Dear James: I Can’t Stop Listening to Wellness Podcasts

In the summer of 2018, 59-year-old David Gould went for his annual checkup, expecting to hear the usual: Everything looks fine. Instead, he was told that he was newly—and oddly—anemic.Two months later, Gould began to experience a strange cascade of symptoms. His ankles swelled to the width of his calves. The right side of his face became so bloated that he could not open his eye. He developed a full-body rash, joint pain, fever, and drenching night sweats. His anemia worsened, and he was requiring frequent blood transfusions. Gould’s physicians were baffled; he was scared. “I started to get my will and affairs in order,” he told me.Almost two years into his ordeal, Gould learned of an initiative at the National Institutes of Health that focuses on solving the country’s most puzzling medical cases. He applied for the program, and his file soon reached the desks of Donna Novacic and David Beck, two scientists then at the NIH. The pair had helped identify a still-unnamed disease, which they had tied to a particular gene and to a particular somatic mutation—a genetic change that had not been passed down from a parent and was present only in certain cells. Gould’s symptoms seemed uncannily similar to those of patients known to have this new disease, and a blood test confirmed the scientists’ hunch: Gould had the mutation.The NIH doctors reached Gould by phone the day he was set to start chemotherapy, which had proved dangerous in another person with the same disease. A bone-marrow transplant, they told him, could be a risky but more effective intervention—one he ultimately chose after extensive discussions with his own physicians. Within weeks, he was no longer anemic, and his once unrelenting symptoms dissipated. A few months after his transplant, Gould felt normal again—and has ever since.When the NIH team published its findings in 2020, the paper created a sensation in the medical community, not only because it described a new genetic disease (now known as VEXAS) but also because of the role a somatic mutation had played in a condition that appeared in adulthood. For many doctors like me—I practice rheumatology, which focuses on the treatment of autoimmune illnesses—the term genetic disease has always implied an inherited condition, one shared by family members and present at birth. Yet what physicians are only now beginning to realize is that somatic mutations may help explain illnesses that were never considered “genetic” at all.Somatic mutations occur after conception—after egg meets sperm—and continue over our lives, spurred by exposure to tobacco smoke, ultraviolet light, or other harmful substances. Our bodies are adept at catching these mistakes, but sometimes errors slip through. The result is a state called “somatic mosaicism,” in which two or more groups of cells in the same body possess different genetic compositions. In recent years, the discovery of conditions such as VEXAS have forced scientists to question their assumptions about just how relevant somatic mosaicism might be to human disease, and, in 2023, the NIH launched the Somatic Mosaicism Across Human Tissues (SMaHT) Network, meant to deepen our understanding of genetic variation across the human body’s cells.Over the past decade, genetic sequencing has become dramatically faster, cheaper, and more detailed, which has made sequencing the genomes of different cells in the same person more practical and has led scientists to understand just how much genetic variation exists in each of us. Tweaks in DNA caused by somatic mutations mean that we have not just one genome, perfectly replicated in every cell of our body. Jake Rubens, the CEO and a co-founder of Quotient Therapeutics, a company that uses somatic genomics to develop novel therapies, has calculated that we each have closer to 30 trillion genomes, dispersed across our many cells. Two adjacent cells, seemingly identical under the microscope, can have about 1,000 differences in their genomes.One medical specialty has long understood the implications of this variation: oncology. Since the 1990s, doctors have known that most cancers arise from somatic mutations in genes that promote or suppress tumor growth, but discoveries such as VEXAS are convincing more researchers that these mutations could help explain or define other types of illnesses too. “We have the data that says many conditions are genetic, but we don’t understand the machinery that makes this so,” Richard Gibbs, the founding director of the Human Genome Sequencing Center at Baylor University, told me. “Maybe somatic mutations are the events that serve as the missing link.” James Bennett, a SMaHT-funded researcher, is confident that the more scientists look at mutations in different cells of the body, the more connections they are likely to find to specific diseases. Until recently, genetic sequencing has been applied almost exclusively to the most accessible type of cells—blood cells—but, as Bennett told me, these cells sometimes have little to do with diseases affecting various organs. The result of SMaHT, he said, will be that “for the first time, we will have an atlas of somatic mutations across the entire body.”The brain, for instance, is often thought of as our most genetically bland organ, because adult brain cells don’t replicate much, and it has rarely been subject to genetic investigation. But in 2015, scientists in South Korea demonstrated that people with a disease called focal epilepsy can develop seizures because of somatic mutations that create faulty genes in a subset of brain cells. This finding has led researchers such as Christopher Walsh, the chief of the genetics and genomics division at Boston Children’s Hospital, to consider what other brain disorders might arise from somatic mutations. He hypothesized that somatic mutations in different parts of the brain could, for instance, explain the varied ways that autism can affect different people, and, in a series of studies, demonstrated that this is indeed the case for a small portion of children with autism. Other researchers have published work indicating that somatic mutations in brain cells likely contribute to the development of schizophrenia, Parkinson’s disease, and Alzheimer’s disease (though, these researchers note, mutations are just one of several factors that contribute to these complex conditions).As much as these mutations might help us better understand disease, some scientists caution that few other examples will be as tidy as cancer, or VEXAS. Yiming Luo, a rheumatologist and genetics expert at Columbia University Irving Medical Center (which I am also affiliated with), told me told me that finding germ-line mutations, which are changes to DNA that a person inherits from a parent’s egg or sperm cell, is much easier than finding significant somatic mutations. A germ-line mutation looks like a red ball in a sea of white balls—difficult, but not impossible, to spot; a somatic mutation is gray, and more easily blends in. “In genetics, it can be hard to separate sound from noise,” Luo said. And even when a scientist feels confident that they have found a real somatic mutation, the next steps—understanding the biologic and clinical implications of the mutation—can take years. Oncologists have had a head start on translating somatic-mutation science into practice, but doing the same in other specialties—including mine—may prove challenging. Dan Kastner, a rheumatologist and one of the lead NIH scientists responsible for the discovery of VEXAS, told me that, although cancer involves mountains of cellular clones that are easily identifiable and begging to be genetically analyzed, pinpointing a single cell that drives, say, a rheumatologic disease is much harder. The story of VEXAS was remarkable because the mutation causing the disease was found in blood cells, which are easy to sample and are the cells most often tested for genetic variation. Finding other disease-causing somatic mutations in rheumatology and related specialties will take skill, cunning, and a willingness to test cells and organs throughout the body.Yet my colleagues and I can no longer ignore the possibility that somatic mutations may be affecting our adult patients. VEXAS, which was unknown to doctors five years ago, may be present in 15,000 people across the U.S. (making it as common as ALS, also known as Lou Gehrig’s disease); if its global prevalence matches that of this country, it could affect about half a million people worldwide. And if, while seeking diagnoses for patients, we stop and consider the possibility that diseases we already know are linked to somatic mutations, this could help improve our practice.Recently, I was called to evaluate a man in his 60s whose medical history was littered with unexplained symptoms and signs—swollen lymph nodes, joint pain, abnormal blood-cell counts—that had stumped his team of specialists. I was struck that his skin was riddled with xanthomas—yellowish, waxy-appearing deposits of fatty tissue—even though his cholesterol levels were normal, and I learned through Googling that among their potential causes was Erdheim-Chester disease, a rare blood-cell disorder that arises due to somatic mutations.I wondered whether I was losing perspective, given my newfound obsession, but because the patient had already had biopsies of a lymph node and his bone marrow, we sent those off for molecular testing. Both samples came back with an identical finding: a somatic mutation associated with Erdheim-Chester. When I emailed a local expert on the disease, I still expected a gentle admonishment for being too eager to invoke an exceedingly uncommon diagnosis. But within minutes, he replied that, yes, this patient likely had Erdheim-Chester and that he would be happy to see the man in his clinic right away.I sat at my computer staring at this reply. I could not have even contemplated the likely diagnosis for this patient a year ago, yet here it was: an adult-onset condition, masquerading as an autoimmune illness, but actually due to a somatic mutation. The diagnosis felt too perfect to be true, and in some ways, it was. Fewer than 1,500 patients have ever been found to have this particular condition. But, at the same time, it made me wonder: If rethinking genetic disease helped this one person, how many others out there are waiting for a similar answer?

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The sun is setting on computers. In October, Google finally—finally—rolled out a new black-background view for its Calendar app. This is just the latest in a string of recent software darkenings. In July, Wikipedia went light-on-dark. And a few years before that, we got dark-theme Google Search. Since 2017, night has fallen on Slack, Reddit, YouTube, Twitter, and mobile Gmail too. Even Microsoft went dark. One by one, the bright, white backgrounds that have defined these and all computer interfaces since the advent of the Macintosh have been slipping into the shadows.Dark mode has its touted benefits: Dimmer screens mean less eye strain, some assert; and on certain displays (including most smartphones), showing more black pixels prolongs battery life. Dark mode also has its drawbacks: Reading lots of text is more difficult to do in white-on-black. But even if these tradeoffs might be used to justify the use of inverted-color settings, they offer little insight into those settings’ true appeal. They don’t tell us why so many people suddenly want their screens, which had glowed bright for years, to go dark. And they’re tangential to the story of how, in a fairly short period of time, we all became creatures of the night mode.Computer programmers, for their part, have always liked the dark. Back when offices were the only places to work, some software companies housed their engineers in what I remember being called “programmer pits”: rooms with closed doors where all the lights were extinguished. In open-plan workplaces, where the pits could not exist, programmers who preferred darkness would go to great lengths to create or preserve it. I recall some plotting to remove the bulbs from overhead lights near their workstations.In the 1990s and early 2000s, I managed a large team of software engineers. They wrote programs for computer desktops, the web, and the handheld devices that predated smartphones. I remember one of them was so averse to lighting that he draped a thick blanket over his monitor and torso, creating a makeshift cave for work. Another built a lighttight cot underneath his cubicle in which to take breaks to recover from the oppressive sun that poured in through office windows. Others merely chose to work very early or very late, under the natural shroud of night.Why? If I’d asked them, they would probably have said: to reduce distractions and improve focus. Programming a computer is a bit like repairing a very tiny machine with precision tools while looking under a microscope. Quiet and calm help facilitate that process. Programmers may also just prefer the dark. (Some have argued that people with “Aspergers-like” tendencies, which are associated with sensitivity to bright lights, may be especially well suited to the tech industry.)But even with the environment dimmed, one source of light persists: the computer itself. Its bright glare could potentially disrupt the very act of writing the programs it might run. Perhaps that’s why code-editing software has long offered white-on-black displays or other dimmed-out custom color themes. If you look at depictions of programmers at work in television or film, you’re likely to see white text on black screens. It’s a visual sign of computer professionals at work.Those of us old enough to remember using command-line text on DOS- or Unix-based computers will recall that light-on-dark displays were, at first, the standard. Surely some of that color scheme’s newfound appeal is pure nostalgia, at least among those users who once typed out documents in WordPerfect or played text-only adventure games such as Zork. To call it “dark mode,” as we do today, and sell it as a wellness tool is a somewhat recent innovation.[Read: I wrote this on a 30-year-old computer]Starting about 10 years ago, the option of a dark or dimmer background began to be included as a system-wide setting on laptops and smartphones. Microsoft launched its Windows “Night Light” mode, with warmer colors, in 2017; Apple followed with its own Dark Mode shortly after. Once that happened, individual software applications followed suit. The light-on-dark appearance could now be marketed as a way to heal your circadian rhythms, but its essential function was the same as ever: a softer, less oppressive glow for people who might be staring at their screens for many hours at a time.The number of people doing so was increasing every day. Even 20 years ago, a computer was still a tool used only occasionally. Desktop computers sat on desks, to be consulted when needed. Even at work, many actions that are now carried out only via computer—such as filing expense reports or taking part in mandatory office trainings—happened in meatspace instead. Home life was also a mixed-media affair. Television was viewed on a television set, through a set-top box or DVD player. Voice calls were made on phones still found on desks or attached to walls. And other ordinary activities, such as paying bills and managing kids’ school affairs, still were carried out on paper, in person—not online.[Read: Universities have a computer-science problem]Between the early aughts and the late 2010s, the rest of humankind caught up with computer programmers. Communication now takes place on a screen. So does knowledge work. Also shopping, entertainment, and the management of daily life. According to one report, Americans checked their phones more than 200 times a day this year, an increase of 40 percent over last year. In short, an ordinary person’s habits of computer use have grown to be a lot more like those of the previously strange guys who were writing software with me at the dawn of the internet.So dark modes spread to serve our changing circumstances. There’s no longer any need to drape a blanket on your office desk; soon enough, every app will achieve this effect on its own. Software companies may even start competing to produce the most effective artificial night. It’s now gotten to the point where Microsoft can engage in dark-mode ballyhoo: Its own “Black” theme “provides the darkest experience,” the company boasts; “if you’re in search of dark mode, this is the theme for you.”Maybe the dark-mode age was inevitable. The bright glow of computers was tolerable—even thrilling—when it still felt new, but as lit-up screens suffused our every waking act, their light was doomed to overwhelm us. Given that software developers are the people who develop software, and their software-making software had been in dark mode from the start, the latest trend should come as no surprise. Of course darkness would have spread from their desktops to everyone’s. From day into night, we are all programming computers now.

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