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Long COVID still has no cure — so these patients are turning to research

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When Lisa McCorkell got COVID-19 in March 2020, her symptoms were mild. Her physicians told her to isolate from others and that she would recover in a few weeks. But the weeks stretched into months and McCorkell, who was working on a master’s degree in public policy at the University of California, Berkeley, started having debilitating and bewildering symptoms: fatigue, dizziness and shortness of breath. Previously an avid runner, McCorkell found her heart racing from simple efforts.

She struggled to find an explanation, and soon realized that her physicians didn’t know any more about her condition than she did. To complicate matters, the limited availability of high-quality testing for the coronavirus SARS-CoV-2 in the early days of the pandemic left many of her doctors wondering whether her symptoms were really due to COVID-19 at all. “I didn’t have health-care providers that took me seriously,” McCorkell says. “That largely pushed me out of the health-care system.”

McCorkell turned instead to those who were experiencing the same puzzling symptoms and frustrations, joining a support group for people with what would eventually be called long COVID. As they compared notes, McCorkell and a handful of others — many of whom had research experience — realized that the information they were sharing might be helpful not only for those with long COVID, but also for those looking to study the condition. So, they founded a non-profit organization, called the Patient-Led Research Collaborative (PLRC), to design, provide advice on and even fund basic and clinical research into long COVID and other chronic illnesses.

A survey run by the group and published in 2021 catalogued the more than 200 symptoms experienced by people with the condition (H. E. Davis et al. eClinicalMedicine 38, 101019; 2021). It is seen by some as putting long COVID on the map. “They really jump-started the interest,” says Lucinda Bateman, a physician in Salt Lake City, Utah, who specializes in treating people who have long COVID and related conditions. “That was really a point from where more broad awareness arose.”

In the past few years, this study and similar patient-led efforts have helped to shape research programmes on long COVID and kick off some early clinical trials of therapies that might otherwise have gone unexplored. Many patient advocates see the efforts as crucial. They also think the results are more helpful for advancing the understanding of long COVID than the current findings from programmes funded by the US$1.15-billion RECOVER initiative led by the US National Institutes of Health (NIH). People with long COVID and their advocates have criticized the initiative for not always listening to the needs of people with long COVID.

Getting involved in research is challenging, given the symptoms of long COVID, but many patient advocates say they have no choice. “They’ve got you over a barrel,” says Margaret O’Hara, who coordinates patient involvement in research for a National Health Service hospital trust in England. O’Hara is on medical leave owing to long COVID. Referring to the research, she says: “You have to do it, because you are the one who is going to suffer for it if you don’t, but at the same time, you’re in bed sick.”

A plethora of symptoms

The PLRC’s survey of long COVID symptoms was the first major research study of the condition. The premise was simple enough: authors surveyed almost 3,800 people in 56 countries, many of whom were members of various long COVID support groups worldwide, including the network Body Politic, from which the PLRC originated. When the authors analysed the data, they found scores of symptoms in at least ten organ systems.

The study showed that the most prevalent problems were fatigue, post-exertional malaise — a worsening of symptoms after exertion — and the cognitive dysfunction that came to be referred to as brain fog. Nearly 86% of participants reported relapses triggered by exertion; 87% said fatigue was a main symptom; and 88% reported brain fog, with no differences in cognitive issues across age groups.

The paper has amassed more than 1,000 citations, been mentioned in some 60 policy statements and is widely considered a seminal paper in long COVID research, owing to its in-depth analysis. For McCorkell, however, its impact is more fundamental. “What we demonstrated with the survey is that patients can lead high-quality research, and that it’s really necessary in order to have the most comprehensive look at a condition.”

The achievement is especially notable considering that the study was conducted by unpaid volunteers, most of whom identify as disabled, and it received no financial support. By contrast, many long COVID research initiatives have tended to focus on a subset of symptoms, which comes with the risk of missing the bigger picture, says McCorkell.

“There’s a lot of complexity in these illnesses, and I think it’s really important to embrace these complexities,” says Beth Pollack, a research scientist at the Massachusetts Institute of Technology in Cambridge, whose work focuses on understanding long COVID and other infection-associated chronic illnesses. With conditions that have a range of symptoms, and for which there is only limited research, building a knowledge base starts by listening to patients’ stories and capturing the nuances of their conditions, Pollack says.

Desperate measures

In early 2020, Martha Eckey, a pharmacist in Minneapolis, Minnesota, developed a COVID-like illness. She experienced a crushing fatigue that no amount of sleep could relieve, and was bedbound for days at a time. The physicians she went to for help had no answers. In desperation, Eckey turned to the online community of people with long COVID.

She found people trying treatments from prescription medications to over-the-counter supplements. But the effectiveness of these was restricted largely to personal anecdotes.

In the hope of getting a more comprehensive, systematic understanding of what worked, Eckey designed a survey called TREAT ME, which asked people with long COVID and those with myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), about their experiences, including whether they had tried any of a list of 150 medications and supplements. More than 4,000 people responded.

Portrait of Martha Eckey

Martha Eckey’s TREAT ME survey found overlap between treatments people were using for long COVID and for other chronic conditions.Credit: John Karp

Eckey found overlap with other chronic conditions. Some treatments revealed by the survey as most effective for long COVID were drugs such as beta blockers and the heart-failure medication Corlanor (ivabradine). These are sometimes used to treat postural orthostatic tachycardia syndrome, a nervous-system disorder that can be triggered by COVID-19. Eckey also found that a number of individuals reported relief after taking naltrexone, a non-opioid drug for treating substance-use disorder. When taken at low doses, it has anti-inflammatory and pain-relieving properties.

Physiotherapist David Putrino, who specializes in rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai in New York City, says that the TREAT ME survey captured something both simple and profoundly important. “It’s a very fundamental question of, ‘what are you taking that’s helping right now?’” he says. The results have helped to guide his research on long COVID.

Listening to patients

TREAT ME attracted the attention of scientists and research foundations, who soon realized that this information could help to shape their efforts. One was the Open Medicine Foundation, a non-profit organization in Agoura Hills, California, that studies infection-associated chronic illnesses such as long COVID and ME/CFS.

Linda Tannenbaum, a clinical laboratory scientist, founded the Open Medicine Foundation in 2012 in response to the difficulties she encountered while seeking a diagnosis and treatment for her daughter, who has ME/CFS. Its first double-blind, randomized, placebo-controlled clinical trial will explore low-dose naltrexone (LDN) and another drug, pyridostigmine, which is used to treat an autoimmune disorder that affects voluntary muscle movements. The medications will be tested separately and in combination. Tannenbaum credits TREAT ME for helping to shape which symptoms will be assessed during the trial.

“The reason we are doing LDN as our first trial is that patients asked for it,” she says. TREAT ME also showed that many people with long COVID said that LDN helped to reduce brain fog (see go.nature.com/3qy2tpj). Given these results, the Open Medicine Foundation also incorporated parameters in the trial to test cognitive function. Both LDN and pyridostigmine have been used to treat long COVID, but as many patients report, physicians are often reluctant to prescribe these drugs because of a lack of formal, randomized, controlled trials showing their effectiveness. “Doctors are very hesitant to go outside approved, or at least medically tested, medications,” says Bateman. In her experience, insurance companies also won’t pay for these medications for people with ME/CFS and long COVID without strong evidence to support their use.

Many patient advocates say that there is insufficient clinical research on the kinds of drug that people are already using. In February, the RECOVER initiative received a further $515 million over the next 4 years to test more interventions and investigate the long-term effects of a SARS-CoV-2 infection. But so far, the only trials it has begun are of the antiviral medication Paxlovid (nirmatrelvir and ritonavir), which started enrolling patients in July 2023, and of ivabradine and intravenous immunoglobulin, which recruited its first participants last month.

Lauren Nichols reads her blood oxygen levels and heart rate from a machine on her finger at her desk in her home

Lauren Nichols, a long COVID patient advocate, helped to lead the Body Politic support group.Credit: Lauren Owens Lambert/Reuters

RECOVER had come under fire for its plan to test the effectiveness of a computer game for relieving brain fog, which critics say won’t meaningfully reduce symptoms, and for its decision to plan an exercise trial, given that many people with long COVID experience post-exertional malaise.

“There are a lot of clinical trials that are focused on more behavioural and on non-pharmaceutical interventions, and that is really not a priority to the patient community,” McCorkell says. “It is a misunderstanding of how severe the condition is, and how much of an impact on people’s quality of life it has taken.”

A spokesperson for RECOVER told Nature that the clinical trial of a computer game has already started enrolling participants and that the exercise trial is still scheduled to begin. They emphasized that these are accessible interventions, which might help some people who are affected, given the wide range of symptoms. They also said that moving these trials forwards will help in developing the framework for testing more treatments.

Lifting the fog

In the weeks after her initial COVID-19 infection, Hannah Davis found herself struggling with severe brain fog, to the point at which she could barely string two sentences together. Davis, who at the time was working as a data analyst and artist, with a particular focus on addressing biases in machine learning, kept waiting for her cognitive function to go back to normal, only for it never to return. “I had, and continue to have, terrible, terrible cognitive impairment,” says Davis, who is one of the co-founders of the PLRC.

Brain fog is having a significant impact on people’s livelihoods, says Wes Ely, a physician-scientist who works in intensive care at Vanderbilt University Medical Center in Nashville, Tennessee. People with long COVID have a form of cognitive impairment that is often “like mild and moderate dementia”, he says.

Ely, who studies treatments for Alzheimer’s disease and related dementias, decided in 2020 to expand into studying the cognitive impairments associated with long COVID. He quickly recognized that the condition is deeply complex, with symptoms that go beyond cognitive impairment.

To gain a comprehensive understanding of the phenomenon, he turned to the patient community, eventually recruiting Davis and Jaime Seltzer, director of scientific and medical outreach at the non-profit organization ME Action in Santa Monica, California. Together, they drafted a clinical trial to test the medication baricitinib, an immunomodulatory drug that is used to treat rheumatoid arthritis and alopecia areata, and acute COVID-19 infections. “I wanted to learn from people who are living with this disease,” says Ely.

The trio, along with other US investigators, designed a 550-person clinical trial of baricitinib as a potential treatment for long COVID. The trial has now been funded by the NIH and will start enrolment later this year.

From Seltzer’s perspective, an effective collaboration between patients and scientists can help both sides equally, because it leads to more effective and targeted research. “We have the resources to help you do what you do even better,” Seltzer says. The lived experiences of patients can shape research priorities in several key ways, she says. These include finding the most efficient way to allocate limited funds on the basis of symptom burden; offering context on the prevalence and severity of symptoms; and identifying how the trial design can capture improvement most effectively. All of this can help lead to faster breakthroughs in treatments, which is of benefit to both patients and researchers, Seltzer says.

Microclot mystery

In late autumn 2022, McCorkell flew to New York City to participate in a trial being conducted by Putrino and his team. This study aimed to look for the presence of tiny blood clots, called microclots, in people with long COVID. It is thought that these cause symptoms such as fatigue and brain fog by impairing blood flow to the brain and body. There are still a lot of unknowns about microclots, including how many people with long COVID have them, how they form and whether the association is causal.

McCorkell gave blood samples that were analysed using fluorescent microscopy, which confirmed she had microclots. McCorkell says it was “a wake-up call”. Until that point, she had been managing her symptoms mainly by avoiding overexertion. But the presence of the clots suggested to her that there might be active damage happening to her body. So, she started taking supplements that TREAT ME survey respondents reported as helpful.

Eckey’s results, which have not yet been published in a peer-reviewed journal, show that of 668 respondents with long COVID, between 40% and 70% found some symptom relief when taking the supplements nattokinase, serrapeptase or lumbrokinase, individually or in combination (see go.nature.com/43xgyoq).

When Putrino saw these results, he decided it was crucial to conduct clinical trials of the supplements. He expects to begin a 120-person study on lumbrokinase in the coming months, and has involved patients at every step of its development.

“Every research trial that we run, we involve the patient community in the protocol,” Putrino says. This includes taking their advice on what trials should be prioritized, what symptoms to assess, how many clinic visits to require and what the testing environment should be like, to minimize the risk of exacerbating their symptoms, he says.

McCorkell says that the supplements she’s been taking have improved her general function by about 10%. Whereas that might not sound like much, she feels it is meaningful progress. Although the long COVID research has been difficult, she sees no other option but to stay involved. “We’re driven by desperation, out of improving our own quality of life.”

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Cosmologist Claudia de Rham on falling for gravity

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The Beauty Of Falling: A Life In Pursuit Of Gravity Claudia de Rham Princeton Univ. Press (2024)

Swiss cosmologist Claudia de Rham is best known for co-developing a theory of gravity that tweaks Albert Einstein’s general theory of relativity. It could help to explain why, for the past several billion years, the Universe has been expanding at an ever faster pace — a ‘late-time’ acceleration that is usually ascribed to a mysterious force called dark energy.

For de Rham, who also spent more than two decades training to be an astronaut and is now at Imperial College London, gravity is the key to understanding both the Universe and the arc of her own life. In her book, The Beauty of Falling, she weaves together physics and memoir in a meditation on gravity as a metaphor for human existence.

De Rham talked to Nature about the beauty of failing and how her dream of flying into space led to her research making sense of gravity.

Why did you want to write this book?

Part of it is sharing. From an external point of view, what we do as theoretical physicists seems a little bit alien. We often just share our successes, and people have this picture of us as individual geniuses who make out-of-the-blue discoveries. The reality is that it is very much team-based, and fun.

Every day, I try out an idea and it fails. And there’s something beautiful in failing, and falling. The book is about gravity, but it is also about embracing this falling, because it’s how we get better — it’s how we understand the world. With gravity, failing has an even deeper meaning. The way that we describe gravity at the moment is with Einstein’s general theory of relativity, which predicts its own downfall.

How so?

If you have a gravitational collapse of matter, the endpoint will be in a black hole, with a singularity at its centre. The singularity means that, if you agree with Einstein’s theory, some quantities you can measure would be infinite. What that really means is that the theory has stopped working there, and it gives a prediction that doesn’t make any sense. So the theory itself is telling you that you shouldn’t trust it any more. And that is not something to be ashamed of. It is an opportunity to learn something more.

In the book, you describe how, as a child, you had a sudden realization. What was it?

The “wow!” moment I had as a kid was when my family and I travelled in Peru, first to Iquitos and then the Amazonian forest. I must have been four years old. At some point, we were staying in hammocks, and as I was swinging there, just staring at the stars through the trees — some of which were a thousand years old, and so tall — I almost had a feeling of weightlessness.

My mother always tells me that I said “now I know I want to belong there, I want to be in the sky”. It wasn’t phrased as “I want to become an astronaut”, but in terms of “I want to belong to this greater thing”.

Claudia de Rham overlooking small village in Peruvian Andes near city of Ayacucho, circa 1981.

At the age of four, traveling in Peru, Claudia de Rham realized she wanted to go to space.Credit: Ellen de Rham

This did turn into a dream of becoming an astronaut. This is notoriously difficult, and the European Space Agency (ESA) has held only three recruitments since 1978. How close did you get to being selected?

For ten years, I waited for the ESA astronaut selection. Then finally, in 2008, the announcement came. There were some pre-selection processes, then different batches of psychological and psychometric tests. You were also tested on how you behave in a team, how you work with others and how you react to stressful situations. More than 8,000 people submitted an application with all the required documents. By the end, only 42 were left to go through medical tests.

I was in a group with six others in Toulouse, France, in a medical centre for a full week of non-stop tests, one after the other, through every single hole of your body. And at the end of the week, I had a meeting with the chief doctor. Everything seemed well, he said; we are just missing the tuberculosis (TB) test. I was laughing — I said, ”Clearly I don’t have TB, it’s going to be fine.“

I went to the airport to catch my flight back to Canada, where I was living at the time. Just when I was boarding the plane, I saw an e-mail from the doctor. The TB test had come up positive.

I had been training for 20–25 years. I had never thought I would get so close. I had big dreams, but I was always very realistic: I knew that the chances would be very small, and I had set up a whole other career path just in case. But when I talked to the doctor, it was the first time I thought, “This really can happen.”

Your ‘fallback’ career is itself very selective.

Being a theoretical physicist is not exactly something you just fall into because you can’t think of doing anything else. It required a lot of work. But I think it wasn’t as high-pressure for me as it might’ve been for others who had always thought that that’s what they wanted to be.

And yet here you are. What drew you to study gravity?

Initially, I was much more interested in higher dimensions, and why we seem to experience three dimensions of space. There could be more, and if so, there must be some phenomenon that explains why we experience only three. One of the questions I was trying to understand was how a particular model with extra dimensions could be related to the late-time acceleration of the Universe.

And the model, I realized at the time, did manifest some features which — from our three-dimensional point of view — looked like massive gravity. ‘Massive gravity’ is a theory that states that the fundamental particle that carries the gravitational force, called the graviton, has an inertial mass.

In general relativity, the graviton is massless, similar to the photon, the particle responsible for electromagnetic waves. And when the fundamental particle carrying a force is massless, the force has infinite range, so can propagate across the entire Universe.

What sort of mass are we talking about?

The graviton shouldn’t be very massive, because otherwise we wouldn’t even experience gravity. But we do feel gravity on Earth, and it can be detected in the Solar System, in our Galaxy and in clusters of galaxies — so the range of gravity should be larger than that. If you translate this distance scale to energy units, that corresponds to roughly 10−32 electronvolts (eV). [That is 38 orders of magnitude lighter than an electron.]

Can the massive graviton be tested experimentally?

Yes. Current observations in gravity and cosmology already put constraints on it. For instance, observations of gravitational waves mean that the graviton’s mass must be less than 10−22 eV. If the graviton had a larger mass than that, then the speed of propagation for gravitational waves of different frequencies would be slightly different, and the signals we have seen would have been slightly different. It’s not a huge effect, but enough to put a constraint.

However, perhaps the best way to probe that in the future would be to detect gravitational waves with much longer wavelengths than those now known.

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How synthetic biologists are building better biofactories

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Scientists have used microorganisms to produce beneficial chemicals for decades. By providing the microbes with enzymes and metabolic pathways, researchers can coax cells to churn out everything from food additives to biofuels.

One advantage of biomanufacturing is ecological: the processes are generally more environmentally friendly than are chemical manufacturing methods. But it’s expensive, mainly because cells won’t create something simply because researchers want them to. The enzymes needed to produce ethanol fuel from plant sugars, for example, must compete with the cell’s own metabolic enzymes for energy, and the yield can be poor.

Building complex products, such as pharmaceuticals, can involve numerous steps carried out by multiple enzymes. When the cell’s ability to develop is pitted against its ability to make a product it doesn’t need, “the cells are going to choose to grow every time”, says Brian Pfleger, a synthetic biologist at the University of Wisconsin–Madison.

Rather than attempting to win this metabolic-resource war, some researchers are trying to sidestep it, introducing parallel biosynthesis pathways that won’t interfere with natural processes. They’ve zeroed in on cofactors: small organic molecules that bind to enzymes and donate (reduce) or accept (oxidize) the electrons needed for enzymes to do their work. Many of these ‘redox’ reactions, in which chemical groups are added, subtracted or restructured in compounds, are energetically expensive for cells. Compounding the problem is the fact that some reactions require a relatively ‘reducing’ environment whereas others require an ‘oxidizing’ environment; making both conditions occur in the same cell is nearly impossible.

Designing synthetic redox cofactors that can be used only by synthetic enzymes could bypass the cell’s natural machinery entirely, ensuring that the two processes no longer need to compete. “It’s still using nature’s same infrastructure,” says Han Li, a chemical and biological engineer at the University of California, Irvine. These non-canonical redox cofactors (NRCs), she says, could allow synthetic biologists to create chemical reactions that are either entirely new to nature, or more efficient than those catalysed by existing enzymes.

Li’s group is among several that are engineering NRCs, and the enzymes to use them. They have already designed synthetic systems that yield more product than previous attempts. But it isn’t easy. Researchers need to find ways to efficiently produce NRCs, ensure that the cofactors and enzymes don’t harm the cells, and modify each enzyme to accept NRCs without disrupting the enzyme’s normal functions.

Scaling up NRC production to industrial levels will bring more challenges. But some researchers think that NRCs could transform chemical manufacturing, making bioproduction cheaper, easier and more viable. “Right now, biomanufacturing can’t compete with fossil-fuel based processes because of cost,” Li says. By decreasing the cost, she says, waste and emissions could decrease as well.

A universal currency

The idea of fleshing out biomanufacturing processes with a parallel set of cofactors has been around since at least the 1950s, when researchers began finding ways to synthesize alternative compounds and searching for the rare enzyme that could use them effectively. But the artificial cofactors were prohibitively expensive to make. And because natural enzymes could switch back and forth between synthetic and natural cofactors, both the cell and biomanufacturing yields suffered. Designing enzymes that specifically used a non-canonical cofactor proved an even harder problem, until advances in genetics and structural biology made protein engineering a relatively straightforward process.

Li was inspired by efforts to produce synthetic nucleotides that could be inserted into DNA, allowing genetic sequences to use six different nucleotides instead of four and drastically expanding the number of amino acids that the DNA could theoretically encode. If the same idea could be applied to cellular metabolism, she reasoned, it would expand the types of product that cells could make. “Why not do this for the universal currency of life?” she says.

Cofactors are indeed a universal currency. Plant, animal and microbial cells all tend to use the same organic molecules to drive enzymatic reactions, such as ATP for energy and S-adenosyl methionine (SAM) as a source of methyl and sulfur-containing chemical groups.

One of the most common cofactors is nicotinamide adenine dinucleotide (NAD), which, with its phosphorylated form NADP, drives metabolic pathways, such as those that break down glucose into carbon dioxide and water. These cofactors exist in two configurations: a reduced form (NADH) that donates electrons and an oxidized form (NAD+) that receives them.

A genomic analysis of the bacterium Escherichia coli estimated that the organism uses NAD in 127 enzymatic reactions and NADP in another 1131. NAD “is so central to life and all the ways that we understand it”, concludes Ruud Weusthuis, a microbial engineer at Wageningen University in the Netherlands.

But that centrality also means that, when a bioengineer wants to coax microbes into producing a new product — an artificial scent, for instance — they face a lot of competition for NAD. Simply providing the cells with more cofactors doesn’t help because the cells’ metabolisms just run faster. And given the choice, natural enzymes prefer to carry out easier reactions that don’t require much energy, making it hard for engineers to restrict where electrons are used. “Electrons are important, and we don’t want to waste them,” Weusthuis says.

NRCs can shift that balance of power. One of the most promising is nicotinamide mononucleotide (NMN), a subunit of NAD (see ‘Electron alternatives’). Bacterial cells naturally synthesize small amounts of NMN when producing the nucleotides that make up DNA and RNA, and adding certain enzymes to the cells can increase production.

Electron alternatives. A graphic showing the chemical structure for NAD, versus synthetic alternatives.

In a 2019 paper2, Li’s team made four changes to an enzyme called glucose dehydrogenase that made it 10 million times more likely to use NMN than NAD. By pairing this modified enzyme with another that can naturally use NMN, the group successfully induced E. coli to produce a pharmaceutical product called levodione using only artificial cofactors. The swap produced about as much levodione as the cells could produce with enzymes that use only NAD, and altering the enzyme’s structure further could increase its efficiency, the researchers say.

Li’s team has also used NMN to power more challenging syntheses, including the scent-related chemical citronellal. Citronellal is difficult to make because cells quickly convert it into other products. Engineering certain enzymes to use NMN exclusively instead of NAD allowed citronellal to accumulate in cells3. But, in a finding that highlights the delicate balance metabolic engineers face, Li’s group also found that when NMN+ concentrations are high, cell growth suffers. Bioengineer William Black, who works with Li at the University of California, Irvine, says that the field is still working to understand how the natural enzymes affected by NMN+ work, and researchers might need to optimize their bacteria on a case-by-case basis.

Beyond NMN

Other researchers are exploring different NRCs. Zongbao Kent Zhao, a bioengineer at the Dalian Institute of Chemical Physics in China, is engineering enzymes to use a cofactor called nicotinamide cytosine dinucleotide (NCD), which uses a cytosine nucleotide in place of the adenine in NAD. Unlike NMN, NCD is entirely artificial: cells do not naturally make it, although enzymes can be engineered to use it as a cofactor. Zhao hopes that this feature will prevent ‘crosstalk’ between the biosynthetic and natural metabolic pathways, which might be able to use NMN in place of NAD when levels of NMN are high, leaving less, therefore, for the desired synthesis reactions.

Zhao’s group has altered two of the enzymes in the E. coli pathway that produces malate4 — a precursor to lactic acid — so that they use NCD instead of NAD. His eventual goal, Zhao says, is to make biofuels such as biodiesel that can be “dropped in” to combustion engines without needing to modify the engines.

Decoupling natural from biosynthetic processes could make the manufacturing process more environmentally friendly, says Pablo Iván Nikel, a biotechnologist at the Technical University of Denmark in Kongens Lyngby. “This seems to be something the industry is craving.” For chemical manufacturers using microorganisms to spin natural substances into useful chemicals, it could solve two major problems, he says: the need for fossil fuels as substrates and the production of toxic waste by-products.

Nikel’s group, for instance, has been trying to find ways to get bacteria to produce fluorinated precursors of compounds such as polytetrafluoroethylene (Teflon), which are highly toxic to manufacture. His group focuses on Pseudomonas putida, a species that thrives in toxic conditions. In 2020, the group described genetic circuits that force this tough bacterium to add fluoride to sugars and other chemicals5 — a biological process that occurs rarely in nature. Now, the team is trying to incorporate NRCs into this process in the hope of making this difficult process more efficient, and eventually to drive reactions using carbon dioxide captured from the atmosphere. “We’re replacing this oil-dependent society with more ecofriendly production systems,” Nikel says.

Han Li posing for a portrait at a laboratory bench

Han Li is one of several researchers investigating non-canonical redox cofactors.Credit: Natalie Tso and Cynthia Dieudonne

NAD isn’t the only redox cofactor that could be replaced with synthetic substitutes. Stephan Hammer, an organic chemist at the University of Bielefeld in Germany, and his team are developing analogues for SAM, which participates in reactions that add methyl groups or sulfur groups called sulfonium to chemical compounds.

Sulfonium reactions are rare in nature, and Hammer says that being able to control them with synthetic SAM substitutes could enable researchers to produce pharmaceutical drugs or label proteins so that they can be tracked in cells. “If you potentially have new cofactors and new reactivities, you can expand on what’s in nature,” he says. But although his group has found ways to synthesize large amounts of different SAM analogues in cells, incorporating them into synthetic pathways has been difficult because the enzymes’ activity is still low, he says.

Science fiction … in cells

Indeed, NRCs present challenges on multiple levels, specialists say. Ideally, they should work with engineered enzymes but not interact with existing enzymes, says Caroline Paul, a biological chemist at the Delft University of Technology in the Netherlands. Her group is working on NMN with Weusthuis, engineering enzymes that use it exclusively rather than interchanging it with NAD. The researchers are also finding ways to modify NMN and other cofactors with chemical tails that tailor the compounds to certain enzymes such as monooxygenases, which cells use to create signalling molecules. Researchers could eventually exploit such designs to use different NRCs at different steps of the reaction in the same cell.

For now, Paul’s team is focusing on lactic acid and ethanol production because these systems are well characterized. From there, she hopes to move onto complex chemicals such as those used in perfumes.

And that’s where NRCs could be particularly useful, says Richard van Kranenburg, a biotechnologist at Amsterdam-based biochemicals company Corbion, the world’s leading producer of industrial lactic acid. “I don’t think we could improve lactic-acid production,” he says. Incorporating NRCs and engineered enzymes would require manufacturers to set up new production pathways to yield a chemical that microorganisms naturally make very efficiently.

But decreasing costs could make biomanufacturing more viable for chemicals such as the natural plant phytoestrogens that are used in some cancer drugs. For plants, phytoestrogen synthesis is a complex, multistep and inefficient process that involves many enzymes, says Jules Beekwilder, a chemical biologist with the chemical manufacturer BASF in Geleen, the Netherlands. Companies could put these enzymes into yeast or bacteria and perhaps produce the chemical in a fermentation tank, but the many production steps mean that energy is lost throughout the process. In those cases, increased output could justify the added expenses, van Kranenburg says. “The cost of your medium doesn’t matter and maybe even the cost of the cofactor does not matter if the product is valuable enough.”

Beekwilder and van Kranenburg are industry advisers for Weusthuis’s and Paul’s research teams, although neither BASF nor Corbion fund the research. Both advisers say that they are excited about the potential of NRCs. “It may be nice to control redox conditions without affecting the physiology of the organism,” Beekwilder says. But he adds that scaling them up to meet consumer demand presents its own set of challenges, such as maintaining the varying levels of oxygen needed for different enzymatic reactions. And although researchers often know what each enzyme does, they might not understand the biophysics well enough to be able to modify the enzyme to accept an NRC. “It’s not so that you can press the button on the computer and it’s done,” he says.

That said, advances in artificial intelligence (AI) are making enzyme engineering much easier than it was just a few years ago. “The idea that we have to crystallize a protein is ending,” Pfleger says, referring to the classic structural-biology technique of X-ray crystallography. “The ability to give proteins new functions or design from scratch is accelerating like crazy.” At the same time, AI tools such as AlphaFold and RoseTTAFold are learning how to decode enzymes’ structure from their sequence and could predict how specific modifications — a new fold that allows the enzyme to accept NMN instead of NAD, for instance — would affect its function.

Li says that she is “very excited” about the possibilities of AI and hopes one day to accumulate enough data to work out which modifications are needed to make any enzyme work with NRCs, and to start automating the process for creating them. Her group has already begun working out design principles that would allow enzymes to switch their preference from NAD to NMN.

Researchers might even be able to modify certain NRC-powered enzymes to be more powerful than their natural counterparts, or to work at different acidities, temperatures or oxygen levels from those that are normally required by natural enzymes. If the enzymes are versatile enough, Li estimates that NMN-powered reactions could end up being significantly cheaper than those that use NAD, owing to the increased efficiency and, potentially, the lower cost of producing NMN compared with NAD.

Still, researchers would prefer to be as efficient as possible. In nature, biosynthetic redox reactions are coupled with secondary reactions that recycle NADH to NAD+, or vice versa, so that the cell can keep the biosynthesis going. Research groups including Li’s are designing ‘recycling’ enzymes that can switch NMN+ to and from NMNH, creating oxidative or reductive conditions in the cell that are independent of NAD. Ultimately, Li hopes to find or develop a universal recycling enzyme or electrode that can switch any NRC back to its oxidized or reduced forms, depending on what the artificial biosynthetic pathway needs.

Not that every enzyme in a complex synthesis pathway would need to depend on an NRC, Hammer notes; the engineered enzymes could be reserved for particularly inefficient bottlenecks, or to make minor modifications to a compound that the cell has already made.

As the roster of NRCs expands, says Weusthuis, the biosynthetic possibilities are endless. “This is science fiction, not in space but in cells.”

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How scientists are making the most of Reddit

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Reddit’s many ‘subreddit’ communities offer channels for discussing science and are of interest to social-media scholars.Credit: Amy Lombard/New York Times/Redux/eyevine

It has been almost 18 months since Elon Musk purchased Twitter, now known as X. Since the tech mogul took ownership, in October 2022, the number of daily active users of the platform’s mobile app has fallen by around 15%, and in April 2023 the company cut its workforce by 80%. Thousands of scientists are reducing the time they spend on the platform (Nature 613, 19–21; 2023). Some have gravitated towards newer social-media alternatives, such as Mastodon and Bluesky. But others are finding a home on a system that pre-dates Twitter: Reddit.

The site was founded in 2005, originally as one all-encompassing forum where users (known as redditors) could post content such as links, texts, images and videos. Anonymous user upvote (or downvote) and comment on each other’s content, deciding on what performs well enough to reach others’ feeds.

Today, Reddit is divided into communities, called subreddits, each with volunteer moderators who review content. These subreddits have names that begin with ‘r/’ and are devoted to all sorts of subjects, such as literature, solo travel and Washington DC. Reddit is regularly irreverent: r/trees is for people to share content about marijuana, whereas r/marijuanaenthusiasts is the place to look at trees. It is sometimes dangerous — some communities have amplified conspiracy theories. And there are subreddits devoted to science, ranging from the broad r/science to more specific ones, such as r/bacteriophages.

As of December 2023, according to Reddit’s own statistics, the site had 73 million daily active users, more than 100,000 active communities and had amassed over 16 billion posts and comments. In February 2024, it was the eighth most visited website in the world, ahead of both Amazon and TikTok (see go.nature.com/3tugxbq). And on 20 March, the company floated on the New York Stock Exchange, where it was initially valued at US$6.4 billion. With most researchers now needing to pay to download useful amounts of data on X, Reddit is another option to survey the Internet hivemind. Although changes made last year threaten researchers’ ability to pull data as easily as they once did, Reddit says access to its data continues to be free for non-commercial researchers and academics.

“As the social-media landscape started changing, we really started thinking about the other spaces besides Twitter that people are using,” says Nicholas Proferes, a social media researcher at Arizona State University’s School of Social and Behavioral Sciences in Phoenix, who co-authored reviews on the use of Reddit for research1,2. Here, Nature reports on how Reddit is providing scientists with continued avenues for connecting with other researchers, gathering data and engaging with the public.

Networking and collaboration

Yvette Cendes’s journey on Reddit began in 2014. Cendes, who is currently a postdoctoral scholar at the Harvard–Smithsonian Center for Astrophysics in Cambridge, Massachusetts, found herself with some downtime during her PhD studies in astronomy, and started poking around on the platform. She came across a thread in which users were panicking over how imminent γ-ray bursts from supernovae were going to wreak havoc and kill people — something that she knew to be untrue. She resolved to jump into the comments and clear things up, and this was the start of her science-communication career.

Since then, Cendes has made a name for herself on Reddit and even created her own subreddit, with nearly 17,000 members. “It’s a very good way to get good knowledge out there,” she says.

Scientists also use Reddit to get tips and tricks from other scientists. The r/biotech subreddit features news about biotechnology innovations and career advice; r/datascience is a community specifically for data-science professionals. There’s even a subreddit devoted to electron microscopy, from which users can seek guidance on the technology.

Portrait of of Yvette Cendes

Yvette Cendes discusses astronomy as a science and a career on Reddit.Credit: Floris Looijesteijn

Not everyone is as forthcoming with their names and credentials on Reddit, which can make networking a bit more challenging than on other sites, says Cendes. But the pseudoanonymity can also be beneficial. Groups such as r/labrats offer safe spaces for scientists to discuss their research or dilemmas with others of similar backgrounds (and these groups are sometimes used by science journalists looking for article ideas). The anonymity provides some protection for people to post without fear of retaliation, and to seek counsel. In one discussion, for instance, a user laments how their principal investigator published a paper based on their research without giving credit, and considers hiring legal support.

Reddit can also be a great jumping-off point for early-career scientists or those trying to pivot between specialties. Kevin Ortiz Ceballos, a graduate student at Harvard University’s Department of Astronomy, happened upon one of Cendes’ posts about how to become an astronomer back when he was in secondary school. He credits it with helping him to switch from literature to physics and eventually astrophysics. Engaging in conversations about professional astronomy before entering the field himself was a huge asset.

“The fact that Yvette made it so accessible gave me the tools I needed to take the necessary steps to study and prepare what I needed to get into astronomy grad school,” he says. The two have since connected in person, and even collaborated on a project that was recently submitted for publication.

With all of its subspaces, Reddit can be overwhelming at first. Cendes encourages potential users to take it slowly, find the communities they are most interested in and go from there — putting keywords in the search function and perusing the different subreddits that come up.

Research and analysis

The information embedded in posts and comments from Reddit’s millions of users can also be a treasure trove for researchers studying online behaviours. In 2022, NASA collaborated with master’s students at the University of British Columbia in Vancouver, Canada, to use Reddit data to locate landslides (see go.nature.com/3tlum6t). The team scraped the site for mentions of ‘landslide’, before analysing and validating relevant mentions to add to the NASA landslides database. According to the team, this verification was needed because a Reddit post about the song ‘Landslide’ by the rock band Fleetwood Mac might “give us insight about the changes and challenges of life, but it doesn’t do much for global disaster detection”.

A 2021 review2 in Social Media + Society, co-authored by Proferes, chronicled 727 manuscripts published between 2010 and 2020, that made use of Reddit data. These studies spanned all sorts of disciplines — from computer science to medicine to social science.

One reason that Reddit is ripe for research is that there are few bureaucratic hurdles to clear compared with what’s required for other studies involving human beings. “It is a publicly accessible web forum in the US and so is not considered to be human-subjects research,” says Proferes. Institutional review boards view Reddit research as “exempt from ethical review”, he says.

However, Proferes and his co-authors emphasize the need for intentionality and sensitivity when collecting data from the site. Consider a subreddit such as r/opiates. Data on substance use are often difficult to procure from in-person interviews or other social science methods, but because of Reddit’s anonymity, people are more open to sharing such information on the platform. However, using the subreddit for research could be seen as invasive by a community that considers itself a semi-private anonymous support network. Certain communities on Reddit are also wary of scientific researchers.

The 2024 review co-authored by Proferes1 lists some of these considerations and suggests steps such as obfuscating usernames in published work and collaborating with moderators.

“Academia and data populations have a very sore history of, frankly, academics coming in and just taking,” says Proferes. The online community “is not getting any benefit whatsoever. It is very exploitative. There’s some real historical reasons, too, why folks may be highly suspicious or dubious about researchers coming in, even in these digital spaces.”

Portrait of Sarah Gilbert

Research findings derived from Reddit posts should be shared with users, says Sarah Gilbert.Credit: Steven Shea

“It’s really easy when you’re working with these large data sets to just think of the data points in them as literal data,” says Sarah Gilbert, research director of the Citizens and Technology Lab at Cornell University in Ithaca, New York, and a co-author of the review. “Spending time in the community and learning the norms and actually reading it, it turns that data into people. It gives a better sense of who is going to be included, more like human-subject research.”

Gilbert also recommends sharing whatever published research comes out of trawling through Reddit data with those who provided the information. “Hopefully what you learnt is beneficial to the community so they can see data is used for something,” she says.

Connecting with non-scientists

Reddit can be a way for scientists to use their expertise to answer any questions the general public might have, says Cendes. She is a regular on r/space, educating users about topics such as the James Webb Space Telescope.

Kelly Zimmerman, a PhD candidate in ecology at Montclair State University in New Jersey, has connected with and educated other users on Reddit. When she started on the platform about 12 years ago, she mostly used it to find journal articles of interest on r/ecology and r/biology. But, like Cendes, she noticed how curious users were about scientific topics that were in her area of expertise, and she now often engages in discussions on subreddits such as r/whatisthisbug.

Although she previously used X, Zimmerman thinks that Reddit provides a more engaging experience. “I felt like I was just talking into a void — there wasn’t a lot of response on Twitter,” she says.

One way for scientists to try their hand at science communication on Reddit is through ‘ask me anything’ (AMA) sessions, in which researchers answer users’ questions in their own time. Moderators pull in verified researchers to provide responses — even renowned theoretical physicist Stephen Hawking participated. (To schedule an AMA with r/askscience, you can e-mail the moderators.)

With both AMAs and general discussion forums, there is an art to making sure that information is communicated effectively and succinctly. “We’re trying to keep it as scientific as possible, but in layman’s terms, so that non-scientists can understand cutting-edge science that’s coming out right now,” says Zimmerman, who also moderates some science subreddits.

Nathan Allen, a synthetic chemist based in Milwaukee, Wisconsin, and a former moderator at r/science, likens it to writing a persuasive e-mail. “On Reddit, you have got to convince the general public that this has some general interest to them, and you’ve got to develop it and build the message and make sure people stay on point,” he says. “You get a lot of practice writing concise explanations of complicated things that people who aren’t necessarily scientists are able to digest and understand.”

When using Reddit in any capacity, Zimmerman encourages scientists to make sure to read the rules before making a post or comment, and to mind their manners, just as they would on any other social-media platform. “Be polite,” she says. “Just because you’re an anonymous username doesn’t mean you should be rude to other people.”

Jennifer Cole, a biologist and anthropologist at Royal Holloway University of London, notes that using Reddit for scientific communication is not without its problems. Moderators do a lot of work behind the scenes and often face a torrent of abuse for trying to maintain standards, says Cole. And although using people’s real names can help with credibility, it can also make academics and experts targets for harassment and abuse. Although the site does not provide support for users who experience abuse, a spokesperson for Reddit noted that the platform has policies to prohibit both harassment and the sharing of personal or confidential information, and that these policies are enforced by the internal safety teams.

It can also be used to spread falsehoods. R/conspiracy has repeatedly posted misinformation about COVID-19 and vaccines. Climate deniers are also present on the platform, although a decade ago the science forum specifically banned climate change deniers. Asked about misinformation, the Reddit spokesperson said that because Reddit is governed by upvotes and downvotes, quality and accurate information tend to rise to the top.

Interviewees agree that Reddit is at its core a social media platform, and social media has the potential to be toxic. But when scientists engage, there’s also a lot of great scientific communication and debunking of misinformation. “Don’t be afraid to talk to the people,” Zimmerman says. Those “who are not scientists are just as curious as we are. There’s nothing special about being a scientist. We are like everybody else, and sometimes folks forget that.”

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How papers with doctored images can affect scientific reviews

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It was in just the second article of more than 1,000 that Otto Kalliokoski was screening that he spotted what he calls a “Photoshop masterpiece”.

The paper showed images from western blots — a technique used to analyse protein composition — for two samples. But Kalliokoski, an animal behaviourist at the University of Copenhagen, found that the images were identical down to the pixel, which he says is clearly not supposed to happen.

Image manipulation in scientific studies is a known and widespread problem. All the same, Kalliokoski and his colleagues were startled to come across more than 100 studies with questionable images while compiling a systematic review about a widely used test of laboratory rats’ moods. After publishing the review1 in January, the researchers released a preprint2 documenting the troubling studies that they uncovered and how these affected the results of their review. The preprint, posted on bioRxiv in February, has not yet been peer reviewed.

Their work “clearly highlights [that falsified images] are impacting our consolidated knowledge base”, says Alexandra Bannach-Brown, a systematic-review methodologist at the Berlin Institute of Health who was not involved with either the review or the preprint. Systematic reviews, which summarize and interpret the literature on a particular topic, are a key component of that base. With an explosion of scientific literature, “it’s impossible for a single person to keep up with reading every new paper that comes out in their field”, Bannach-Brown says. And that means that upholding the quality of systematic reviews is ever more important.

Pile-up of problems

Kalliokoski’s systematic review examined the reliability of a test designed to assess reward-seeking in rats under stress. A reduced interest in a reward is assumed to be a proxy symptom of depression, and the test is widely used during the development of antidepressant drugs. The team identified an initial pool of 1,035 eligible papers; 588 contained images.

By the time he’d skimmed five papers, Kalliokoski had already found a second one with troubling images. Not sure what to do, he bookmarked the suspicious studies and went ahead with collating papers for the review. As the questionable papers kept piling up, he and his colleagues decided to deploy Imagetwin, an AI-based software tool that flags problems such as duplicated images and ones that have been stretched or rotated. Either Imagetwin or the authors’ visual scrutiny flagged 112 — almost 20% — of the 588 image-containing papers.

“That is actually a lot,” says Elizabeth Bik, a microbiologist in San Francisco, California, who has investigated image-related misconduct and is now an independent scientific-integrity consultant. Whether image manipulation is the result of honest error or an intention to mislead, “it could undermine the findings of a study”, she says.

Small but detectable effect

For their final analysis, the authors examined all the papers that met their criteria for inclusion in their review. This batch, consisting of 132 studies, included 10 of the 112 that the team had flagged as having potentially doctored images.

Analysis of these 10 studies alone assessed the test as 50% more effective at identifying depression-related symptoms than did a calculation based on the 122 studies without questionable images. These suspicious studies “do actually skew the results”, Kalliokoski says — although “not massively”, because overall variations in the data set mask the contribution from this small subset.

Examples from this study “cover pretty much all types of image problems”, Bik says, ranging from simple duplication to images that showed evidence of deliberate alteration. Using a scale that Bik developed to categorize the degree of image manipulation, the researchers found that most of the problematic images showed signs of tampering.

The researchers published their review in January in Translational Psychiatry without telling the journal that it was based in part on papers that included suspicious images. The journal’s publisher, Springer Nature, told Nature that it is investigating. (The Nature news team is editorially independent of its publisher, Springer Nature).

When they published their preprint the following month, the researchers included details of all the papers with suspicious images. They also flagged each study on Pubpeer, a website where scientists comment anonymously on papers. “My first allegiance is towards the [scientific] community,” Kalliokoski says, adding that putting the data out is the first step.

Bring reviews to life

The process of challenging a study’s integrity, giving its authors a chance to respond and seeking retraction for fraudulent studies can take years. One way to clear these muddied waters, says Bannach-Brown, is to publish ‘living’ systematic reviews, which are designed to be updated whenever papers get retracted or new research is added. She has helped to develop one such method of creating living reviews, called Systematic Online Living Evidence Summaries.

Systematic-review writers are also keen to see publishers integrate standardized ways to screen out dubious studies — rather than waiting until a study gets retracted.

Authors, publishers and editorial boards need to work together, Bannach-Brown says, to “catch some of these questionable research practices before they even make it to publication.”

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is social media really behind an epidemic of teenage mental illness?

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A teenage girl lies on the bed in her room lightened with orange and teal neon lights and watches a movie on her mobile phone.

Social-media platforms aren’t always social.Credit: Getty

The Anxious Generation: How the Great Rewiring of Childhood is Causing an Epidemic of Mental Illness Jonathan Haidt Allen Lane (2024)

Two things need to be said after reading The Anxious Generation. First, this book is going to sell a lot of copies, because Jonathan Haidt is telling a scary story about children’s development that many parents are primed to believe. Second, the book’s repeated suggestion that digital technologies are rewiring our children’s brains and causing an epidemic of mental illness is not supported by science. Worse, the bold proposal that social media is to blame might distract us from effectively responding to the real causes of the current mental-health crisis in young people.

Haidt asserts that the great rewiring of children’s brains has taken place by “designing a firehose of addictive content that entered through kids’ eyes and ears”. And that “by displacing physical play and in-person socializing, these companies have rewired childhood and changed human development on an almost unimaginable scale”. Such serious claims require serious evidence.

Haidt supplies graphs throughout the book showing that digital-technology use and adolescent mental-health problems are rising together. On the first day of the graduate statistics class I teach, I draw similar lines on a board that seem to connect two disparate phenomena, and ask the students what they think is happening. Within minutes, the students usually begin telling elaborate stories about how the two phenomena are related, even describing how one could cause the other. The plots presented throughout this book will be useful in teaching my students the fundamentals of causal inference, and how to avoid making up stories by simply looking at trend lines.

Hundreds of researchers, myself included, have searched for the kind of large effects suggested by Haidt. Our efforts have produced a mix of no, small and mixed associations. Most data are correlative. When associations over time are found, they suggest not that social-media use predicts or causes depression, but that young people who already have mental-health problems use such platforms more often or in different ways from their healthy peers1.

These are not just our data or my opinion. Several meta-analyses and systematic reviews converge on the same message25. An analysis done in 72 countries shows no consistent or measurable associations between well-being and the roll-out of social media globally6. Moreover, findings from the Adolescent Brain Cognitive Development study, the largest long-term study of adolescent brain development in the United States, has found no evidence of drastic changes associated with digital-technology use7. Haidt, a social psychologist at New York University, is a gifted storyteller, but his tale is currently one searching for evidence.

Of course, our current understanding is incomplete, and more research is always needed. As a psychologist who has studied children’s and adolescents’ mental health for the past 20 years and tracked their well-being and digital-technology use, I appreciate the frustration and desire for simple answers. As a parent of adolescents, I would also like to identify a simple source for the sadness and pain that this generation is reporting.

A complex problem

There are, unfortunately, no simple answers. The onset and development of mental disorders, such as anxiety and depression, are driven by a complex set of genetic and environmental factors. Suicide rates among people in most age groups have been increasing steadily for the past 20 years in the United States. Researchers cite access to guns, exposure to violence, structural discrimination and racism, sexism and sexual abuse, the opioid epidemic, economic hardship and social isolation as leading contributors8.

The current generation of adolescents was raised in the aftermath of the great recession of 2008. Haidt suggests that the resulting deprivation cannot be a factor, because unemployment has gone down. But analyses of the differential impacts of economic shocks have shown that families in the bottom 20% of the income distribution continue to experience harm9. In the United States, close to one in six children live below the poverty line while also growing up at the time of an opioid crisis, school shootings and increasing unrest because of racial and sexual discrimination and violence.

The good news is that more young people are talking openly about their symptoms and mental-health struggles than ever before. The bad news is that insufficient services are available to address their needs. In the United States, there is, on average, one school psychologist for every 1,119 students10.

Haidt’s work on emotion, culture and morality has been influential; and, in fairness, he admits that he is no specialist in clinical psychology, child development or media studies. In previous books, he has used the analogy of an elephant and its rider to argue how our gut reactions (the elephant) can drag along our rational minds (the rider). Subsequent research has shown how easy it is to pick out evidence to support our initial gut reactions to an issue. That we should question assumptions that we think are true carefully is a lesson from Haidt’s own work. Everyone used to ‘know’ that the world was flat. The falsification of previous assumptions by testing them against data can prevent us from being the rider dragged along by the elephant.

A generation in crisis

Two things can be independently true about social media. First, that there is no evidence that using these platforms is rewiring children’s brains or driving an epidemic of mental illness. Second, that considerable reforms to these platforms are required, given how much time young people spend on them. Many of Haidt’s solutions for parents, adolescents, educators and big technology firms are reasonable, including stricter content-moderation policies and requiring companies to take user age into account when designing platforms and algorithms. Others, such as age-based restrictions and bans on mobile devices, are unlikely to be effective in practice — or worse, could backfire given what we know about adolescent behaviour.

A third truth is that we have a generation in crisis and in desperate need of the best of what science and evidence-based solutions can offer. Unfortunately, our time is being spent telling stories that are unsupported by research and that do little to support young people who need, and deserve, more.

Competing Interests

The author declares no competing interests.

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Scientists made a six-legged mouse embryo — here’s why

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This six-legged animal isn’t an insect: it’s a mouse with two extra limbs where its genitals should be. Research on this genetically engineered rodent, which was published on 20 March in Nature Communications1, has revealed a way in which changes in DNA’s 3D structure can affect how embryos develop.

Developmental biologist Moisés Mallo, at the Gulbenkian Science Institute in Oeiras, Portugal, and his colleagues were studying one of the receptor proteins, Tgfbr1, in a signalling pathway that is involved in many aspects of embryonic development. The scientists inactivated the Tgfbr1 gene in mouse embryos about halfway through development to see how the change affected spinal-cord development.

Then, Mallo’s graduate student, Anastasiia Lozovska, came to his office to tell him she’d found that one of the bioengineered embryos had genitals that looked similar to two extra hind limbs. Her finding sent the research down an unexpected path. “I didn’t choose the project, the project chose me,” Mallo says.

3D reconstruction of the limb skeleton of a Tgfbr1-cKO fetus obtained by OPT and after segmentation of the limb skeleton. Extra hindlimbs are in magenta. Ossification shown in yellow.

A 3D reconstruction of the skeleton of the genetically altered embryo shows its extra and normal limbs (magenta and turquoise, respectively).Credit: Anastasiia Lozovska et al/Nat. Comms

Researchers have long known that, in most four-limbed animals, both the external genitalia (penis or clitoris) and hind limbs develop from the same primordial structures.

When Mallo’s team looked further into the six-legged mouse phenomenon, they found that Tgfbr1 directs these structures to become either genitalia or limbs by altering the way that DNA folds in the structure’s cells. Deactivating the protein changed the activity of other genes, resulting in extra limbs and no true external genitalia.

The researchers hope to determine whether Tgfbr1 and its relatives affect DNA structure in other systems such as metastatic cancer, and in immune function. They are also examining whether the same mechanism underlies the development of the reptilian hemipenis, a double penis that, in snakes, forms from primordial organs in lieu of legs.

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Overcoming low vision to prove my abilities under pressure

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Dr Kamini Govender, at the University of the Free State, South Africa, outside the Microbiology and Biochemistry department.

Postdoctoral fellow Kamini Govender developed her own strategies to deal with a low-vision disability and gain work–life balance.Credit: University of the Free State, South Africa

During her PhD in pharmaceutical chemistry at the University of KwaZulu-Natal in eThekwini, South Africa, Kamini Govender helped to develop a greener method for human-insulin biosynthesis in bacteria — one that avoided the toxic solvents typically used1. During the COVID-19 pandemic, she collaborated with South African colleagues at the University of KwaZulu-Natal and the University of Zululand to screen antiviral drugs2 and test the effectiveness of hand sanitizers3. Alongside her educational and scientific goals, she has navigated and conquered many barriers arising from a rare genetic eye condition called retinitis pigmentosa that results in a narrow field of vision.

Now a postdoctoral fellow at the University of the Free State in Bloemfontein, South Africa, Govender investigates biocatalysis pathways that represent a more sustainable, renewable and economical method than routine catalysis. An advocate for equity in science, she tells Nature about some of the challenges she has faced, the stigma she still experiences and the coping mechanisms she has developed for life in the laboratory and beyond.

At what point did you learn about your eye condition?

In grade nine, at the age of 14, I was diagnosed with retinitis pigmentosa, a condition of the retina cells that affects peripheral and night vision. My central vision is OK up to a certain point — up to my nose. If my eye is not directly on an object, I can’t really see it. My peripheral vision is severely constricted. So that’s my challenge.

It hasn’t been easy. It was a struggle to accept the fact that I can’t do certain things that other people can. There is a lot of stigma around being disabled. It took me a while to actually say, at university, that I have this condition. I think I finally accepted the fact that I have low vision towards the end of my PhD.

Still, sometimes I feel aware of people judging me. When I went to the 72nd Lindau Nobel Laureate Meeting in Germany last June, dedicated to physiology and medicine, I struggled with not wanting to use my white stick. I was self-conscious about it. But if I don’t walk with the stick, I’m very likely to get hurt. So I had to come to terms with using it. I’ve realized that I am a very proud person — so it can be hard to seek help.

How did you manage your condition during your studies?

Throughout my time at the University of KwaZulu-Natal, I tried to compensate for my disability by working longer hours, including weekends or at night. In certain instances, that led to migraines or eye pain. During my undergraduate degree, I did tell the disability unit at the university, and I was given extra time to complete exams. But once I went into my honours, master’s and PhD studies, I needed other types of support, so I developed my own strategies.

What kinds of strategy have you developed?

I use my laptop to zoom in on text when reading papers. But it’s extra challenging. It takes me longer to read: sometimes, I inadvertently skip over words and I have to take breaks to avoid eye strain. I have tried text-to-speech readers, but I find that to be a slow way of consolidating information from peer-reviewed academic papers. Often, I don’t have time to listen to the whole paper. I usually want to be more selective. For tasks such as this, maybe artificial intelligence will be helpful in the future for screening information more quickly.

As for managing lab work, I have found my own coping mechanisms. For example, when doing agarose gel electrophoresis, instead of using a clear casting tray, I use a black casting tray to see contrast better, because my depth perception hinders the loading of the gels. But it still takes me longer than it takes my peers.

When performing lab procedures, I clear my bench, and work with equipment and materials directly in front of me.

Now, doing biocatalysis for my postdoctoral research, I’m working with enzymes. So I’m working with a lot of small tubes that I use for polymerase chain reactions, sampling and gas chromotograpy, as well as doing biotransformations, or transfers between tubes. Before I start, I write down everything I will need in my lab book. I do a lot of planning to set everything up.

Sometimes, when I drop things on the floor, it will take me five minutes to spot a tube, because it’s clear. There are always challenges, but I’ve tried to overcome them.

As a student, I dedicated a lot of energy and felt a lot of pressure to prove myself. I worked very hard and persevered. But that meant that during my PhD at the University of KwaZulu-Natal, my work–life balance suffered. After I finished my doctorate in 2020, I had burnout because I had been pushing myself to finish in three years. I was trying to keep up an unsustainable pace.

How did you recognize this burnout — and reverse it?

From the constant, unrelenting work — long days, including weekends — I had fatigue. I experienced exhaustion. I was tired, and depressed. I had vitamin D deficiency, possibly from spending so much time in the lab that I wasn’t getting enough sunlight.

Over time, I have learnt to practise better self-care by knowing when to stop. I began to exercise and adopted a better diet. I learnt to relax more, by listening to music, walking outdoors and spending time at the beach. I recently started yoga. That’s helped me to calm down and meditate.

I also like cooking. It reminds me of being in the lab, except that you get to eat whatever you cook. The downside — in both cases — is the dishes, which I don’t like!

Is there sufficient support in academia for students with disabilities?

I feel that more needs to be done to include people with disabilities. In the sciences, few of these people make it to the level that I have, because of all the hurdles they come across. It’s easier to quit and give up.

There is a kind of narrow-mindedness. Certainly, in South Africa, and maybe globally, there needs to be more education, awareness, acceptance and empathy around people with disabilities.

There are policies in place for people with disabilities, but in the higher levels of academia, such as in PhD programmes and beyond, there is very little representation. My disability is not something that you can see. So if I don’t tell you about it, you will never know.

I would like to find channels, such as speaking at events to empower women and girls in the sciences, and chairing conference panel sessions to promote inclusivity in science, such as at the World Forum for Women in Science. Those would be good places to start speaking up. I want to encourage other people with disabilities, and girls, to study science.

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This super-Earth is the first planet confirmed to have a permanent dark side

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An artist's illustration of the exoplanet LHS 3844b.

One side of the planet LHS 3844b (artist’s impression) is thought to be in perpetual daylight.Credit: NASA/JPL-Caltech/R. Hurt (IPAC)

Imagine if it were always night-time in the Western Hemisphere and always daytime in the Eastern Hemisphere, and the only way for Londoners to see the Sun was to fly to somewhere like Tokyo.

In a study published today in The Astrophysical Journal, scientists provide the most compelling evidence to date that a planet has this feature1, called tidal synchronization or 1:1 tidal locking. Astronomers think that many exoplanets are similarly ‘stuck’ — including most of the candidates with potential to sustain life.

“This thing that has been theoretical now feels real. This is actually what these planets look like,” says Nicolas Cowan, an astronomer at McGill University in Montreal, Canada, and a co-author of the study.

Two sides of the story

When a planet orbits very close to its star, its near side experiences a much stronger pull than its far side does. Over time, the imbalance, called a tidal force, is thought to slow the planet’s rotation until it is in perfect synchrony with its orbit. This means that the time taken for the planet to rotate once on its axis is the same as that needed for it to travel once around its star. The Moon is thought to have undergone this process, which explains why it has a ‘far side’ that never faces Earth.

Many exoplanets are thought to be 1:1 tidally locked on account of their close proximity to their host star, but that status is difficult to prove. Measuring an exoplanet’s orbit is straightforward; pinning down its rotation is much harder, especially if the planet has an atmosphere that obscures its spinning surface from view.

The scientists turned to a particular exoplanet that is close to its star to finally prove the tidal locking hypothesis. In 2019, researchers using the Spitzer Space Telescope measured the intensity of light coming off this planet2, called super-Earth LHS 3844b. Cowan and his co-authors realized that these measurements could tell them the temperature of the planet’s Earth-facing surface, because the planet probably has no atmosphere.

Planets that are not tidally synchronized heat up as a result of the conflict between their rotation and the massive tidal force exerted by their star. The team found the surface of LHS 3844b to be relatively cool — as would be expected for a tidally synchronized planet.

Compelling case

“This is the most compelling evidence one could possibly gather with currently existing information or instrumentation,” says Emily Rauscher, a theoretical astrophysicist at the University of Michigan in Ann Arbor.

Astronomer Emily Whittaker at the University of California, Los Angeles, notes that the paper assumes LHS 3844b has no atmosphere, but that a 2022 study which they co-authored left room for a thin, Earth-like atmosphere3. They say this could complicate the new paper’s argument, but agree that the evidence the team has laid out does point to tidal synchronization.

More evidence is expected soon. “James Webb is great for this,” says Cowan. The James Webb Space Telescope (JWST) will allow astronomers to study the rotation of exoplanets orbiting slightly further from their stars than LHS 3844b does. Astronomers now think that such planets, which can sustain an atmosphere and mild temperatures, constitute most of the Milky Way’s habitable real estate. If the JWST finds them to be tidally synchronized like LHS 3844b, Cowan says, then “probably a good fraction of planets, certainly most habitable planets, are tidally locked”.

As for in what sense such planets could be habitable, Cowan can’t currently speculate. These worlds “don’t have tides, or seasons or day–night cycles”, he says. “Could you get the same kind of diversity and complexity of life evolving? I have no idea.”

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crypto-funded researchers grapple with FTX collapse

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Sam Bankman-Fried, former chief executive of the now-bankrupt cryptocurrency exchange FTX, has been sentenced to 25 years in prison after being convicted of fraud and money laundering last year.

Meanwhile, the broader fallout from the collapse of FTX continues — and has ramifications on research that his organizations funded.

Bankman-Fried co-founded FTX in 2019. Before its collapse, the company allocated tens of millions of dollars to effective altruism — a movement that involves wealthy companies or individuals donating funds to charitable causes — and to tackling long-term risks to humanity, such as climate change.

This included giving money to research organizations and scientists, many of which now face the prospect of returning the funds to avoid possible legal action.

One research organization that did not want to be named for sensitivity reasons said that the situation was a “source of great stress and confusion”, adding that it was allocated funds “in good faith” but was now being pressed to return the money.

Others are concerned that news of the fraud has damaged the perception of effective altruism itself. “It appeared, up until the fraud was revealed, that [FTX] had a genuine interest in making the world a better place,” says Jake Eberts, communications director of the US-based medical-research advocacy organization 1Day Soone. “It was frustrating to see how the community had been led astray.”

Future fund

At its peak, FTX’s parent company, the FTX Foundation, was responsible for managing more than US$700 billion in annual cryptocurrency trading and was valued at $32 billion. But in November 2022, Bankman-Fried was found to be siphoning money to a sister company and himself, leading to a mass withdrawal of funds by FTX customers and the company declaring itself bankrupt later that month. Many people lost their investments in the collapse.

Before any fraudulent activity came to light, FTX had announced it would allocate some of its money to scientific organizations, charities and individual researchers, making “grants and investments to ambitious projects to improve humanity’s long-term prospects” through a body called the FTX Future Fund.

The fund awarded more than 250 grants from March 2022. One of the largest recipients was Lightcone Infrastructure, a California-based company that promotes projects to tackle long-term goals for humanity and runs an online forum for effective altruists, called LessWrong. “In total, we received something close to $4 million,” says Oliver Habryka, the company’s chief executive. The subsequent collapse of FTX “had a huge effect on us”, he says. “Currently half of my job is probably still dealing with that fallout.”

The FTX contribution amounted to “around 50 to 60%” of Lightcone’s total funds, says Habryka. Some of the money helped to pay for the Lightcone Offices in Berkeley, California, which had to close in early 2023; some was allocated to running LessWrong.

By the time the fraudulent activity came to light, many of the funds had already been spent, leaving Lightcone in a difficult situation. “We are talking to the FTX estate about what are reasonable settlement numbers and how we can return things,” says Habryka. “We were very heavily impacted by FTX. I’ve put [in] a decent chunk of my personal money to keep the organization afloat. But we have no chance of giving back most of the money because it was already committed, and I don’t know where we’d get the money from.”

Cancelled plans

1Day Sooner received a considerably smaller sum from the FTX Future Fund than Lightcone — less than $400,000, accounting for about 4% of the organization’s funding — which they decided to return when news of the fraudulent activity broke. Losing the money still had an impact, says Eberts. “It did require curtailing plans.”

The organization had planned to use the funds to support future pandemic preparedness in Africa and take steps towards a pandemic insurance fund for developing countries. The idea was to create a mechanism in the World Health Organization that industrialized countries would contribute to, he says. “The Future Fund grant would have been used on “lobbying to get this proposal [discussed] at the World Health Assembly”.

Those plans have been cancelled. “We decided to shelve indefinitely the pandemic insurance fund,” says Eberts. “It was a moonshot in a lot of ways, but the required funding was not forthcoming from other funders.” When news of the FTX fraud broke, “we were all devastated”, he adds.

Sawyer Bernath, executive director of the Berkeley Existential Risk Initiative (BERI) in California, has been through a similar experience. The Future Fund awarded his organization, which seeks to tackle long-term threats to humanity through research collaborations, nearly $400,000 in grants, about 10 percent of BERI’s total funding, for five projects. After the bankruptcy was announced, BERI decided to return the money. For three projects, the cash had not yet been spent. For “the remaining two, we did end up spending because it was very time-sensitive,” says Bernath. “When we did decide to return everything, we used some of our general funds to fill in.”

Operationally, returning the funds has not been too much of a problem, says Bernath, but the “psychological impacts” have been big. “In terms of the existential-risk community, we were really gearing up to this big change with all the money that FTX was committing to things,” he says. “Right at the upswing where everyone was excited, all of a sudden it turned out to be all fake.”

The bankruptcy came as a surprise, and he now finds that there is less funding available from other philanthropic organizations. “When FTX was offering all this money there was a push for mega projects, [worth] $100 million,” he says. “No one talks about that any more.”

The fallout is likely to continue. “Many of the charities that received this money have been negatively affected,” says Bernath, noting that FTX customers also suffered losses. “Many lost all of their life savings, because they felt like this was a trustworthy company, as did we,” he says. “I hope they’re able to get that back.”

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