cas, cuts out pieces of the phage’s genome and uses it as a template to identify all other phages of the same type. Using this method, the bacterial cell can quickly discover and neutralize any infectious phage by destroying the phage’s genetic material. In recent years, scientists have harnessed the CRISPR-Cas system for use in gene editing technology.

Westra wanted to know under what conditions do bacteria use their innate immune system versus their adaptive immune system: How do they decide?

In studies using the bacterial pathogen Pseudomonas aeruginosa, his lab found that the decision to use adaptive vs. innate immunity is controlled almost exclusively by nutrient levels in the surrounding environment. When nutrient levels are low, the bacteria use the adaptive immune system, CRISPR-Cas; when nutrient levels are high, the bacteria rely on their innate immune system. He recognized that this means we can artificially guide the evolution of bacterial defense by controlling elements in their environment.

When we need to attack pathogenic bacteria for medical purposes, such as in a sick or infected patient, we turn to antibiotics. However, many strains of bacteria have developed resistance to antibiotics, leaving humans vulnerable to infection.

Additionally, our antibiotics tend to kill broad classes of microbes, often damaging the beneficial species we harbor in our bodies along with the pathogenic ones we are trying to eliminate. Phage therapy—a medical treatment where phages are administered to a patient with a severe bacterial infection—might be a good way to circumvent antibiotic resistance while also attacking bacteria in a more targeted manner, harming only those that harm us and leaving the others be.

Although it is difficult to manipulate bacterial nutrients within the context of a patient’s body, we can use antibiotics to direct this behavior. Antibiotics that are shown to limit bacterial growth will induce the bacteria to use the CRISPR-Cas strategy, mimicking the effects of a low-nutrient environment; antibiotics that work by killing bacteria will induce them to use their innate defenses. In this way, it may be possible to direct the evolution of bacterial defense systems in order to reveal their weaknesses and target them with phage therapy.

The Rise and Fall of the Dinosaurs

Stephen Brusatte, PhD The University of Edinburgh, 2021 Blavatnik Awards UK Life Sciences Laureate|

Stephen Brusatte is a paleontologist, “and paleontologists”, he says, “are really historians”. Just as historians study recorded history to learn about the past, paleontologists study prehistory for the same reasons.

The Earth is four and a half billion years old, and humans have only been around for the last three hundred and fifty thousand of those years. Dinosaurs were the largest living creatures to ever walk the earth; they started out around the size of house cats, and over eighty million years they evolved into the giant T. rexes, Stegosauruses, and Brontosauruses in our picture books.

They reigned until a six-mile-wide asteroid struck the Earth sixty-six million years ago at the end of the Cretaceous period, extinguishing them along with seventy-five percent of the other species on the planet. Brusatte called this day “the worst day in Earth’s history.” However, the demise of dinosaurs paved the way for mammals to take over.

Fossils can tell us a lot about how life on this planet used to be, how the earth and its occupants respond to climate and environmental changes, and how evolution works over long timescales. Particularly, fossils show how entirely new species and body plans emerge.

Each fossil can yield new knowledge and new discoveries about a lost world, he said. It can teach us how bodies change and, ultimately, how evolution works. It is from fossils that we know that today’s birds evolved from dinosaurs.

Life Sciences Panel Discussion

Victoria Gill started the life sciences panel discussion by asking all three of the awardees if, and how, the COVID-19 pandemic changed their professional lives: did it alter their scientific approach or were they asking different questions?

Westra replied that the lab shutdown forced different, non-experimental approaches, notably bioinformatics on old sequence data. He said that they found mobile genetic elements, and the models of how they moved through a population reminded him of epidemiological models of COVID spread.

Marioni shared that he was inspired by how the international scientific community came together to solve the problem posed by the pandemic. Everyone shared samples and worked as a team, instead of working in isolation as they usually do. Brusatte agreed that enhanced collaboration accelerated discoveries and should be maintained.

Questions from the audience, both in person and online, covered a similarly broad of a range of topics. An audience member asked about where new cell types come from; Marioni explained that if we computationally look at gene transcription changes in single cells over time, we can make phylogenetic trees showing how cells with different expression patterns arise.

A digital attendee asked Brusatte why birds survived the asteroid impact when other dinosaurs didn’t. Brusatte replied that the answer is not clear, but it is probably due to a number of factors: they have beaks so they can eat seeds, they can fly, and they grow fast. Plus, he said, most birds actually did not survive beyond the asteroid impact.

Another audience member asked Brusatte if the theory that the asteroid killed the dinosaurs was widely accepted. He replied that it is widely accepted that the impact ended the Cretaceous period, but some scientists still argue that other factors, like volcanic eruptions in India, were the prime mover behind the dinosaurs’ demise.

Another viewer asked Westra why the environment impacts a bacterium’s immune strategy. He answered that in the presence of antibiotics that slow growth, infection and metabolism are likewise slowed so the bacteria simply have more time to respond. He added that the level of diversity in the attacking phage may also play a role, as innate immunity is better able to deal with multiple variants.

To wrap up the session, Victoria Gill asked about the importance of diversity and representation and wondered how to make awards programs like this more inclusive. All three scientists agreed that it is hugely important, that the lack of diversity is a problem across all fields of research, that all voices must be heard, and that the only way to change it is by having hard metrics to rank universities and departments on the demographics of their faculty.

Innovating in Physical Sciences & Engineering

Speakers

Artem Mishchenko, PhD
The University of Manchester, 2021 Blavatnik Awards UK Physical Sciences & Engineering Finalist

Themis Prodromakis, PhD
University of Southampton, 2021 Blavatnik Awards UK Physical Sciences & Engineering Finalist

Sinead Farrington, PhD
The University of Edinburgh, 2021 Blavatnik Awards UK Physical Sciences & Engineering Laureate

Programmable van der Waals Materials

Artem Mishchenko, PhD The University of Manchester, 2021 Blavatnik Awards UK Physical Sciences & Engineering Finalist

Materials science is vital because materials define what we can do, and thus define us. That’s why the different eras in prehistory are named for the materials used: the Stone Age, the Bronze Age, the Iron Age, the Copper Age. The properties of the materials available dictated the technologies that could be developed then, and the properties of the materials available still dictate the technologies that can be developed now.

Van der Waals materials are materials that are only one or a few atoms thick. The most well-known is probably graphene, which was discovered in 2004 and is made of carbon. But now hundreds of these two-dimensional materials are available, representing almost the whole periodic table, and each has different properties. They are the cutting edge of materials innovation.

Mishchenko studies how van der Waals materials can be made and manipulated into materials with customizable, programmable properties. He does this by stacking the materials and rotating the layers relative to each other. Rotating the layers used to be painstaking, time-consuming work, requiring a new rig to make each new angle of rotation. But his lab developed a single device that can twist the layers by any amount he wants. He can thus much more easily make and assess the properties of each different material generated when he rotates a layer by a given angle, since he can then just reset his device to turn the layer more or less to devise a new material. Every degree of rotation confers new properties.

His lab has found that rotating the layers can tune the conductivity of the materials and that the right combination of angle and current can make a transistor that can generate radio waves suitable for high frequency telecommunications. With infinite combinations of layers available to make new materials, this new field of “twistronics” may generate an entirely new physics, with quantum properties and exciting possibilities for biomedicine and sustainability.

Memristive Technologies: From Nano Devices to AI on a Chip

Themis Prodromakis, PhD University of Southampton, 2021 Blavatnik Awards UK Physical Sciences & Engineering Finalist

Transistors are key elements in our electronic devices. They process and store information by switching between on and off states. Traditionally, in order to increase the speed and efficiency of a device one increased the number of transistors it contained. This usually entailed making them smaller. Smartphones contain seven billion transistors! But now it has become more and more difficult to further shrink the size of transistors.

Themis Prodromakis and his team have been instrumental in developing a new electronic component: the memristor, or memory resistor. Memristors are a new kind of switch; they can store hundreds of memory states, beyond on and off states, on a single, nanometer-scale device. Sending a voltage pulse across a device allows to tune the resistance of the memristor at distinct levels, and the device remembers them all.

One benefit of memristors is that they allow for more computational capacity while using much less energy from conventional circuit components. Systems made out of memristors allow us to embed intelligence everywhere by processing and storing big data locally, rather than in the cloud. And by removing the need to share data with the cloud, electronic devices made out of memristors can remain secure and private. Prodromakis has not only developed and tested memristors, he is also quite invested in realizing their practical applications and bringing them to market.

Another amazing application of memristors is linking neural networks to artificial ones. Prodromakis and his team have already successfully connected biological and artificial neurons together and enabled them to communicate over the internet using memristors as synapses. He speculates that such neuroprosthetic devices might one day be used to fix or even augment human capabilities, for example by replacing dysfunctional regions of the brain in Alzheimer’s patients. And if memristors can be embedded in a human body, they can be embedded in other environments previously inaccessible to electronics as well.

What Do We Know About the Higgs Boson?

Sinead Farrington, PhD The University of Edinburgh, 2021 Blavatnik Awards UK Physical Sciences & Engineering Laureate

In the Standard Model of particle physics, the bedrock of modern physics, fermions are the elementary particles comprising all of the stable matter in the universe, while bosons—the other collection of elementary particles—are the ones that transmit forces. The Higgs boson, whose existence was theoretically proposed in 1964, is a unique particle; it gives mass to the other particles by coupling with them.

Sinéad Farrington led the group at CERN that further elucidated the properties of the Higgs boson and thus bolstered the Standard Model. The Standard Model “effectively encapsulates a remarkably small set of particles that make up everything we know about and are able to create,” explained Farrington.

“The Higgs boson is needed to maintain the compelling self-consistency of the Standard Model. It was there in theory, but the experimental observation of it was a really big deal. Nature did not have to work out that way,” Farrington said.

Farrington and her 100-person international team at the Large Hadron Collider demonstrated that the Higgs boson spontaneously decays into two fermions called tau leptons. This was experimentally challenging because tau is unstable, so the group had to infer that it was there based on its own degradation products. She then went on to develop the analytical tools needed to further record and interpret the tau lepton data and was the first to use machine learning to trigger, record, and analyze the massive amounts of data generated by experiments at the LHC.

Now she is looking to discover other long-lived but as yet unknown particles beyond the Standard Model that also decay into tau leptons, and plans to make more measurements using the Large Hadron Collider to further confirm that the Higgs boson behaves the way the Standard Model posits it will.

In addition to the satisfaction of verifying that a particle predicted by mathematical theorists actually does exist, Farrington said that another consequence of knowing about the Higgs boson is that it may shed light on dark matter and dark energy, which are not part of the Standard Model. Perhaps the Higgs boson gives mass to dark matter as well.

Physical Sciences & Engineering Panel Discussion

Victoria Gill started this session by asking the participants what they plan to do next. Farrington said that she would love to get more precise determinations on known processes, reducing the error bars upon them. And she will also embark on an open search for new long-lived particles—i.e. those that don’t decay rapidly—beyond the Standard Model.

Prodromakis wants to expand the possibilities of memristive devices, since they can be deployed anywhere and don’t need a lot of power. He envisions machine-machine interactions like those already in play in the Internet of Things as well as machine-human interactions. He knows he must grapple with the ethical implications of this new technology, and mentioned that it will also require a shift in how electricity, electronics, and computational fabrics are taught in schools.

Mishchenko is both seeking new properties in extant materials and making novel materials and seeing what they’ll do. He’s also searching for useful applications for all of his materials.

A member of the audience asked Farrington if, given all of the new research in quantum physics, we have new data to resolve the Schrӧedinger’s cat conundrum? But she said no, the puzzle still stands. That is the essence of quantum physics: there is uncertainty in the (quantum) world, and both states exist simultaneously.

Another wondered why she chose to look for the tau lepton as evidence of the Higgs boson’s degradation and not any other particles, and she noted that tau was the simplest to see over the background even though it does not make up the largest share of the breakdown products.

An online questioner asked Prodromakis if memristors could be used to make supercomputers since they allow greater computational capacity. He answered that they could, in principle, and could be linked to our brains to augment our capabilities.

Someone then asked Mishchenko if his technology could be applied into biological systems. He said that in biological systems current comes in the form of ions, whereas in electronic systems current comes in the form of electrons, so there would need to be an interface that could translate the current between the two systems. Some of his materials can do that by using electrochemical reactions that convert electrons into ions. But the materials must also be nontoxic in order to be incorporated into human tissues, so he thinks this innovation is thirty to forty years away.

The last query regarded whether the participants viewed themselves as scientists or engineers. Farrington said she is decidedly a physicist and not an engineer, though she collaborates with civil and electrical engineers and relies on them heavily to build and maintain the colliders and detectors she needs for her work.

Prodromakis was trained as an engineer, but now works at understanding the physics of devices so he can design them to reliably do what he wants them to do. And Mishchenko summarized the difference between them by saying the engineering problems are quite specific, while scientists mostly work in darkness. At this point, he considers himself an entrepreneur.

Innovating in Chemistry

Speakers

David P. Mills, PhD
The University of Manchester, 2021 Blavatnik Awards UK Chemistry Finalist

Matthew Powner, PhD
University College London, 2021 Blavatnik Awards UK Chemistry Finalist

Building High Temperature Single-Molecule Magnets

David P. Mills, PhD The University of Manchester, 2021 Blavatnik Awards UK Chemistry Finalist

David Mills’ lab “makes molecules that have no right to exist.” He is specifically interested in the synthesis of small molecules with unusual shapes that contain metal ions, and using these as tiny molecular magnets to increase data storage capacity to support high-performance computing. Mills offers a bottom-up approach to this problem: he wants to make new molecules for high density data storage. This could ultimately make computers smaller and reduce the amount of energy they use.

Single-Molecule Magnets (SMMs) were discovered about thirty years ago. They differ from regular magnets, which derive their magnetic properties from interactions between atoms, but they still have two states: up and down. These can be used to store data in a manner similar to the bits of binary code that computers currently use. Initially, SMMs could only work at extremely cold temperatures, just above absolute zero. For many years, scientists were unable to create an SMM capable of operation above −259oC, only 10oC above the temperature of liquid helium, which makes them decidedly less than practical for everyday use.

Mills works with a class of elements called the lanthanides, sometimes known as the rare-earth metals, that are already used in smartphones and hybrid vehicles. One of his students utilized one such element, dysprosium, in the creation of an SMM that was dubbed, dysprosocenium. Dysprosocenium briefly held its magnetic properties even at a blistering −213oC, the warmest temperature at which any SMM had ever functioned. This temperature is starting to approach the temperature of liquid nitrogen, which has a boiling point of −195.8°C. If an SMM could function indefinitely at that temperature, it could potentially be used in real-world applications.

When developing dysprosocenium, the Mills group and their collaborators learned that controlling molecular vibrations is essential to allowing the single-molecule magnet to work at such high temperatures. So, his plan for the future is to learn how to control these vibrations and work toward depositing single-molecule magnets on surfaces.

The Chemical Origins of Life

Matthew Powner, PhD University College London, 2021 Blavatnik Awards UK Chemistry Finalist

The emergence of life is the most profound transition in the history of Earth, and yet we don’t know how it came about. Earth formed four-and-a-half billion years ago, and it is believed that the earliest life-forms appeared almost a billion years later. However, we don’t know what happened in the interim.

Life’s Last Universal Common Ancestor (LUCA) is believed to be much closer to modern life forms than to that primordial originator, so although we can learn about life’s common origins from LUCA, we can’t learn about the true Origin of Life. Where did life come from? How did the fundamental rules of chemistry give rise to life forms? Why did life organize itself the way that it did?

Matthew Powner thinks that to answer these vital existential questions, which lie at the nexus of chemistry and biology, we must simultaneously consider all of life’s components—nucleic acids, amino acids and peptides, metabolic reactions and pathways—and their interactions. We can’t just look at any one of them in isolation.

Since these events occurred in the distant past, we can’t discover it—we must reinvent it. To test how life came about, we must build it ourselves, from scratch, by generating and combining membranes, genomes, and catalysis, and eventually metabolism to generate energy.

In this presentation, Powner focused on his lab’s work with proteins. Our cells, which are highly organized and compartmentalized machines, use enzymes—proteins themselves—and other biological macromolecules to synthesize proteins. So how did the first proteins get made? Generally, the peptide bonds linking amino acids together to make proteins do not form at pH 7, the pH of water and therefore of most cells. But Powner’s lab showed that derivatives of amino acids could form peptide bonds at this pH in the presence of ultraviolet light from the sun, and sulfur and iron compounds, all of which were believed to have been present in the prebiotic Earth.

Chemistry Panel Discussion

Victoria Gill started this one off by asking the chemists how important it is to ask questions without a specific application in mind. Both agreed that curiosity defines and drives humanity, and that the most amazing discoveries arise just from trying to satisfy it. Powner says that science must fill all of the gaps in our understanding, and the new knowledge generated by this “blue sky research” (as Mills put it) will yield applications that will change the world but in unpredictable ways. Watson and Crick provide the perfect example; they didn’t set out to make PCR, but just to understand basic biological questions. Trying to drive technology forward may be essential, but it will never change the world the same way investigating fundamental phenomena for its own sake can.

One online viewer wanted to know if single-molecule magnets could be used to make levitating trains, but Mills said that they only work at the quantum scale; trains are much too big.

Other questions were about the origin of life. One wanted to know if life arose in hydrothermal vents, one was regarding the RNA hypothesis (which posits that RNA was the first biological molecule to arise since it can be both catalytic and self-replicating), and one wanted to know what Powner thought about synthetic biology. In terms of hydrothermal vents, Powner said that we know that metabolism is nothing if not adaptable—so it is difficult to put any constraints on the environment in which it arose.

He said that the RNA world is a useful framework in which to form research questions, but he no longer thinks it is a viable explanation for how life actually arose since any RNA reactions would need a membrane to contain them in order to be meaningful. And he said that synthetic biology—the venture of designing and generating cells from scratch, and even using non-canonical nucleic acids and amino acids beyond those typically used by life forms—is a complementary approach to the one his lab takes to investigate why biological systems are the way they are.

The Future of Research in the UK: How Will We Address the Biggest Challenges Facing Our Society?

Contributors

Stephen Brusatte, PhD
The University of Edinburgh, 2021 Blavatnik Awards UK Life Sciences Laureate

Sinead Farrington, PhD
The University of Edinburgh, 2021 Blavatnik Awards UK Physical Sciences & Engineering Laureate

Victoria Gill moderated this discussion with the Blavatnik laureates, Stephen Brusatte and Sinead Farrington. First, they discussed how COVID-19 affected their professional lives. Both of them spoke of how essential it was for them to support their students and postdocs throughout the pandemic. These people may live alone, or with multiple roommates, and they may be far from family and home, and both scientists said they spent a lot of time just talking to them and listening to them. This segued into a conversation about how the rampant misinformation on social media about COVID-19 highlighted the incredible need for science outreach, and how both laureates view it as a duty to communicate their work to the public by writing popular books and going into schools.

Next, they tackled the lack of diversity in STEM fields. Farrington said that she has quite a diverse research group—but that it took effort to achieve that. This led right back to public outreach and schooling. She said that one way to increase diversity would be to develop all children’s’ analytical thinking skills early on to yield “social leveling” and foment everyone’s interest in science. Brusatte agreed that increased outreach and engagement is an important way to reach larger audiences and counteract the deep-seated inequities in our society.

Lastly, they debated if science education in the UK is too specialized too early, and if it should be broader, given the interdisciplinary nature of so many breakthroughs today. Brusatte was educated under another system so didn’t really want to opine, but Farrington was loath to sacrifice depth for breadth. Deep expert knowledge is important.

The Science of Tomorrow: Blavatnik Awards for Young Scientists in Israel

Overview

The Blavatnik Awards for Young Scientists in Israel is one of the largest prizes ever created for early-career researchers in Israel. Given annually to three outstanding, early-career faculty from Israeli universities in three categories—Life Sciences, Physical Sciences & Engineering, and Chemistry—the awards recognize extraordinary scientific achievements and promote excellence, originality, and innovation.

On August 2, 2021, the New York Academy of Sciences celebrated the 2020 and 2021 Laureates at the Israel Academy of Sciences and Humanities in Jerusalem, Israel. The multidisciplinary symposium, chaired by Israel Prize winners Adi Kimchi and Mordechai (Moti) Segev, featured a series of lectures on everything from a new class of RNA to self-assembling nanomaterials.

In this eBriefing, you’ll learn:

  • The secret life of bats, and how the brain shapes animal behavior
  • How genetic information in unchartered areas of the human genome—known as long noncoding RNA—could be used to develop treatments for cancer, brain injury, and epilepsy
  • Creative ways of generating light, X-rays, and other types of radiation for practical applications such as medical imaging and security scanners
  • The intricate choreography of protein assembly within cells, and how this dance may go awry in disease

Speakers

Yossi Yovel, PhD
Tel Aviv University

Igor Ulitsky, PhD
Weizmann Institute of Science

Emmanuel Levy, PhD
Weizmann Institute of Science

Ido Kaminer, PhD
Israel Institute of Technology

Life Sciences of Tomorrow

Speakers

Yossi Yovel, PhD
Tel Aviv University

Igor Ulitsky, PhD
Weizmann Institute of Science

From Bat Brains to Navigating Robots

Yossi Yovel, PhD, Tel Aviv University 

In this presentation, Yossi Yovel describes his studies on bats and their use of echolocation to perceive and navigate through the world. To monitor bats behaving in their natural environment, he has developed miniaturized trackers—the smallest in the world—capable of simultaneously detecting location, ultrasonic sounds, movement, heart rate, brain activity, and body temperature changes.

By attaching these small sensors to many individual bats, Yovel is able to monitor large groups of free-flying bats—a task which would be almost impossible in other mammals. His current and future studies include applying bat echolocation theory to engineering acoustic control of autonomous vehicles.

Further Readings

Yovel

Moreno, K. R., Weinberg, M., Harten, L., Salinas Ramos, V. B., Herrera M, L. G., Czirják, G. Á., & Yovel, Y.

Sick bats stay home alone: fruit bats practice social distancing when faced with an immunological challenge

Annals of the New York Academy of Sciences, 2021.

Amichai, Eran, and Yossi Yovel.

Echolocating bats rely on an innate speed-of-sound reference

Proceedings of the National Academy of Sciences, 2021.

Geva-Sagiv, M., Las, L., Yovel, Y., & Ulanovsky, N.

Spatial cognition in bats and rats: from sensory acquisition to multiscale maps and navigation.

Nature Reviews Neuroscience, 2015

Decoding the Functions of Long Non-coding RNA

Igor Ulitsky, PhD, Weizmann Institute of Science

Igor Ulitsky outlines his investigation of the biology of a subtype of genetic material—long non-coding RNA (lncRNA)—an enigmatic class of RNA molecules. Similar to other classes of RNA molecules, lncRNAs are transcribed from DNA and have a single-strand structure; however, lncRNAs do not encode proteins. Even though non-coding regions of the genome comprise over 99% of our genetic material, little is actually known about how these regions function.

Ulitsky’s work has shown dynamic expression patterns across tissues and developmental stages, which appear to utilize diverse mechanisms of action that depend on their sub-cellular positions. These discoveries have unlocked the potential of using lncRNAs as both therapeutic agents and targets with promising leads for the treatment of diseases such as cancer, brain injury, and epilepsy.

Further Readings

Ulitsky

H. Hezroni, D. Koppstein, M.G. Schwartz, A. Avrutin, D.P. Bartel, I. Ulitsky.

Principles of Long Noncoding RNA Evolution Derived from Direct Comparison of Transcriptomes in 17 Species

Cell Reports, 2015

R.B. Perry, H. Hezroni, M.J. Goldrich, I. Ulitsky.

Regulation of Neuroregeneration by Long Noncoding RNAs

Molecular Cell, 2018

A. Rom, L. Melamed, N. Gil, M. Goldrich, R. Kadir, M. Golan, I. Biton, R. Ben-Tov Perry, I. Ulitsky.

Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability

Nature Communications, 2019

Chemistry and Physical Sciences & Engineering of Tomorrow

Speakers

Emmanuel Levy, PhD
Weizmann Institute of Science

Ido Kaminer, PhD
Israel Institute of Technology

Playing LEGO with Proteins: Principles of Protein Assembly in Cells

Emmanuel Levy, PhD, Weizmann Institute of Science 

In this presentation, Emmanuel Levy describes how defects in protein self-organization can lead to disease, and how protein self-organization can be exploited to create novel biomaterials. Levy has amassed a database of protein structural information that helps him to predict, browse, and curate the structural features—charged portions, hydrophobic and hydrophilic pockets, and point mutations—within a protein that govern the formation of quaternary structures. By combining this computational approach with experimental data Levy is able to uncover new mechanisms by which proteins operate within cells.

Further Readings

Levy

H. Garcia-Seisdedos, C. Empereur-Mot, N. Elad, E.D. Levy.

Proteins Evolve on the Edge of Supramolecular Self-assembly

Nature, 2017

M. Meurer, Y. Duan, E. Sass, I. Kats, K. Herbst, B.C. Buchmuller, V. Dederer, F. Huber, D. Kirrmaier, M. Stefl, K. Van Laer, T.P. Dick, M.K. Lemberg, A. Khmelinskii, E.D. Levy, M. Knop.

Genome-wide C-SWAT Library for High-throughput Yeast Genome Tagging

Nature Methods, 2018

H. Garcia-Seisdedos, J.A. Villegas, E.D. Levy.

Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering

Angewandte Chemie International Edition, 2019

Shining Light on the Quantum World with Ultrafast Electron Microscopy

Ido Kaminer, PhD, Israel Institute of Technology

Ido Kaminer discusses his research on light-matter interaction that spans a wide spectrum from fundamental physics to particle applications. Part of his presentation addressed the long-standing question in quantum theory over the predictability of motions quantum particles. He also demonstrated the first example of using free electrons to probe the motion of photons inside materials. Finally, he talked about the potential applications of tunable X-rays generated from the compact equipment in his lab, for biomedical imaging and other applications.

Further Readings

Kaminer

R. Dahan, S. Nehemia, M. Shentcis, et al., I. Kaminer.

Resonant Phase-matching Between a Light Wave and a Free Electron Wavefunction

Nature Physics, 2020

K. Wang, R. Dahan, M. Shentcis, Y. Kauffmann, A.B. Hayun, O. Reinhardt, S. Tsesses, I. Kaminer.

Coherent Interaction between Free Electrons and a Photonic Cavity

Nature, 2020

Y. Kurman, N. Rivera, T. Christensen, S. Tsesses, M. Orenstein, M. Soljačić, J.D. Joannopoulos, I. Kaminer.

Control of Semiconductor Emitter Frequency by Increasing Polariton Momenta

Nature Photonics, 2018

New Developments in Human Healthspan and Longevity

Overview

Although advances made in health and safety have more than doubled life expectancy throughout much of the world since 1900, it hasn’t been without consequence. Disease, disability, and frailty have all impacted the quality of life associated with these later years. This unfortunate reality was recently illuminated by the COVID-19 pandemic, which severely affected this population, likely due to physiological changes and preexisting conditions. Fortunately, a primary goal of geroscience researchers is to attenuate age-related health issues so that older people not only enjoy an improved quality of life, but also maintain the resilience to survive severe diseases and infections.

While it’s irrefutable that we cannot avoid aging, it’s no longer within the realm of science fiction for us to temper and even reverse the aging process. On May 19, 2021, the New York Academy of Sciences hosted a virtual symposium that brought together geroscience experts spanning various disciplines, including genetics, endocrinology, gerontology, clinical psychology, and more. Speakers discussed targeting the key hallmarks of aging, developing biomarkers for geriatric therapies, and translating findings that extend healthspan and lifespan to the clinic.

Symposium Highlights

  • The Target Aging with Metformin study uses the FDA approved anti-diabetic metformin, which targets the hallmarks of aging, to investigate the prevention of age-related diseases.
  • Precluding the age-associated decline of chaperon-mediated autophagy restrains the aggregating effects of Alzheimer’s disease and extends lifespan in murine models.
  • Lower IGF-1 levels in older adults are associated with decreased cognitive impairment, age-related diseases, and mortality.
  • Epigenetic clocks can be applied to study biological aging differences, with accelerated epigenetic aging correlating with the prevalence and incidence of morbidity and mortality.
  • The metabolome is a powerful locus of opportunity to bridge the gap between genotype and age.
  • Alternative splicing is upregulated in response to declining mitochondrial function and increasing age.
  • Senescent cells upregulate pro-survival pathways, and their elimination alleviates diverse age-related conditions.
  • The mitochondrial-derived peptides humanin and MOTS-c are associated with increased longevity in animal models and humans.

Speakers

Nir Barzilai, MD
Albert Einstein College of Medicine

Ana Maria Cuervo, MD, PhD
Albert Einstein College of Medicine

Sofiya Milman, MD
Albert Einstein College of Medicine

Morgan Levine, PhD
Yale School of Medicine

Daniel Promislow, PhD
University of Washington

Luigi Ferrucci, MD, PhD
National Institute on Aging, National Institutes of Health

James Kirkland, MD, PhD
Mayo Clinic

Pinchas Cohen, MD
USC Leonard Davis School of Gerontology

Targetable Aging Processes

Speakers

Nir Barzilai, MD
Albert Einstein College of Medicine

Ana Maria Cuervo, MD, PhD
Albert Einstein College of Medicine

Keynote: Age Later: Translational Geroscience

Aging is the strongest risk factor for all age-related diseases, with diverse maladies accumulating during the later years of life. Hence, to abate or avert the relevant disorders, it’s critical to target the central driver—aging itself. Physician Nir Barzilai, the founding director of the Institute for Aging Research, investigates the genetics of longevity by studying centenarians and their offspring, interrogating the hypothesis that these individuals have genes that prolong aging and protect against age-related diseases.

Using Slow Off-Rate Modified Aptamer, Barzilai’s team assessed 5,000 proteins in a population of 1,000 individuals between the ages of 65-95, a period during which aging accelerates. Results demonstrated a significant change in the level of hundreds of proteins as a function of age. Among the top hits were proteins from collagen breakdown of tissue and cellular products, highlighting the pivotal role this process plays in aging, and suggesting that deterring disintegration may be a universal biomarker for geroprotection.

Metformin, a long-standing FDA approved anti-diabetic, targets the complement of aging indications.

A predominant challenge to translating advances made in geroscience from animal models to humans is the FDA, which currently doesn’t consider aging a disease indication or preventable condition. Barzilai and others are utilizing metformin, an FDA-approved anti-diabetic, to refute this contention. Various groups have shown that metformin has substantial effects on human healthspan, including delaying type-2 diabetes mellitus (T2DM). In this patient subset, metformin also impedes cardiovascular disease, cognitive decline, and Alzheimer’s and is associated with decreased cancer incidence, with population effects approaching 30% in all cases.

Barzilai’s team designed the Target Aging with Metformin, or TAME, study to investigate whether or not there’s a shift in the timeline of disease occurrence between a cohort receiving metformin versus a control cohort. Various biomarkers of aging and age-related diseases will be used to provide convergent evidence of broad, age-related effects, while also establishing a resource for innovation and discovery of emergent biomarkers.

“The most important thing for us is to develop biomarkers that will change when we use a gerotherapuetic,” Barzilai asserted, as this will expedite therapeutic prospects.

Targeting Selective Autophagy in Aging and Age-related Diseases

Physician-scientist Ana Maria Cuervo’s research seeks to understand the molecular basis of autophagy dysfunction with age and the contribution of defects in this cellular pathway to diseases such as neurodegeneration, metabolic disorders, and cancer. Autophagy belongs to the proteostasis network, which regulates protein content and quality control.

Chaperon-mediated autophagy (CMA) is a subset of the mammalian autophagy program that directly targets proteins to the lysosome for degradation. CMA has been shown to decrease with age in human and animal models. Cuervo’s lab developed a fluorescent murine reporter construct to visualize CMA and track the kinetics of its activity in different organs.

Blocking this pathway in neurons resulted in the aggregation of proteins like α-synuclein (α-syn), tau, and others that are causal in Alzheimer’s Disease (AD). Additionally, CMA reporter mice crossed with a mouse model of AD revealed that CMA activity dramatically decreases in the neurons of AD mice.

Leveraging these findings, Cuervo’s group generated a mouse model to restore CMA activity conditionally. Mice with preserved CMA exhibited an extended median and maximal lifespan compared to controls. Evaluation of the proteostasis network in mice with and without CMA restoration revealed major changes in the proteome. Mice in which CMA was preserved more closely resembled younger animals than their age-matched controls.

“By acting in one of these pathways, we can have an impact in the other hallmarks of aging… because of this interconnection among [them],” Cuervo emphasized.

A compound to selectively activate CMA was developed and tested in an AD model, with results illustrating a reduction in tau pathology and microglial activation in the presence of this agent.

Further Readings

Barzilai

Ismail K, Nussbaum L, Sebastiani P, et al.

Compression of Morbidity Is Observed Across Cohorts with Exceptional Longevity.

J Am Geriatr Soc. 2016 Aug;64(8):1583-91.

Sathyan S, Ayers E, Gao T, et al.

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging Cell. 2020 Nov;19(11):e13250.

Lehallier B, Gate D, Schaum N, et al.

Undulating changes in human plasma proteome profiles across the lifespan. 

Nat Med. 2019 Dec;25(12):1843-1850.

Kulkarni AS, Gubbi S, Barzilai N.

Benefits of Metformin in Attenuating the Hallmarks of Aging.

Cell Metab. 2020 Jul 7;32(1):15-30.

Zhang ZD, Milman S, Lin JR, et al.

Genetics of extreme human longevity to guide drug discovery for healthy ageing.

Nat Metab. 2020 Aug;2(8):663-672.

Cuervo

Kaushik S, Cuervo AM.

Proteostasis and aging.

Nat Med. 2015 Dec;21(12):1406-1415.

Bourdenx M, Martín-Segura A, Scrivo A, et al.

Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.

Cell. 2021 May 13;184(10):2696-2714.e25.

Kaushik S, Cuervo AM.

The coming of age chaperone-mediated autophagy.

Nat Rev Mol Cell Biol. 2018 Jun;19(6):365-381.

Dong S, Aguirre-Hernandez C, Scrivo A, et al. 

Monitoring spatiotemporal changes in chaperone-mediated autophagy in vivo. 

Nat Commun. 2020 Jan 31;11(1):645.

Dong S, Wang Q, Kao Y-R, et al.

Chaperone-mediated autophagy sustains haematopoietic stem-cell function.

Nature. 2021 Mar;591(7848):117-123.

Biomarkers for Therapies

Speakers

Sofiya Milman, MD
Albert Einstein College of Medicine

Morgan Levine, PhD
Yale School of Medicine

Translational Geroscience: Role of IGF-1 in Human Healthspan and Lifespan

Physician Sofiya Milman conducts translational research to uncover the genomic mechanisms regulating the endocrine and metabolic pathways involved in age-related conditions like diabetes, cardiovascular disorders, and Alzheimer’s.

“The goal of geroscience is really to extend healthspan, and not necessarily lifespan,” Milman opened. “What we’re really trying to do is to compress the period of morbidity.”

To discover the biological pathways that allow humans to live long, healthy lives, Milman’s team focused on IGF-1: a reduction of this factor has been consistently shown to extend healthspan and lifespan in models. IGF-1 levels peak during the teenage years before gradually declining. If the reduction of IGF-1 protects from aging, Milman reasoned that lower IGF-1 levels would delay aging and prevent age-related diseases.

Examining a cohort of centenarians expressing lower levels of IGF-1 revealed a 50% reduction in cognitive impairment compared to higher IGF-1 level controls. Genetic studies demonstrated that centenarians were enriched for rare mutations in the IGF-1 receptor that diminished signaling. Additionally, individuals 65+ with low IGF-1 had less cognitive impairment, and delayed onset of cognitive impairment, multi-morbidities, and mortality.

Milman’s team also addressed the link between IGF-1 and age. Younger individuals with lower levels of IGF-1 were at an increased risk for mortality and age-related diseases compared to older individuals, while higher levels of IGF-1 in older adults were associated with increased risk. This suggests that the IGF-1 network aligns with the concept of antagonistic pleiotropy, wherein a factor that’s beneficial to individuals when they’re younger may become harmful when they’re older. It’s advantageous to maintain functionality of proteostasis and resilience as an individual gets older, but IFG-1 inhibits programs involved in these processes.

“So from this, we think it would be wise to maintain IGF-1 levels in youth, but to reduce them with aging,” Milman concluded.

Epigenetic Biomarker of Aging for Lifespan and Healthspan

Biological age is defined by changes or alterations in a living system that renders it more vulnerable to failure and is behind the age-related increase in susceptibility to chronic diseases. Unlike chronological age, it is very difficult to measure because it’s unobservable.

Morgan Levine integrates theories and methods from statistical genetics, computational biology, and mathematical demography to develop biomarkers of aging for humans and animal models. Among this work are efforts to establish systems-level outcome measures of aging to facilitate evaluation for gero-protective interventions.

“There’s some disagreement on how we actually quantify [biological age],” Levine started. “But I would argue that it’s really important to try and do so, because quantifying [this] will really help us in a number of endeavors in the field.”

Levin’s lab is particularly interested in epigenetic aging, as aging drastically remodels the DNA methylation landscape, with widespread increases and decreases as a function of age.

Senescent cells and cells with disrupted energy production show accelerated epigenetic aging.

Epigenetic clocks estimate DNA methylation across the genome and combine supervised machine-learning approaches to develop predictors of biological age.

“We think people who have a predicted [epigenetic] age that’s younger than their chronological age should be actually aging slower, whereas the opposite is true for people that have a genetic age that is predicted higher,” said Levine.

Applying these measures to diseased states yielded several pertinent findings. For example, individuals who have pathologically diagnosed Alzheimer’s post-mortem show accelerated epigenetic aging in their brain relative to their chronological age. Tissue differences were also captured, revealing that tissues seem to age asynchronously, with highly proliferative tissues and tumor cells having accelerated aging compared to slower aging brain tissue.

Levine’s group also evaluated cellular senescence and energy disruption, with results revealing that near senescent, HRAS oncogene induced senescent, and replicative stress senescent cells have an acceleration in epigenetic age compared to early parental control cells. Additionally, deletion of mitochondrial DNA accelerated epigenetic aging, while caloric restriction in mice stalled their epigenetic clocks.

Further Readings

Milman

Argente J, Chowen JA, Pérez-Jurado LA, et al.

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology.

EMBO Mol Med. 2017 Oct;9(10):1338-1345.

Gubbi S, Quipildor GF, Barzilai N, et al.

40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain.

J Mol Endocrinol. 2018 Jul;61(1):T171-T185.

Levine

Hannum G, Guinney J, Zhao L, et al.

Genome-wide methylation profiles reveal quantitative views of human aging rates.

Mol Cell. 2013 Jan 24;49(2):359-367.

Levine M, McDevitt RA, Meer M, et al.

A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin.

Elife. 2020 Nov 12;9.

Horvath S.

DNA methylation age of human tissues and cell types.

Genome Biol. 2013;14(10):R115.

Levine ME, Lu AT, Quach A, et al.

An epigenetic biomarker of aging for lifespan and healthspan.

Aging. 2018 Apr 18;10(4):573-591.

Liu Z, Leung D, Thrush K et al.

Underlying features of epigenetic aging clocks in vivo and in vitro.

Aging Cell. 2020 Oct;19(10):e13229.

Omics for Therapies

Speakers

Daniel Promislow
University of Washington

Luigi Ferrucci
National Institute on Aging, National Institutes of Health

Metabolomics in the Search for Biomarkers and Mechanisms of Aging

Daniel Promislow applies metabolomics and systems biology approaches to study aging, with a focus on understanding the evolutionary and molecular traits that shape fitness in the natural human population. Although genome-wide association studies have allowed researchers to identify thousands of polymorphisms associated with the complement of measurable traits, including aging, the disparities identified explain less than half of 1% of the phenotypic variations.

Many genes interacting with each other ultimately influence phenotypes, and the biological distance between the two is astronomical. To bridge this gap, researchers use endophenotypes—from the epigenome, transcriptome, proteome, metabolome, and microbiome—along with various omics approaches. Promislow’s lab focuses on the metabolome, which integrates information from the environment and genotype to ultimately affect aging.

Promislow’s team utilizes translational metabolomics in various insect and animal models to understand and translate aging patterns to human populations. Applying this approach to Drosophila demonstrated that the metabolome could predict stress resistance, completely separating groups of sensitive or resistant flies to a metabolic stressor by principal component analysis. These effects could not be recapitulated with a whole fly genome sequence dataset. Evaluating response to diet restriction (DR) also revealed changes in metabolite levels with age. Among nearly 200 different inbred strains, roughly 75% showed a benefit to DR.

“Interestingly, the effect of specific genetic variants on the lifespan response was very weak,” Promislow began. “But we did find genes that were associated with metabolites, which were associated with the lifespan response, reinforcing this idea…that the metabolite profile can be a kind of bridge between genotype and phenotype.”

Promislow’s group also demonstrated that the metabolome could serve as a biological clock, revealing that shorter-lived genotypes appeared to have a higher biological age than expected for their chronological age.

Translational Potential of the Biology of Aging

As individuals age, the incidence of chronic disease increase, and disease progression quickens. Physician-scientist Luigi Ferrucci aims to interrogate the causal pathways that lead to progressive physical and cognitive decline in aging.

Cellular damage is accumulated during a person’s life, eventually reaching a pathology threshold that becomes clinically relevant when the damage presents as a disorder. Conventionally, the disease is often only addressed once it reaches this stage. The problem with this approach is that the present disease is often a marker of a more profound and invasive disorder to come.

“[Instead], we need to measure the underlying force that determines the emergence of diseases and their consequences,” Ferrucci argued.

By interfering with the basic mechanisms of aging to curtail it, broader effects of abating multiple chronic disorders can be achieved.

Cellular damage is accumulated over the course of an individual’s lifetime, with disease presenting once the clinical threshold for a given disorder is reached.

The rate of biological aging can be defined by the ratio of cellular damage accumulation to repair capacity. If the rate of damage accretion is fast, but the repair capacity is high, there won’t be an accumulation of damage, and aging will be slowed. However, when damage outpaces repair, aging accelerates.

Repair pathways require energy to operate effectively, and mitochondrial function declines dramatically with age. Ferrucci’s team discovered that this decline is associated with an upregulation of alternative splicing of mitochondrial proteins. Delving deeper into this mechanism, they applied gene set enrichment analysis to 5,325 RNAs with at least one splice variant significantly altered in response to changing mitochondrial function, as measured by AMPK and aging.

Among the top hits were GLUT4, VEGFA, IRS2, mTOR, PI3K, ULK1, ACC1, NRF2, and PGC1-α. Of note, the splice A variant of the topmost hit, VEGFA, appeared to be geronic, while the B variant appeared to be anti-geronic, with the ratio of these variants declining with age. Thus, alternative splicing is a method by which the body copes with energy decline due to mitochondrial dysfunction.

Further Readings

Promislow

Laye MJ, Tran V, Jones DP, et al.

The effects of age and dietary restriction on the tissue-specific metabolome of Drosophila.

Aging Cell. 2015 Oct;14(5):797-808.

Hoffman JM, Ross C, Tran V, et al.

The metabolome as a biomarker of mortality risk in the common marmoset.

Am J Primatol. 2019 Feb;81(2):e22944.

Nelson PG, Promislow DEL, Masel J.

Biomarkers for Aging Identified in Cross-sectional Studies Tend to Be Non-causative.

J Gerontol A Biol Sci Med Sci. 2020 Feb 14;75(3):466-472.

Ferrucci

Fabbri E, An Y, Zoli M, et al.

Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers.

J Gerontol A Biol Sci Med Sci. 2015 Jan;70(1):63-70.

Choi S, Reiter DA, Shardell M, et al.

31P Magnetic Resonance Spectroscopy Assessment of Muscle Bioenergetics as a Predictor of Gait Speed in the Baltimore Longitudinal Study of Aging.

J Gerontol A Biol Sci Med Sci. 2016 Dec;71(12):1638-1645.

Translational Research for Healthspan and Lifespan

Speakers

Pat Furlong, Panelist
Parent Project Muscular Distrophy

Roman J. Giger
University of Michigan School of Medicine

Senolytics: The Path to Translation

Physician-scientist James Kirkland studies the impact of cellular aging, specifically senescence, on age-related dysfunction and chronic diseases to develop methods for removing these cells and attenuating their deleterious effects. Senescent cells accumulate with aging and diseases, eliminating cells around them due to their senescence-associated secretory phenotype (SASP), which 30%-70% of senescent cells exhibit under most conditions.

Kirkland’s team applied a bioinformatics-based approach to analyze SASP proteomic databases, revealing that pro-survival networks are upregulated, with diverse senescent cells relying on different pathways. Several agents, termed senolytics, were identified that could target multiple nodes of these cascades.

“We’re moving away from the one drug, one target, one disease approach here,” said Kirkland,  “to try and use agents that have multiple targets, or combinations of agents, to go after networks, and to go after senescent cells by doing this, and thereby improve…multiple conditions.”

Dasatinib (D), a SRC kinase inhibitor, preferentially killed senescent preadipocytes, which relied on survival pathways that signal through this kinase. Quercetin (Q) eliminated senescent human umbilical endothelial cells (HUVECs), which partly act through the Bcl-2 family and others that this cell type is susceptible to.

In an in vivo experiment, combining Dasatinib with Quercetin (D+Q) cleared transplanted luciferase-expressing senescent preadipocytes from mice, explicitly targeting those cells with a SASP. A single dose of senolytics also alleviated radiation-induced gait disturbance in mice, with the effects persisting long-term. Bi-weekly dosing reduced physical dysfunction in older mice, as measured by parameters of maximal speed, including treadmill and hanging endurance, grip strength, and daily activity, with D+Q significantly increasing performance across the board.

Many conditions have now been shown to be alleviated by various senolytics in a range of mouse models, with D+Q delaying death from all causes, and increasing healthspan and median lifespan.

Keynote: Mitochondrial-derived Peptides (MDPs) and the Regulation of Aging Processes

The discovery of mitochondrial peptides (MDPs), encoded from small genes less than 100 codons in length, established the birth and advancement of the microprotein subfield. Physician Pinchas Cohen works to understand mitochondrial biology and characterize MDPs, exploiting findings to target aging. MDPs are secreted from cells and circulate within the body.

“Overall, they serve as protective factors, or hormones if you will, that act in the brain, the heart, the liver, the muscle, and other organs,” Cohen stated.

Among these MDPs, Cohen’s lab identified humanin, encoded from the 16S region of mtDNA, and MOTS-c, encoded from the 12S region.

Humanin has a strong protective effect on neurons and against atherosclerosis, mitigates the side effects of chemotherapy while enhancing its benefit, and is related to longevity in model organisms and humans. Cohen’s lab employs mitochondrial-wide association studies (MiWAS) to link the dysfunction of MDPs to disease. MiWAS identified a single-nucleotide polymorphism (SNPs) in the humanin gene (rs2854128) associated with reduced levels and cognitive decline in humans and mice. Supplementing humanin in mice carrying this SNP improved their cognition.

MOTS-c is a novel exercise mimetic that has potential utility in numerous age-related diseases. Mice on a high fat diet receiving MOTS-c had dramatically lower weight compared to controls. MOTS-c treatment also improved exercise tolerance and performance in middle-aged and old mice, with older mice displaying the most dramatic improvement.

MOTS-c levels are diminished in older mice, and supplementation of MOTS-c in this cohort increases both median and maximum lifespan compared to controls.

Cohen’s group also identified a link between a SNP in MOTS-c–K14Q–which nullifies MOTS-c activity and the risk of diabetes in males of the Asian population. Evaluating Japanese males from three cohorts revealed a 50% increase in the risk of diabetes for carriers, with almost double the risk seen exclusively in men who were sedentary. Like other MDPs, MOTS-c is reduced with age, and its administration to mice significantly extends lifespan.

“I think that everything we do in the aging field can be reduced to trying to simulate the beneficial effects of a healthy lifestyle, particularly diet…and exercise,” Cohen said. “We think that…mitochondria are the main source of action [here] by inducing the production of peptides such as MOTS-c, humanin, and others.”

Further Readings

Kirkland

Zhu Y, Tchkonia T, Pirtskhalava T, et al.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.

Aging Cell. 2015 Aug;14(4):644-58.

Kirkland JL, Tchkonia T.

Senolytic drugs: from discovery to translation.

J Intern Med. 2020 Nov;288(5):518-536.

Ogrodnik M, Miwa S, Tchkonia T, et al.

Cellular senescence drives age-dependent hepatic steatosis.

Nat Commun. 2017 Jun 13;8:15691.

Xu M, Pirtskhalava T, Farr JN, et al.

Senolytics improve physical function and increase lifespan in old age.

Nat Med. 2018 Aug;24(8):1246-1256.

Justice JN, Nambiar AM, Tchkonia T, et al.

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

EBioMedicine. 2019 Feb;40:554-563.

Cohen

Mehta HH, Xiao J, Ramirez R, et al.

Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment.

Metabolomics. 2019 Jun 6;15(6):88.

Zempo H, Kim SJ, Fuku N, et al.

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

Aging. 2021 Jan 19;13(2):1692-1717.

Yen K, Mehta HH, Kim SJ, et al.

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan.

Aging. 2020 Jun 23;12(12):11185-11199.

Miller B, Kim SJ, Kumagai H, et al.

Peptides derived from small mitochondrial open reading frames: Genomic, biological, and therapeutic implications.

Exp Cell Res. 2020 Aug 15;393(2):112056.

Zempo H, Kim SJ, Fuku N, et al.

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.

Aging. 2021 Jan 19;13(2):1692-1717.

Psychedelics to Treat Depression and Psychiatric Disorders

Overview

Currently the FDA categorizes psychedelics such as LSD and psilocybin as Schedule I drugs, indicating that these substances have no medical value. Despite this classification, a resurgence of research in approved labs has demonstrated therapeutic benefits of psychedelics for treatment of psychiatric disorders.

Of note, a recent trial on the effects of MDMA-assisted therapy for post-traumatic stress disorder (PTSD) showed a reduction in the severity of patient symptoms compared with the placebo arm of the trial, providing hope for the future approval of MDMA for therapeutic use.  The exciting findings from this study as well as and investigations into other psychedelics are instigating a paradigm shift for treatment-resistant psychiatric conditions, along with increased public interest and efforts to legalize psychedelics for medicinal use.

The New York Academy of Sciences hosted a panel discussion bringing together leading scientists in the fields of pharmacology, neuroscience, and psychiatry to discuss how psychedelics work in the brain to produce therapeutic benefits for depression and other mood disorders.  The conversation commenced a description of the socio-political context of psychedelics research, spanning the rise of psychedelics research in the 1950s, restrictions in the 1960s, renewed interest in the 1990s, and present day clinical trials for patients with depression and various other mood disorders. 

The program continued by spotlighting the different types of classical and non-traditional psychedelics that are currently being investigated (e.g., psilocybin, MDMA, and ketamine) and how they work to produce therapeutic effects. Panelists concluded the conversation by sharing insights into the use of psychedelics in treatment settings, including explaining the process of facilitated treatment and the role of the therapist/guide during the psychedelic experience (including preparatory therapy, peak effects, and integration).

In this eBriefing, you will learn:

  • The socio-political history of psychedelic research for human health
  • The difference between classic and non-traditional psychedelics
  • The effects of psychedelics on the brain and targets
  • The role of the hallucinogenic experience
  • The role of psychological support during the psychedelic experience

Event Sponsors

Gold

Bronze

Psychedelics for the Treatment of Depression and Psychiatric Disorders

Moderator

John Krystal, MD
Yale School of Medicine

Speakers

Roland Griffiths, PhD
Johns Hopkins University School of Medicine

David E. Nichols, PhD
Heffter Research Institute

Rachel Yehuda, PhD
Icahn School of Medicine at Mt. Sinai

John Krystal, MD
Yale School of Medicine

Dr. John Krystal is the Robert L. McNeil, Jr., Professor of Translational Research; Professor of Psychiatry, Neuroscience, and Psychology; and Chair of the Department of Psychiatry at the Yale University. He is also Chief of Psychiatry and Behavioral Health at Yale-New Haven Hospital.  He is a graduate of the University of Chicago, Yale University School of Medicine, and the Yale Psychiatry Residency Training Program.

Dr. Krystal has published extensively on the neurobiology and treatment of schizophrenia, alcoholism, PTSD, and depression. Notably, his laboratory discovered the rapid antidepressant effects of ketamine in humans. He is the Director of the NIAAA Center for the Translational Neuroscience of Alcoholism and the Clinical Neuroscience Division of the VA National Center for PTSD. Dr. Krystal is a member of the U.S. National Academy of Medicine and a Fellow of the American Association for the Advancement of Science. Currently, he is co-director of the Neuroscience Forum of the U.S. National Academies of Sciences, Engineering, and Medicine; and editor of Biological Psychiatry (IF=12.1).

He has chaired the NIMH Board of Scientific Counselors and served on the national advisory councils for both NIMH and NIAAA. Also, he is past president of the American College of Neuropsychopharmacology (ACNP) and International College of Neuropsychopharmacology (CINP).

Roland Griffiths, PhD
Johns Hopkins University School of Medicine

Roland Griffiths is Professor in the Departments of Psychiatry and Neurosciences and Director of the Center for Psychedelic and Consciousness Research at the Johns Hopkins University School of Medicine.  His principal research focus in both clinical and preclinical laboratories has been on the behavioral and subjective effects of mood-altering drugs and he is author of over 400 scientific publications.  He has conducted extensive research with sedative-hypnotics, caffeine, and novel mood-altering drugs.

About 20 years ago, he initiated a research program at Johns Hopkins investigating effects of the classic psychedelic substance psilocybin, the active component in “magic mushrooms.” Remarkably, many research participants rate their experience of psilocybin as among the most personally meaningful of their lives, and they attribute enduring positive changes in moods, attitudes and behavior months to years after the experience.  Completed and ongoing studies include those in healthy volunteers, in beginning and long-term meditators, and in religious leaders.

Therapeutic studies with psilocybin include treatment of psychological distress in cancer patients, major depressive disorder, nicotine addiction, anorexia nervosa, and various other psychiatric disorders. Related studies of brain imaging and drug interactions are examining pharmacological and neural mechanisms of action.  His research group has also conducted a series of survey studies characterizing various naturally-occurring and psychedelic-occasioned transformative experiences including mystical experiences, entity and God-encounter experiences, Near Death experiences, and experiences claimed to reduce depression, anxiety, and substance use disorders.

David E. Nichols, PhD
Heffter Research Institute

David E. Nichols previously held the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology and in addition was a Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at the Purdue University College of Pharmacy.  He was continuously funded by the NIH for nearly three decades and served on numerous government review panels.  His two principal research areas focused on drugs that affect serotonin and dopamine transmission in the CNS.

He began medicinal chemistry research on hallucinogens in 1969 and has been internationally recognized as a top expert on the medicinal chemistry of psychedelics (hallucinogens).  He has published more than 300 scientific articles, book chapters, and monographs.  In 1993 he founded the Heffter Research Institute, which has supported and funded clinical research with psilocybin and led the so-called “renaissance in psychedelic research.”

Rachel Yehuda, PhD
Icahn School of Medicine at Mt. Sinai

Rachel Yehuda, Ph.D. is the Director of the Center for the Study of Psychedelic Psychotherapy and Trauma, Vice Chair for Veterans Affairs for the Psychiatry Department and a Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai as well as the Director of Mental Health at the Bronx Veterans Affairs Medical Center and the Director of the Traumatic Stress Studies Division.

Throughout her career her research has focused on the study of the enduring effects of trauma exposure, particularly PTSD, as well as associations between biological and psychological measures. She has investigated novel treatment approaches for PTSD and the biological factors that may contribute to differing treatment outcomes for the purpose of developing personalized medicine strategies for treatment matching in PTSD. This work has resulted in an approved US patent for a PTSD blood test.

Recently, Dr. Yehuda’s laboratory has used advances in stem cell technology to examine PTSD gene expression networks in induced neurons.  The Center for Psychedelic Psychotherapy and Trauma integrates sophisticated brain imaging and molecular neuroscience in PTSD with clinical trials using MDMA assisted psychotherapy and other related medicines. She has authored more than 450 published papers, chapters, and books in the field of trauma and resilience, focusing on topics such as PTSD prevention and treatment, molecular biomarkers of stress vulnerability and resilience, and intergenerational effects of trauma and PTSD.

Further Readings

John Krystal

Abdallah CG and Krystal JH

Ketamine and Rapid Acting Antidepressants: Are We Ready to Cure, Rather Than Treat Depression?

Behavioral Brain Research. 2020 July 15;(30): 112628

Charney D and Duman R

A New Rapid-Acting Antidepressant

Cell. 2020 April 2;1(181): 7

Abdallah CG, Sanacora G, Charney DS, and Duman R

Ketamine: A Paradigm Shift for Depression Research and Treatment

Neuron. 2019 Mar 6;101(5):774-778

Roland Griffiths

Scharper J

Crash Course in the Nature of Mind

Johns Hopkins University Magazine. Fall 2017

Griffiths RG, Johnson MW, and Carducci MA, et al

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

Journal of Psychopharmacology. 2016 Dec; 30(12):1181-1197

David E. Nichols

Nichols DE

How Does One Go About Performing Research with Psychedelics?

Multidisciplinary Association for Psychedelic Studies Bulletin. Fall 1997

Nichols DE

Psychedelics

Pharmacological Reviews. 2016 April;68(2):264-255

Nichols DE

Studies of the Relationship between Molecular Structure And Hallucinogenic Activity

Pharmacology, Biochemistry, and Behavior. 1986 Feb;2:335-340

Nichols DE

Psilocybin: From Ancient Magic to Modern Medicine

The Journal of Antibiotics. 2020 May 12;73:679-686

Nichols DE, Johnson MW, and Nichols CD

Psychedelics as Medicines: An Emerging New Paradigm

Clinical Pharmacology and Therapeutics. 2016 Nov 4;101(2):209-219

Rachel Yehuda

Vermetten E and Yehuda R

MDMA-assisted Psychotherapy for Posttraumatic Stress Disorder: A Promising Novel Approach to Treatment

Neuropsychopharmacology. 2020 Jan;45(1):231-232

Yehuda R

Mount Sinai: Five Things to Know About MDMA-Assisted Psychotherapy for PTSD

Multidisciplinary Association for Psychedelic Studies (MAPS) in the Media. 2020 Feb 20

Making STEM Education Accessible for All

STEM education is more important than ever. In our ever-changing, technology-driven world, students must be equipped with the knowledge and skills afforded by STEM learning—problem solving, critical thinking, curiosity, and persistence, among many others. STEM expertise is also desperately needed to address the many challenges facing our world, particularly those identified by the UN Sustainable Development Goals. Yet in many places throughout the world—in developed and developing countries alike—students lack access to meaningful STEM learning.

On February 23, 2021, The New York Academy of Sciences hosted a discussion between Chief Learning Officer Hank Nourse and Mmantsetsa Marope, Executive Director of the World Heritage Group. They explored the impacts of STEM education on individual, national, and global development.

In this eBriefing, you will learn:

  • What high-quality STEM education looks like
  • How STEM learning benefits individuals
  • The importance of STEM education to national and global development
  • How we might ensure equitable access to STEM learning, particularly in the face of growing inequities exacerbated by the COVID-19 pandemic

Advancing STEM Education for All

Speakers

Mmantsetsa Marope
World Heritage Group

Hank Nourse
The New York Academy of Sciences

Mmantsetsa Marope, PhD
World Heritage Group

Mmantsetsa Marope is widely regarded as a thought leader on education, the future of education and work, and learning systems capable of preparing students for rapidly changing and unpredictable futures. She is Executive Director of the World Heritage Group, an organization dedicated to building resilient, agile, and future-forward education systems. She is Honorary President of the Indian Ocean Comparative and International Education Societies and Lead Global Advisor for China’s Education and Innovation for Development EXPO.

Prior to founding the World Heritage Group, Dr. Marope spent four decades in the civil service and the nonprofit sectors, including senior roles at the World Bank and, most recently, UNESCO, where she served as Director of the International Bureau of Education. Dr. Marope holds a PhD in education from the University of Chicago, an MEd from Penn State University, and BA and CDE degrees from the University of Botswana and Swaziland.

Hank Nourse
The New York Academy of Sciences

Hank Nourse leads the Academy’s Global STEM Alliance (GSA), a bold initiative to advance science, technology, engineering, and mathematics education worldwide. With hundreds of partners, and reaching participants in over 100 countries, the GSA directly engages tens of thousands of students and teachers annually, providing mentorship, skill building, and professional development spanning K-12 and higher education.

Prior to joining the Academy in 2015, Hank spent more than 15 years developing online learning and assessment programs for the K–12 market, primarily at Scholastic, a global children’s publishing and media company. He holds a Master’s degree in International Educational Development from Teachers College, Columbia University, and a Bachelor’s degree from Gonzaga University.

The Route to Robust Quantum Computing

An illustrated graphic of a computer chip, or a similar piece of electronic equipment.

Shruti Puri, PhD, helps explain the challenges and the potential computational power this exciting new technology may bring about.

By Liang Dong, PhD

Shruti Puri, PhD, Yale University

Quantum computing is a radically new way to store and process information based on the principles of quantum mechanics. While conventional computers store information in binary “bits” that are either 0s or 1s, quantum computers store information in quantum bits, or qubits. A qubit can be both 0 and 1 at the same time, and a series of qubits together remember many different things simultaneously.

Everyone agrees on the huge computational power this technology may bring about, but why are we still not there yet? To understand the challenges in this field and its potential solutions, we recently interviewed Shruti Puri, PhD, who works at the frontier of this exciting field. Puri is an Assistant Professor in the Department of Applied Physics at Yale University, and a Physical Sciences & Engineering Finalist of the 2020 Blavatnik Regional Awards for Young Scientists, recognized for her remarkable theoretical discoveries in quantum error correction that may pave the way for robust quantum computing technologies.

What is the main challenge you are addressing in quantum computing?

Thanks to recent advances in research and development, there are already small to mid-sized quantum computers made available by big companies. But these quantum computers have not been able to implement any practical applications such as drug and materials discovery. The reason is that quantum computers at this moment are extremely fragile, and even very small noise from their working environment can very quickly destroy the delicate quantum states. As it is almost impossible to completely isolate the quantum states from the environment, we need a way to correct quantum states before they are destroyed.

At a first glance, quantum error correction seems impossible. Due to the measurement principle of quantum mechanics, we cannot directly probe a quantum state to check if there was an error in it or not, because such operations will destroy the quantum state itself.

Fortunately, in the 1990s, people found indirect ways to faithfully detect and correct errors in quantum states. They are, however, at a cost of large resource overheads. If one qubit is affected by noise, we have to use at least five additional qubits to correct this error. The more errors we want to correct, the larger number of additional qubits it will consume. A lot of research efforts, including my own, are devoted to improving quantum error correction techniques.

What is your discovery? How will this discovery help solve the challenge you mention above?

In recent years, I have been interested in new qubit designs that have some in-built protection against noise. In particular, I developed the “Kerr-cat” qubit, in which one type of quantum error is automatically suppressed by design. This reduces the total number of quantum errors by half! So, quantum computers that adopt Kerr-cat require far fewer physical qubits for error correction than the other quantum computers.

Kerr-cat is not the only qubit with this property, but what makes the Kerr-cat special is that it is possible to maintain this protection while a user tries to modify the quantum state in a certain non-trivial way. As a comparison, for ordinary qubits, the act of the user modifying the state automatically destroys the protection. Since its discovery, the Kerr-cat has generated a lot of interest in the community and opened up a new direction for quantum error correction.

As a theoretician, do you collaborate with experimentalists? How are these synergized efforts helping you?

Yes, I do collaborate quite closely with experimentalists. The synergy between experiments and theory is crucial for solving the practical challenges facing quantum information science. Sometimes an experimental observation or breakthrough will provide a new tool for a theorist with which they can explore or model new quantum effects. Other times, a new theoretical prediction will drive experimental progress.

At Yale, I have the privilege to work next to the theoretical group of Steve Girvin and the experimental groups of Michel Devoret and Rob Schoelkopf, who are world leaders in superconducting quantum information processing. The theoretical development of the Kerr-cat qubit was actually a result of trying to undo a bug in the experiment. Members of Michel’s group also contributed to the development of this theory. What is more, Michel’s group first experimentally demonstrated the Kerr-cat qubit. It was just an amazing feeling to see this theory come to life in the lab!

Are there any other experimental developments that you are excited about?

I am very excited about a new generation of qubits that are being developed in several other academic groups, which have some inherent protection against noise. Kerr-cat is one of them, along with Gottesman-Kitaev-Preskill qubit, cat-codes, binomial codes, 0−π qubit, etc. Several of these designs were developed by theorists in the early 2000s, and were not considered to be practical. But with experimental progress, these have now been demonstrated and are serious contenders for practical quantum information processing.  In the coming years, the field of quantum error correction is going to be strongly influenced by the capabilities that will be enabled by these new qubit designs. So, I really look forward to learning how the experiments progress.

Transformative Research in Rare Diseases: 2020 Innovators in Science Award Symposium

By definition, a rare disease is one that afflicts relatively few people compared to the general population. Collectively, though, there are over 7,000 of these conditions known, causing immense suffering for an estimated 300 million patients. Because most rare diseases stem from specific genetic mutations, they’ve proven difficult to treat.

Genome sequencing and molecular medicine might soon change those grim statistics, though. For example, using short DNA or RNA sequences complementary to the messenger RNA for a gene, researchers can inhibit the expression of the associated protein. These complementary sequences—called antisense oligonucleotides—could soon be delivered as drugs to treat many rare diseases.

On October 2, 2020, The New York Academy of Sciences and Takeda Pharmaceuticals hosted the Frontiers in Rare Diseases: 2020 Innovators in Science Award Symposium, an event highlighting breakthroughs in rare diseases research and honoring 2020 Innovators in Science Award Winners Adrian Krainer, PhD and Jeong Ho Lee, MD, PhD. Presentations, a panel discussion, and a virtual poster session covered the basic science, recent clinical breakthroughs, and remaining challenges in this rapidly evolving field.

Symposium Highlights

  • While many rare diseases are inherited, others arise through mutations in somatic cells during life.
  • Antisense oligonucleotides can alter the expression of specific genes, potentially mitigating or reversing many genetic diseases.
  • Clinical trials for rare disease therapies must be tailored to the pathogenesis of each disease.
  • Redirecting neural stem cells to become neurons could treat many neurodegenerative diseases.
  • The COVID-19 pandemic is inspiring new collaborations that could be adapted to rare disease research.

Speakers

Jeong Ho Lee, MD, PhD
Korea Advanced Institute of Science and Technology

Adrian Krainer, PhD
Cold Spring Harbor Laboratory

Annemieke Aartsma-Rus, PhD
Leiden University Medical Center

Don Cleveland, MD, PhD
University of California, San Diego

Huda Zoghbi, MD
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital

Brad Margus
Cerevance

Graciana Diez-Roux, PhD
Telethon Institute of Genetics and Medicine

David Fajgenbaum, MD
University of Pennsylvania

Anne Heatherington, PhD
Takeda Pharmaceuticals

Sponsors

The Winner’s Circle

Speakers

Jeong Ho Lee, MD, PhD
Korea Advanced Institute of Science and Technology

Adrian Krainer, PhD
Cold Spring Harbor Laboratory

Not Born This Way

Jeong Ho Lee, Early-Career Scientist winner of the 2020 Innovators in Science Award, discussed his work studying how somatic cell mutations—mutations that occur after development, during the normal process of cell division—result in rare neurological diseases caused by somatic cell mutations in the brain. Much of the recent boom in work on genetic diseases has focused on germline mutations. Because these mutations occur early in embryonic development, they show up in many types of cells throughout the body and are passed on to future offspring. These rare germline mutations can often be identified by sequencing the genomes of cells in easily accessible tissues, such as blood or skin. With advances in next-generation sequencing, “it’s become much easier to identify the germline mutations coding for many rare neurological disorders,” said Lee.

Somatic cell mutations occur throughout life, in every part of the body.

Nonetheless, germline mutations account for only a minority of rare neurological disorders. For example, 98% of epilepsy cases cannot be explained by germline mutations.

“We hypothesized that somatic cell mutations may be responsible for these unexplained neurological [diseases],” said Lee.

Somatic cell mutations occur during the ordinary cell division process that takes place billions of times in developing embryos, and continues to occur throughout life as somatic, or non-gamete, cells turn over.

DNA replication isn’t perfect, and human cells average 0.1 to 3 mutations per genome every time they divide. Lee theorized that a patient who hadn’t inherited an epilepsy-causing germline mutation might instead acquire somatic cell mutations in a subset of brain cells during development or later in life. If that happened, the mutation would only show up in the affected area of the brain, not in any other cells of the body.

One treatment for certain types of epilepsy is to resect the portion of the brain causing the seizures. Lee and his colleagues took samples of the brain tissue resected in these operations, along with blood samples from the same patients, and performed deep DNA sequencing to identify somatic mutations that occurred only in the affected brain tissue, not in the blood. They identified such mutations, including ones unique to genes involved in motor nerve activity, in 30% of the patients. When the scientists introduced the same mutations into a small percentage of neurons in developing mice, the animals developed epilepsy.

Next, the investigators looked at brain tumors, which can also cause epilepsy. One rare brain tumor type involves both glial cells and neurons, triggering epilepsy. Sequencing genetic information from cells in the tumors revealed that in 46% of affected patients, the glial cells and the neurons in the tumor shared an identical mutation.

“It means that the…neural stem cell already contained this… mutation,” said Lee, “and differentiated into the neuron and the glial cell.”

That could explain the high rate of disease recurrence in patients with these tumors; even if surgeons remove the entire tumor, the mutant stem cells might continue to produce more defective neurons and glial cells, which could then seed the growth of a new tumor.

To confirm that, Lee’s team collected an additional round of samples, this time sequencing cells not only from resected brain tumors and blood, but also from the subventricular zone in each patient’s brain, an area rich in undifferentiated neural stem cells. They found the tumor-associated mutation in the subventricular zone samples as well as the tumors, indicating that the error occurred in the neural stem cells, whose neuronal and glial descendants then migrated to where the tumor grew.

The researchers are also looking at neurodegenerative disorders such as Alzheimer’s disease.

“We hypothesized that somehow brain somatic mutation maybe accumulates over aging, and maybe associates with [Alzheimer’s disease development],” said Lee.

By performing deep sequencing on brain tissues from patients with and without Alzheimer’s disease, he and his colleagues identified somatic mutations unique to the diseased brains, supporting their theory.

In addition to identifying the underlying mechanisms behind neurological diseases, Lee is trying to help patients in other ways. In one effort, he has begun providing his results to clinicians to use in genetic counseling. Because conditions caused by somatic mutations aren’t heritable, while those caused by germline mutations are, patients who might be considering having children need to know which category they’re in.

The investigators are also trying to find ways to repair or mitigate the effects of somatic mutations in the brain, but it’s a tall order.

“Even if we found a molecular genetically validated target in the patient’s brain, it would be very difficult to develop a traditional drug to penetrate the blood-brain barrier and regulate the target,” Lee explained.

Instead, he’s hopeful that chemically modified strings of nucleic acids, called antisense oligonucleotides, will be able to target the somatic mutations he’s identified.

“I believe in the next five, ten, or twenty years, we probably can solve a lot of the rare neurological disorders,” he said.

Different Diseases, Different RNA Splices

Adrian Krainer won the 2020 Innovators in Science Senior Scientist Award, recognizing years of work spent developing treatments for rare diseases. Krainer and his colleagues were the first to develop an effective drug to treat spinal muscular atrophy. Affecting about 1 in 10,000 people worldwide, spinal muscular atrophy is an inherited genetic disease caused by a defect in the SMN1 gene. SMN1 encodes the SMN protein, which is essential for motor neuron survival. Patients with the mutation experience progressive loss of motor neurons, leading to loss of muscle control and, in most forms of the disease, early death.

Another gene, SMN2, also encodes the SMN protein, but cells usually splice out one of the protein coding sequences, or exons, from the SMN2 messenger RNA, preventing it from making the full-length protein. As a result, 80-90% of the protein translated from SMN2 RNA is truncated, nonfunctional, and rapidly degraded by the cell. Krainer reasoned that preventing the exon-skipping event might allow patients’ unmutated SMN2 genes to produce more functional SMN protein, overcoming the deficit caused by their mutated SMN1 genes. To do that, his team turned to antisense oligonucleotides, which encode the complementary, or antisense, sequence of a specific RNA target. When introduced into a cell, the antisense oligonucleotide binds specifically to its target sequence, triggering various cellular responses.

By designing an antisense oligonucleotide that altered the splicing of SMN2 messenger RNA, the researchers were able to get SMN1-mutant cells to produce more functional SMN protein. Subsequent preclinical and clinical trials proved that their antisense oligonucleotide also works in spinal muscular atrophy mouse models and in patients, respectively, significantly mitigating their motor neuron losses.

“Therefore this is a way that allows them to make closer to normal levels of a functional SMN protein in the presence of this drug,” said Krainer.

The oligonucleotide, now sold as nusinersen (Spinraza), was approved in the US in 2016 and the EU in 2017. Over 11,000 patients now receive it worldwide.

Nusinersen (Spinraza) pioneered many aspects of molecular medicine.

Based on the success of nusinersen, Krainer and his colleagues have begun looking at other RNA processing events to target with antisense oligonucleotides. One project focuses on familial dysautonomia, an inherited genetic disorder that affects only 310 known patients worldwide. These individuals have profound defects in their sensory neurons and autonomic nervous system, leading to symptoms that range from insensitivity to pain to difficulty swallowing.

“It is a very severe disease, a rare disease with a complex set of symptoms,” said Krainer, adding that “median survival is about 40 years of age.”

The condition is caused by a mutation in the gene for a protein called ELP1. As in SMN2, the mutation causes one exon of the gene’s messenger RNA to be spliced out, leading to a loss of functional ELP1 protein.

“So, we started targeting this aberrant splicing event using the same screening strategy and the same chemistry that we used…for spinal muscular atrophy,” said Krainer.

That effort identified an antisense oligonucleotide that can reverse the ELP1 RNA splicing defect in cultured cells from patients, as well as a transgenic mouse model.

“We feel that this is ready for clinical development; it is a challenge, though, because of the rarity of this disease,” said Krainer.

With only a few hundred patients in the US and Israel, the market for familial dysautonomia therapies is minuscule, and effective screening of potential carriers of the affected gene has led to very few new patients being born.

Not all RNA splicing-related diseases are rare, though. Work by several researchers has shown that in at least some cases, a change in the splicing of messenger RNA can help cancer cells grow. Alternatively, spliced forms of the messenger RNA for the PKM gene can produce two different isoforms of the metabolic enzyme pyruvate kinase. PKM1 predominates in normal adult tissues, while tumors and some developing tissues favor PKM2 production.

Using the same approach that worked in their rare disease work, Krainer’s team screened antisense oligonucleotides and identified candidates that bound the PKM messenger RNA and directed its splicing to favor PKM1 protein production. Putting these oligonucleotides into hepatocellular carcinoma cells causes the cells to shift their metabolism and slow their growth. In a mouse model of hepatocellular carcinoma, injecting the antisense oligonucleotides led to a significant reduction in tumor growth compared to control animals treated with saline solution.

Further Reading

Lee

Lee JH, Lee JE, Kahng JY, et al.

Human Glioblastoma Arises from Subventricular Zone Cells with Low-Level Driver Mutations

Nature. 2018 Aug;560(7717):243-247.

Lee, JH, Lee JH.

The Origin-of-Cell Harboring Cancer-Driving Mutations in Human Glioblastoma

Nat Med. 2015 Mar 23; 21(4):395-400.

Yoon, Seon-Jin, Junseong Park, Dong-Su Jang, Hyun Jung Kim, Joo Ho Lee, Euna Jo, Ran Joo Choi, et al.

Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

Nat Commun. 2019 July 12; 10(1):3090.

Krainer

Hua Y, Sahashi K, Rigo F, et al.

Peripheral SMN Restoration Is Essential for Long-Term Rescue of a Severe SMA Mouse Model

Nature. 2011 Oct 6; 478(7367):123-126.

Sinha R, Kim YJ, Nomakuchi T, et al.

Antisense Oligonucleotides Correct the Familial Dysautonomia Splicing Defect in IKBKAP Transgenic Mice

Nucleic Acids Res. 2018 Jun 1; 46(10):4833-4844.

Wang Z, Jeon HY, Rigo F, Bennett CF, Krainer AR.

Manipulation of PK-M Mutually Exclusive Alternative Splicing by Antisense Oligonucleotides

Open Biol. 2012 Oct; 2(10):120133.

Bennett CF, Krainer AR, Cleveland DW.

Antisense Oligonucleotide Therapies for Neurodegenerative Diseases

Annu Rev Neurosci. 2019 Jul 8; 42: 385-406.

Muscle and Brains

Speakers

Annemieke Aartsma-Rus, PhD
Leiden University Medical Center

Don Cleveland, MD, PhD
University of California, San Diego

The Kindest Cut

Annemieke Aartsma-Rus began the meeting’s third session with a presentation about her group’s efforts to address Duchenne muscular dystrophy with antisense oligonucleotides. While Krainer’s approach to rare diseases focuses on conditions where an exon needs to be added back into a messenger RNA, Aartsma-Rus described a case where it’s better to remove one.

Duchenne muscular dystrophy is an X-linked genetic disorder. In most cases, a mutation in the dystrophin gene shifts the messenger RNA’s reading frame, causing translation of the dystrophin protein to fail.

“Patients become wheelchair dependent around the age of 12, need assisted ventilation around the age of 20, and generally die in the second to fourth decade of life,” said Aartsma-Rus.

A related but milder disorder, Becker muscular dystrophy, also involves a deletion in the dystrophin gene but doesn’t shift the messenger RNA’s reading frame. As a result, patients with Becker muscular dystrophy produce partially functional dystrophin and exhibit a slower disease progression.

Skipping an exon in the RNA can fix a frame-shift mutation.

Looking at the affected DNA and RNA sequences, Aartsma-Rus reasoned that most Duchenne muscular dystrophy patients could make Becker-like dystrophin, if their cells could simply skip the affected exon in their dystrophin messenger RNA. To test that, she and her colleagues developed chemically modified antisense oligonucleotides that would remain stable in blood and tissues, and began testing them as potential drugs. By designing an oligonucleotide that targeted RNA splicing, the team restored dystrophin expression in cultured cells carrying a Duchenne muscular dystrophy mutation.

The researchers discovered a potential roadblock in a mouse model: antisense oligonucleotides injected into the animals’ tail veins were absorbed almost entirely by the liver and kidneys. The investigators could inject the molecules directly into muscles instead, but that clearly wouldn’t be a practical way to deliver treatment to patients.

“We have over 700 different muscles, and you’ll have to treat patients repeatedly,” said Aartsma-Rus, “so local injection of each and every muscle weekly or even monthly is likely not realistic.”

However, in a mouse model of Duchenne muscular dystrophy, the team discovered that oligonucleotides injected into the animals’ tail veins were absorbed into muscles ten times better than they had been in wild-type mice.

“The first time we thought we’d made a mistake, so we repeated it a couple of times,” said Aartsma-Rus, “but every time we saw that there was higher uptake by the dystrophic muscle than the healthy muscle.”

Dystrophin deficiency causes muscle cells to become more permeable, leading to leakage of cellular components, but this leakage works in both directions; the dystrophic cells readily absorbed oligonucleotides that healthy cells excluded.

Flush with this preclinical victory, the team began setting up clinical trials in 2007. The initial multi-center, open-label trial found that the antisense oligonucleotides caused no serious side effects, and eight of the twelve patients tested saw their conditions remain stable throughout the trial. To evaluate efficacy, the investigators moved into a phase 2b trial, which continued to show dose-dependent effectiveness in treated patients. However, a larger phase 3 trial yielded disappointment, with no significant difference in outcomes between treated and control patients.

“So, what happened [to explain why] we see these beneficial effects in the phase 2 trial, but in the phase 3 trial we see no effect?” Aartsma-Rus asked.

Analyzing the results and the disease further, she realized that the trials were built on the flawed assumption that the patients’ progression would be linear. Instead, they realized that younger patients tend to remain stable for an extended period, followed by a rapid decline later in life. By mixing different ages in the phase 3 trial, patients with worse disease symptoms likely masked any treatment benefits in those with milder symptoms.

Looking at the trial’s failure, Aartsma-Rus concluded that she and her colleagues should have opened discussions with regulatory agencies sooner, and studied the natural history of the disease more thoroughly, before initiating the phase 3 study. Unfortunately, the expensive late-stage failure has soured companies on further clinical development of exon-skipping antisense oligonucleotides for Duchenne muscular dystrophy. Aartsma-Rus has since focused on preventing such an outcome in the future.

“Now we have an open dialogue with academics, with patients, with regulators in the EU, and it is also starting in the US, developing new outcome measures,” she said, adding that “future trials will be better.”

Batting for Lou Gehrig

Don Cleveland discussed his group’s efforts to treat neurodegenerative diseases in the brain, especially those that develop gradually with age. In many of these conditions, such as Alzheimer’s and Parkinson’s disease and amyotrophic lateral sclerosis, “the genes that contribute to disease are all widely expressed…throughout the nervous system, not within individual classes of neurons,” said Cleveland. Mechanistic studies have suggested that decreasing the expression of the defective gene products in some of these cells could moderate the course of disease, so Cleveland and his colleagues set out to do just that.

The researchers first focused on amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. About four to five million people alive today will die of ALS, a progressive neurodegenerative condition that can be inherited or occur spontaneously in adults. One inherited form of the disease stems from a mutation in the gene for superoxide dismutase, which causes neurons to die through mechanisms that aren’t entirely clear yet.

Using the same strategy as his co-speakers, Cleveland’s lab designed antisense oligonucleotides that bind specifically to the superoxide dismutase messenger RNA and target it for degradation in the cell. That decreases the level of the enzyme, an intervention that had previously been shown to ameliorate ALS progression in a mouse model of the disease. The next challenge was delivering the oligonucleotides to affected neurons in the brain.

Antisense oligonucleotides have immense potential to be used as drugs against a wide range of diseases.

“These DNA drugs were ten to fifteen times the size of a typical drug, and they’re heavily charged,” said Cleveland, “so the pharmacology textbooks all said that there was no uptake mechanism that would permit them to be efficiently taken up [by neurons].” Nonetheless, he continued, “we tried it anyway, and it turns out that the cells of the nervous system hadn’t read the textbooks.”

Injecting the antisense oligonucleotides into the cerebrospinal fluid of mice genetically modified to develop severe ALS doubled the animals’ survival times.

While the superoxide dismutase defect was the first ALS mutation discovered, the most common cause of the inherited form of the disease is a mutation in a gene called ORF72, which inserts extra nucleotides into a non-coding region of the gene. This causes defective messenger RNA to accumulate, killing neurons because of a lack of functional ORF72 gene products and the accumulation of toxic byproducts of the altered gene. Antisense oligonucleotides targeting the defective RNA, however, inhibit its accumulation without reducing the production of working ORF72 gene products in cultured cells.

In an animal model of the ORF72 defect, the results were even more impressive.

“We dosed these animals [with the antisense oligonucleotides] at the age of disease onset and asked what happens, and the answer is we prevented further disease development for the life of those animals with a single dose injection applied at the initial signs of disease,” said Cleveland.

His team initiated clinical trials on this therapy in 2018, just seven years from the date when researchers had first published the data showing the ORF72 mutation caused ALS.

Although it’s an important target for research, inherited ALS accounts for only 10% of the disease’s total cases. In 90% of patients, the condition develops spontaneously due to somatic cell mutations later in life. Many of these cases involve mutations in the TDP-43 gene, which encodes a nuclear protein that regulates Stathmin-2, which in turn plays a critical role in regulating the cytoskeleton in neurons. TDP-43 normally binds the Stathmin-2 precursor RNA and ensures that it gets spliced properly into messenger RNA. Mutations that inactivate TDP-43 cause a loss of functional Stathmin-2, which is a hallmark of sporadic ALS.

Using cultured neurons, Cleveland and his colleagues found that a properly designed antisense oligonucleotide could compensate for the loss of TDP-43 activity, restoring normal RNA splicing and Stathmin-2 expression.

“This now enables a strategy for therapy for sporadic ALS,” said Cleveland.

If the result holds in other preclinical models, he expects to take that approach into clinical trials in 2023.

Besides correcting specific defects within a cell, antisense nucleotides can potentially redirect a cell’s fate entirely. That’s the central theme of another project in Cleveland’s lab, in which the team is causing astrocytes to change their identities. Astrocytes are companion cells in the nervous system that arise from the same stem cells as neurons. Using antisense oligonucleotides, the investigators can suppress two genes that direct cells into the astrocyte lineage, causing them to become neurons instead. Cleveland is initially focusing on treating Parkinson’s disease with this approach, but he explained that “this…conversion of astrocytes into replacement neurons may be broadly applicable for neurogenic disease.”

Further Readings

Aartsma-Rus

Aartsma-Rus A, Ginjaar IB, Bushby K.

The Importance of Genetic Diagnosis for Duchenne Muscular Dystrophy

J Med Genet. 2016 Mar;53(3):145-151.

Verhaart IEC, Aartsma-Rus A.

Therapeutic Developments for Duchenne Muscular Dystrophy

Nat Rev Neurol. 2017 Jul;15(7): 373-386.

Verhaart IEC, Robertson A, Wilson IJ, et al.

Prevalence, Incidence and Carrier Frequency of 5q-Linked Spinal Muscular Atrophy – a Literature Review

Orphanet J of Rare Dis. 2017 Jul 4;12(1):124.

Cleveland

Cleveland DW, Bruijn LI, Wong PC et al.

Mechanisms of Selective Motor Neuron Death in Transgenic Mouse Models of Motor Neuron Disease

Neurology.  1996 Oct;47(4 suppl 2): S54-61; discussion S61-62.

A Spectrum of Phenotypes

Speaker

Huda Zoghbi
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital

Maybe Not So Rare

Huda Zoghbi gave the meeting’s keynote presentation, which covered her work on Rett syndrome. Caused by spontaneous mutations in the MECP2 gene on the X chromosome, Rett syndrome is a progressive neurodegenerative disease that primarily manifests itself in girls. MECP2 is critical for gene regulation in neurons. Because females carry two copies of the X chromosome and an inactivate one in each cell, an inactivating mutation in MECP2 impairs the function of 50% of the affected individual’s neurons. That manifests itself as a rapid regression in motor and cognitive abilities by age two.

In boys, who have only one X chromosome, inactivation of MECP2 is generally lethal before age two. They don’t live long enough to develop the classic symptoms of Rett syndrome. However, recent work has revealed that some males acquire mutations that cause less severe defects in MECP2.

“What we’ve learned is when people carry milder mutations, we will see milder phenotypes, such as mild learning disability with…neuropsychiatric features,” said Zoghbi.

These individuals’ phenotypes can range from autism to hyperactivity or schizophrenia, but most die by middle age due to neurodegeneration. Females with mild defects in MECP2 show non-random inactivation of their X chromosomes, favoring the healthy copy of the gene and enabling them to develop and live normally. Some patients also have duplications in their MECP2 genes, often leading to severe neurological problems and premature death.

To understand the mechanisms driving Rett syndrome, Zoghbi and her colleagues developed a series of genetically modified mice carrying various duplications or mutations in MECP2. Consistent with the findings in humans, these animals display a spectrum of phenotypes depending on the severity of their MECP2 disruptions.

“The brain is very sensitive to the activities and functions of this protein, and we’ve done a lot of studies on both the loss and the gain models,” said Zoghbi.

She and her colleagues found that all types of neurons require functional MECP2 to operate normally.

Mutations affecting different types of neurons can cause a wide range of neurological phenotypes.

Next, Zoghbi and her colleagues tried inactivating MECP2 in excitatory and inhibitory neurons separately. They found that in both cases, animals developed obesity, lost motor coordination, and died young. However, targeting MECP2 only in inhibitory neurons led to more learning and social defects in the animals, while inactivating it only in excitatory neurons caused more anxiety and tremors. These phenotypes represent the downstream effects of the genes MECP2 would normally regulate.

“Given that it’s important for practically every cell, really there’s two major ways you can think of treating this disorder, either gene replacement therapy…or perhaps exploring modulation of the [MECP2 regulatory] circuit,” said Zoghbi.

Taking the latter approach, the investigators implanted electrodes into the brains of mice to deliver small electrical pulses. This type of deep brain stimulation, which has been shown to reverse many types of neuronal signaling and development defects, is already approved for human treatment of several neurological disorders. Stimulating the brains of Rett syndrome model mice leads to significant recovery in their learning, memory, and motor abilities that persists for weeks after treatment.

“It was really quite a dramatic rescue in that all these phenotypes normalize, and their normalization…lasted for several weeks,” said Zoghbi.

The treated animals’ neurons also displayed gene expression patterns similar to wild-type animals, whereas untreated animals showed significant gene dysregulation.

“The Rett brain, at least in mice, is responsive to neuromodulation,” said Zoghbi.

Looking at the MECP2 gene itself, Zoghbi’s team identified regulatory sequences that control its expression level. Altering these sequences to increase or decrease the amount of MECP2 expressed in mice underscored their earlier findings, showing that even modest changes in MECP2 levels led to detectable neurological phenotypes.

Like other speakers at the meeting, Zoghbi and her colleagues are also exploring the potential of antisense oligonucleotides as therapies. That approach seems especially promising for patients with duplications in MECP2 that lead to overexpression of the gene. In mice that recapitulate this condition, the researchers found that treatment with antisense oligonucleotides against MECP2 could reduce the amount of functional protein in neurons down to wild-type levels. The treatment reversed the animals’ motor defects.

Titrating the antisense oligonucleotide dosage also revealed that even modest decreases in excess MECP2 can lead to major improvements in symptoms.

“If you can even partially decrease the protein…you will probably rescue quite a bit of the features of the disease,” Zoghbi said. She added, “I’ve really never worked with a protein that is so exquisitely sensitive to the levels.”

Further Readings

Zoghbi

Neul JL, Fang P, Barrish J, et al.

Specific Mutations in Methyl-CpG-Binding Protein 2 Confer Different Severity in Rett Syndrome

Neurology. 2008 Apr 15;70(16):1313-1321.

Zoghbi H.

Genetic Aspects of Rett Syndrome

J Child Neurol. 1988;3 Suppl:S76-78.

.

The Way Forward

Panelists

Graciana Diez-Roux, PhD
Telethon Institute of Genetics and Medicine

David Fajgenbaum, MD
University of Pennsylvania

Anne Heatherington, PhD
Takeda Pharmaceuticals

Silver Linings

The meeting’s general session concluded with a panel discussion led by Brad Margus, co-founder and CEO of Cerevance. With a background in business, Margus moved into rare disease drug development after his daughter was diagnosed with ataxia-telangiectasia, a genetic disorder that causes neurodegeneration and immune dysfunction. The panel also featured Graciana Diez-Roux, chief scientific officer at the rare disease-focused Telethon Institute; David Fajgenbaum, a physician-scientist who both studies and suffers from Castleman syndrome; and Anne Heatherington, a data scientist for Takeda Pharmaceuticals with extensive experience studying Duchenne muscular dystrophy.

Panel members discussed the need for improvement in collaborations between patients and researchers.

“There is a lot of miscommunication within the rare disease research space, [but] I think there’s been a really great trend for groups like Takeda and others toward engaging patients in the research process,” said Fajgenbaum, adding that “I also think clinicians can really be a part of this.”

Besides improving clinical trial recruitment, involving patients more directly in research can have far-reaching benefits for scientists.

“It’s incredible how our PhD students, when they have the chance [to interact] with the patients and [get] to know the patients’ organizations…how their motivation and their love for what they do changes,” Diez-Roux said.

Besides increasing collaborations between patients and scientists, all of the panelists endorsed the need for strong, well-defined partnerships with pharmaceutical companies. Margus described his company’s efforts to improve data collection and sharing for ataxia-telangiectasia, which included building a system that uses wearable devices to collect movement data from patients around the clock.

“The data [are] truly owned by the families and the community, and we can make decisions about sharing the data with academics or any researcher in the world in a matter of days,” said Margus.

Good partnerships require more than just good databases, though. Academic researchers accustomed to independent, curiosity-driven experimental design and flexible deadlines sometimes have trouble accommodating pharmaceutical companies’ urgent, goal-directed needs.

“I think the model has to be somewhere between…the industry knowing how to deal with the academic research and academic researchers being open to notice that industries have…different goals in some respects,” said Diez-Roux.

The group also discussed the impact of the COVID-19 pandemic. In the short term, of course, the global shutdown caused by the SARS-CoV-2 virus has halted or delayed many rare disease studies. However, panelists agreed that some of the innovative approaches developed for the pandemic response could transform many aspects of rare disease research in the future.

“We have been very involved in a lot of the COVID alliances, and have been steeped in novel ways of working,” said Takeda’s Heatherington.

As an example, she pointed to the company’s involvement in multi-corporation consortia to develop new therapies and even entirely new platforms for therapies.

“That’s a real breakthrough in terms of how we do our business, that extent of collaboration for [competitors to] come together,” Heatherington continued.

At the same time, “the public is realizing more how important research is, and this goes for COVID, but I think it goes for all diseases,” said Diez-Roux. Both she and Heatherington also pointed out that the pandemic has underscored the potential tradeoffs between speed and safety in therapeutic development, and highlighted the importance of oversight in clinical trials.

The meeting concluded with a virtual poster session, featuring rapid-fire presentations of some of the newest research in rare diseases and offering attendees the ability to interact with the presenters directly. Like the other presentations, the posters represented the diversity and enthusiasm of rare disease researchers.

“What makes me optimistic is the passion and the knowledge…and the fact that we have people that are so dedicated to rare diseases,” said Heatherington.

Further Readings

Heatherington

Bhattacharya I, Manukyan Z, Chan P, et al.

Making Every Subject Count: A Case Study of Drug Development Path for Medication in a Pediatric Rare Disease

Clin Pharmacol Ther. 2016 Oct;100(4):330-332.

Dwivedi G, Fitz L, Hegen M, et al.

A Multiscale Model of Interleukin-6-Mediated Immune Regulation in Crohn’s Disease and Its Application in Drug Discovery and Development

CPT: Pharmacometrics Syst Pharmacol. 2014 Jan 8;3:e89.

Diez-Roux

Diez-Roux G, Ballabio A.

Sulfatases and Human Disease

Annu Rev Genomics Human Genet. 2005;6:355-379.

Diez-Roux G, Banfi S, Sultan M, et al.

A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo

PLoS Biol. 2011 Jan 18;9(1):e1000582.