Jacob Yale has a lot in common with many 16-year-olds. His favorite pastime is playing video games, especially those involving his favorite NBA team, the San Antonio Spurs. He loves hitting the tennis courts. His favorite food is pizza.
He’s also autistic. It means it’s tough for him to keep eye contact during a conversation. He has friends, but he also has trouble reading behavioral context clues. And that can make him anxious in social situations. In that respect, Jacob is not alone: Many autistic patients have difficulty connecting with others, to sense when someone is sad or frustrated or annoyed.
Randy Yale, Jacob’s dad, said Jacob's school has been helpful, giving him extra time to finish tasks and offering him help when he needs it. But Randy said one thing the school can’t do is help Jacob with his anxiety. “One of the ways that the spectrum presents itself is that you don’t always pick up on social cues,” Randy explained. “When Jacob was in Cub Scouts, I felt like he looked like an outsider. He’d always just stand at the perimeter of a group activity.”
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While Jacob has come a long way from his Cub Scouts era, elements of his social blind spots remain. He prefers activities that he can do by himself—like playing those NBA games on his phone.
So on a gray April afternoon, during Jacob’s spring vacation, he took a break from virtual hoops and spent time instead at Yale University’s Child Study Center, where he is working with researchers on experimenting with a pill that purports to help autistic patients with how they socialize.
A pill, balovaptan, could help with some of the sociability problems autistic people like Jacob face. It’s so promising that it’s been named a breakthrough therapy by the Food and Drug Administration, which means in initial, early trials, it’s shown not only success but also a potential treatment pathway for a disorder that the medical community had, until now, struggled to both understand and treat.
Jacob is among many children in America testing the drug and whether it works: Does it make working in groups easier? Does it make starting and maintaining friendships more possible? Does it make eye contact and engaging in small talk and reading behavioral cues simultaneously—all hallmarks of how people interact with each other that autistic patients struggle with—just a little less awkward and painful?
For Jacob and millions of other people with autism facing these issues daily, it could—and more important, it could be the game changer autism research desperately needs.
Roger Jou is an assistant clinical professor at the Yale Child Study Center. He’s one of 30 site investigators across the United States on what’s called the Aviation study, which is looking to study balovaptan on kids who are autistic but high-functioning, meaning that patients don't have a formal intellectual disability.
“Although there are medications available to help manage such secondary conditions, we’ve yet to find any that address the social and communication skill issues at the heart of autism,” the study’s site states, explaining its American-based study is searching for 300 kids between the ages of 5 and 17 to join and examine how balovaptan could help high-functioning autistic children overcome social anxiety and related issues.
Jou didn’t plan on being at the cutting edge of autism research. At the University of Pittsburgh, Jou started getting interested in the interplay between brain and behavior—how neurology and the body worked in step for what we perceived as healthy behavior, but how missteps in that close partnership sent behavior haywire.
He thought he could use brain imaging like magnetic resonance imaging to visually see exactly when and where those missteps occurred. But the brain is more confusing and knotted than a maze, and to this day—despite cutting edge imaging technology and advances in medicine that have harbored potential cures to mysterious illnesses—we still don’t understand it.
That’s also why pseudoscience has often derailed autism research. Vaccinations have long been blamed as potential instigators of the condition, with the anti-vaxxing movement gaining steam in recent years and leading to a separate health crisis of returning vicious diseases that we’d thought were long dead. Science hasn’t helped either, often linking odd health aspects—pregnancy, drinking milk—with a “rise” in autism, which only serves to panic parents. Among children who show signs of autism, quack therapies— “chelation,” or intentional mercury poisoning meant to bind and remove chemical imbalances, clay-based detox baths, stem cell transplants in shoddy clinics, exorcism, intestinal worms, and more horrifying attempts to “rid” a child of the condition—have been used, and while the FDA has cracked down on these “cures,” there isn’t much in the way of explaining autism that it can combat with. It doesn’t help that autism and violence are falsely linked in the media, causing fear-mongering.
Jou, along with his colleagues, is hoping his research will help demystify the condition. He realized through looking at thousands of brain scans in pursuit of his Ph.D. that nowhere was the brain’s role in determining how the body acted more murky and confusing than in autism. “Autism has always been fascinating to me because it involves something [sociability] that we innately do without thinking,” he told me one afternoon in a fluorescent-lit classroom at the Yale Child Study Center decorated with children’s paintings. “To me, that was so fascinating, that something we’re born doing and don’t think about, that we do automatically, that those skills and abilitIes can be different in other people and that those differences can be due to underlying neurobiology.”
To Jou, autism should be comprehensible the way strokes are. We know what triggers the chain of events that cause a stroke: A blocked artery or burst vessel stops blood from getting to the brain leads to a stroke. Autism, similarly, should follow the same process: Some biochemical difference should set off a series of events that leads to autism.
The problem is, we don’t know what that difference could be. More confusingly, autism is a spectrum, which means some of its patients display signs of it that are almost ignorable to the untrained eye, and others are dependent on caretakers for their day-to-day experiences.
“For [non-autistic people] growing up, you really do these things automatically—trying to infer other people’s mental states, using their body language and behavior to infer what’s inside their thought process, looking at their eye movements,” Jou said. “That’s an automatic thing. But we don’t know why that’s not automatic here.”
That was what Jou found so fascinating—the fact that something so automatic, so innately human, seemed not to click for a group of people and also show up in varying degrees. And that we can’t seem to figure out what the hiccup is in the neural mechanism makes understanding the condition and tailoring a way to help autistic people operate in the modern world even more pressing, according to Jou. “No one intervention is good for everyone,” Jou said. “It’s kind of like depression medication: You don’t prescribe one medicine, you need to tailor an intervention.”
In 2015, at F. Hoffman-LaRoche Laboratories in Basel, Switzerland, Federico Bolognani, a researcher specializing in autism, was leading a group of scientists working on an innovative project with a moonshot goal: develop a pill that could address the next frontier of neuroscience. The lab, along with the biopharmaceutical company Genentech, has had a long history of exploring the type of head-scratching medical mysteries of the brain that have baffled doctors and researchers alike.
“There is no known cure and there are currently no approved medicinal therapies which treat the core characteristics of autism such as restrictive interests and communication, repetitive behaviors, [and more],” Bolognani told The Daily Beast in an email.
But there was a clue, a possible pathway that could perhaps help ease the social anxiety experienced by many people with autism. In the years after World War II, a Chicago-born biochemist, Vincent du Vigneaud, devoted his work to understanding the chemical building blocks of hormones produced within the body. Du Vigneaud initially looked at insulin and the role sulfur played in the hormone so crucial to the regulation of glucose in the blood that patients whose pancreas couldn’t properly regulate it would suffer from diabetes, sometimes even death if not properly monitored.
That led du Vigneaud to look at other hormones that had sulfur swirled into their building blocks, for which he would later go on to win the Nobel Prize in chemistry in 1955. The posterior pituitary gland, nestled in the rear of the pituitary glands, released sulfur-containing hormones at the direction of the brain’s control center, the hypothalamus. One of these hormones was oxytocin, which would garner fame as the “love hormone,” or what was released when a person bonded with another. That butterflies-in-the-stomach feeling, that fierce parental protection of a newborn, that crazy in love heart-eye emoji—it was helped along by sulfur in oxytocin.
But du Vigneaud found another hormone that seemed to have a chemical role in our bonding relationships and social interactions: vasopressin. Vasopressin was mysterious, a bit of a wallflower compared to its more flamboyant hormonal cousin oxytocin. Like oxytocin, vasopressin was a sulfur-containing hormone that traveled from the hypothalamus, sent to the body by the posterior pituitary gland for two important, if yawn-worthy, roles: It regulated pH levels so the kidney wouldn’t fail; and it squeezed the arterioles that led to capillaries, raising blood pressure so that blood could flow through.
For decades, vasopressin was thought to just be that: a sort of behind-the-scenes crew captain that maintained the body’s plumbing and quietly ensured that its alleyways wouldn’t collapse and send the body into a biochemical storm. But in the late 1990s, biochemists began describing oxytocin’s role in maternal bonding and falling in love, making oxytocin part of the common parlance. Quietly, though, vasopressin emerged as oxytocin’s partner in crime, potentially working in concert with oxytocin to help animals bond with each other.
The first studies that showed vasopressin could be playing background social matchmaker involved the prairie vole, a rodent about the size of a mouse. Scientists found that withholding vasopressin sometimes led prairie voles to mate without bonding and flattened parental bonding (in some voles, it led to an increase in self-grooming). Curiously, some studies even showed that vasopressin played a role in helping voles mediate aggression and social bonding with fellow voles of the tribe.
These were voles, to be sure, not humans. But the studies raised a key question: Did vasopressin seemed to have an oxytocin-like bonding role, separate from its clinical front-desk job, that helped humans bond?
It seemed so, with researchers calling it the “dark matter of social neuroscience.” But researchers began to wonder too how the voles’ antisocial behavior without vasopressin—the seeming inability to bond with others yet otherwise normal mating behaviors tinged with social hiccups—could potentially be related to autism in humans. Could vasopressin be the missing link?
At Roche, Bolognani and his team certainly think that could be the case. A few years ago, they began developing balovaptan, which prevented vasopressin from binding to its receptor, which would prevent vasopressin’s normal operations in the brain.
Initial trials were almost immediately promising. Bolognani said autistic individuals who previously had had trouble communicating and bonding with others seemed to be able to do so. “[Balovaptan] is the first medicine to demonstrate improvements in socialization and communication in a large controlled multi-center Phase II trial in people with autism,” he said. “The current available treatments that are used to help improve social behaviors are non-pharmacological interventions, such as behavioral and developmental therapies.”
That balovaptan—a daily pill—shows promise in helping autistic people with an aspect of their lives that often causes them isolation is remarkable to say the least. Autistic individuals, until now, have relied on a regimen of cognitive and behavioral therapies to help integrate them into the “normal” world.
That’s been helpful thus far. And as we know, patients do not universally express autism—Jacob is high functioning and can probably look forward to being an independent adult. But researchers have continued to search for the biochemical reasoning for autism and whether there is in fact a way to address what seems to be a common symptom of awkwardness, trouble being empathetic, and relating to others. Might a pill help with that?
Bolognani said balovaptin’s role is to “[modulate] key social behaviors that can be challenging for individuals with autism… it may result in improvements in their communication and how they interact with others, e.g. initiating conversations with friends and family.”
In other words, balovaptan is positioning itself to be a standard in autistic treatment among the myriad out there helping to make the daily lives of autistic people more comfortable in migrating and negotiating today’s socially complex world. It’s hard enough to figure out sarcasm, to navigate work and play and everything in between with the careful social cadence required of our modern digital world. It’s yet another to have to deal with a potential hormone backfiring on you.
Yet, for all the promise, it’s easy to all envision a darker reality to balovaptan—one where it becomes a drug to amp up focus like Adderall or calm anxieties like Xanax, a generational crutch to make it through modern life. Perhaps you are about to go to a college party for the first time, or venture on a date, or head to a professional event. You might not be autistic, but you might reach for balovaptan to help with these high-intensity social interactions—maybe you’re a shy, introverted type who could use a little help with chitchat. Could balovaptan become a drug abused by the non-autistic and socially anxious among us?
Bolognani is clinical in his emailed response when posed the question of potential abuse. “So far, we have no evidence that suggests it may result in treatment abuse, either from a biological point of view or from the data generated so far,” he said. That may be true, but it’s important to remember the drug has been used in controlled settings, with young patients like Jacob Yale who have their parents on board and carefully doling out the medication, meticulously working with researchers in understanding how it works.
Jou, while a lead investigator, is actually kept purposefully in the dark about the trials. He doesn’t know if he’s delivering a placebo or the real drug, and he doesn’t even know if any of the pills he’s received are supposed to work or not. All he’s there to do is to provide meticulous notes and collect data.
And most of the data has been on teenagers. While the study is open to kids as young as 5, Jou said it makes sense that adolescents have made up most of the people who are being considered as subjects.
That all goes back to the idea that autism is on a spectrum, and people experience it differently both throughout their lives and between patients. “In younger children, it makes sense that you’d want to focus on non-medical interventions first,” he noted. “For a kindergartner, we recommend not jumping to medication. You want to exhaust those before any behavioral therapy.” Jou is also hesitant to look at balovaptan as a “miracle drug” or something that could potentially be universally prescribed to anyone. “It’s very important that this is a fit, and that’s true for any medication,” he said. “Just because you’re on the autism spectrum doesn’t mean that you need some kind of intervention.”
Despite this, balovaptan has garnered acclaim within the Food and Drug Administration, which put the clinical trials on a special track and identified it as a Breakthrough Therapy, which means balovaptan stands to potentially help treat a disorder for which we previously had little understanding and offers extensive promise based on its clinical trials. It also means that the FDA will expedite the development and review of balovaptan to push it out to the public; Bolognani declined to answer when that might be.
Jacob Yale fidgets, pulling on the drawstring of his hoodie, his eyes darting from corner to corner but rarely landing on a person when he speaks. He’s shy, the corners of his mouth peaking into a smile; he often lets his dad, Randy, do the talking, despite Randy’s prods for Jacob to share more.
Randy and his wife first noticed that Jacob was different when he was in elementary school. When fire alarms would go off during a drill, Jacob would crouch, the wailing sirens painful (“He still does not like them,” Randy said; Jacob scrunched his nose in agreement).
When Jacob was in second grade, the Yale family—yes, that’s their surname, which they share with the university they work with for Jacob’s treatment—visited the Yale Child Study Center, where Jou now works, and had a diagnostic exam run on him. He was on the spectrum.
For Jacob, the results didn’t really matter so much as the fact that for a boy who didn’t quite find the spotlight comfortable, being autistic put him in right in the center of attention. “I felt different,” he said. “It felt weird, people were paying attention [to me].” He paused. “This is my identity.”
But Jacob seemed always to teeter totter when it came to social interactions. So when Yale Child Study Center sent out a note seeking autistic kids for an experimental program, Randy thought Jacob might be a good fit.
“We [Randy and his wife, Jacob’s mom] had a conversation, we talked about it,” Randy said. “We asked about side effects. We asked, ‘Where are you as far as the study?’ and they said it’s been studied in adults, that it’s Phase 2, that they understood the interactions with other drugs.”
So they signed up, together as a family, for the 39-week trial. Every morning, Jacob wakes up at 6 a.m. (even when this interview took place during spring break) to eat something and pop the pill. Randy helps here: He wakes Jacob up, reminds him to take the pill, and most importantly, takes notes about Jacob: Has he changed socially? Is he exhibiting behavior that makes it seem like he’s more socially at ease?
Jacob—who’s been in the experimental phase since February—said he didn’t notice anything. “It’s just normal,” he shrugged, though he doesn’t really like the blood drawing part. “It’s just what it is.” Randy hasn’t either—“He’s still the same”—and I ask if they’re disappointed.
At this point, Jou interjected. He wanted to stress that this wasn’t about changing Jacob—no way was that the intention of balovaptan. “When we’re talking about social communication challenges, this [balovaptan] might improve someone’s ability, but not necessarily change them as a person,” he emphasized. He likened balovaptan’s role in improving social communication to that of antidepressants: “If someone is going through depression and they take a depression medication, it improves their depression,” he said. “They’re the same person, they're less depressed.”
Randy agreed. “I want to make it clear: There’s nothing wrong with Jacob,” he said. “We don’t want a cure.”
Jacob starts to squirm; it’s about time for him to leave for tennis. And there’s been a bribe, too: “After every session, we go to Pepe’s for pizza,” Randy said. It’s time to go.
