Meet the Company Trying to Democratize Clinical Trials With AI

A decade ago, Pablo Graiver was working as a VP at Kayak, the online airfare aggregator, when he sat down to dinner with an old friend—a heart surgeon from his home country of Argentina. The talk turned to how tech was doing more to save folks a few bucks on a flight to Rome than to save people’s lives. The biggest problem in healthcare? “Clinical trials,” she said. “They’re a disaster.”

Right now, the US has exactly 19,816 clinical trials open and ready to recruit patients—trials of promising new therapeutics to fight everything from HIV to cancer to Alzheimer’s. About 18,000 of them will get stuck on the tarmac because they won’t get enough people enrolled. And a third of those will never get off the ground at all, for the same reason.

So where are all the patients? Well, the vast majority of them either don’t know the trials exist, or don’t know they can participate. Since 2000, the government has kept details of every clinical drug trial in a national registry, but it’s a nightmare for the average human to navigate. So most pharma companies use recruitment firms to painstakingly comb through patient medical records and find people who might be a good fit—geographically, genetically, and generationally. Each patient hunt is basically a one-off. Like, say if every time you wanted to fly somewhere you had to search on the websites of United, Delta, American, Frontier, Alaska, and Southwest one at a time. And then do the same thing for hotels. (Man, the early aughts were bleak, weren’t they?)

Graiver’s new company, Antidote, does for clinical trials what Kayak and Orbitz and Priceline did for travel. It gives that painful patient matching problem an e-commerce solution. “Fundamentally, it’s just a question of structuring information,” says Graiver. “Which is something the tech world is great at. I was shocked no one had done it already.”

The information that most needed help was something called inclusion/exclusion criteria. It’s what makes a patient eligible to enroll (or not) in a trial: things like age, sex, prior treatment regimes, and current health status. When drugmakers submit new trial details to ClinicalTrials.gov, most of it gets entered as structured data, the kind of thing you enter in a drop-down menu. But eligibility criteria gets entered in a free text field, where you can write whatever you want. That lack of structure means a machine can’t read it—unless it’s been properly trained.

That’s what Antidote does. Graiver’s company started by amassing thousands of clinical studies from ClinicalTrials.gov and the World Health Organization, and they hired clinical experts to manually standardize all that free-wheeling trial jargon into structured language a search engine could understand. Then they trained it to categorize and identify studies using that language.

If you search for adult onset diabetes, it will know to pull up trials for Type 2 diabetes, and diabetes mellitus 2, and T2DM—since they’re all ways to describe the same disease. Called TrialReach at the time, the company proceeded slowly, focusing first only on diabetes and Alzheimer’s studies.

Then in 2015, Graiver’s platform got a big boost from big pharma. For two years prior, Novartis, Pfizer, and Eli Lilly had worked together to organize their trial data to be machine-readable. But as they looked to expand the consortium, the three pharma giants realized a need for a more neutral host organization. So they gave the tech to Graiver. Today, three years and a new name later, Antidote has annotated more than 14,000 trials—about 50 percent of what’s listed on ClinicalTrials.gov—spanning 726 conditions.

The result of all this data structuring is that Antidote can take a number (say, 50) and return studies that say something like this: “Ages Eligible for Study: Child, Adult, Senior” but not studies like this: “Ages Eligible for Study: 75 years and older.” And the interface is pretty slick. You type in your condition, where you live, then choose your age and sex. For a 50-year-old woman living in St. Louis, Missouri with lung cancer, 617 trials pop up. On the next screen, Antidote asks how far you’d be willing to travel; within 20 miles the trial options narrow to 69. If you know what kind of mutation is causing your lung cancer, Antidote can winnow down the number even further. At this point, you could print out a list of the trials, take them to your oncologist, and discuss your options.

Or, you can click on any trials you’re interested in, register your email with Antidote, and they’ll send you contact information for the trial organizers, along with next steps. They’ll also keep you updated on any new trials for which you might be a match.

The service is totally free for patients, who can find it on their own or through a widget on websites for patient organizations. Through 231 of those partnerships, including with the American Kidney Fund, Muscular Dystrophy Association, and Lung Cancer Alliance, Antidote says it reaches more than 15 million people per month. On the website of JDRF—the leading Type 1 Diabetes research fund in the world—27,863 people have searched for a trial using the Antidote widget since it launched in 2016. That’s more than in the previous 10 years combined using JDRF’s existing search tool.

“It makes it less of a wild goose chase for patients,” says Esther Schorr, COO of PatientPower, an online cancer news site and Antidote partner. Surveys of their 30,000 member community have shown an uptick in trial enrollment since the widget went up about a year ago. “There’s just so much information for the common man or woman to get through. Technology can really make a patient’s journey easier.”

It’s also making things easier (and cheaper) for drugmakers. Antidote makes money chiefly by selling limited access to this user database to the world’s biggest pharma companies and clinical research institutions, helping them to fill their own trials.1 When you enter your email address, you’re consenting not just to having your personal information shared with the sponsor of a particular trial, but to having your deidentified data shared with third parties.

Antidote maintains that it still keeps up some kind of a firewall; pharma companies can’t just contact you out of the blue—they have to place a request through Antidote, that you can accept or deny. But the broad consent language in the company’s privacy policy gives Antidote a lot of latitude with how it can use your name, age, sex, location, and any other details you provide about your medical condition.

It’s a tradeoff between privacy and care that many patients are confronting these days. Like the seniors filling their homes and wardrobes with IoT-enabled sensors to keep track of their movement and heart rates. Or the record number of Americans letting companies mine their DNA, so they can know if they’re at higher risk for genetic diseases like Alzheimer’s or cancer. For Antidote’s users, the promise of a cure—however distant—is well worth the risk.

_1 Correction appended 01/30/18 5:40pm EST This story was changed to clarify how Antidote earns revenues by providing clinical trial sponsors access to eligible patients.

Read more: https://www.wired.com/story/meet-the-company-trying-to-democratize-clinical-trials-with-ai/

How the Religious Freedom Division Threatens LGBT Healthand Science

When Marci Bowers consults with her patients, no subject is off limits. A transgender ob/gyn and gynecologic surgeon in Burlingame, California, she knows how important it is that patients feel comfortable sharing their sexual orientation and gender identity with their doctor, trust and honesty being essential to providing the best medical care. But Bowers knows firsthand that the medical setting can be a challenging place for patients to be candid. That for LGBT people, it can even be dangerous.

"I know from talking with patients that they're often denied services, not just for surgery and hormone therapy, but basic medical care," Bowers says. "I've had patients show up in an emergency room who were denied treatment because they were transgender."

Experiences like these are what make the creation of a new "Conscience and Religious Freedom" division within the US Department of Health and Human Services so troubling. Announced last week by acting secretary of HHS Eric Hargan, the division's stated purpose is to protect health care providers who refuse to provide services that contradict their moral or religious beliefs—services that include, according to the division's new website, "abortion and assisted suicide."

But the division's loose language could leave room for physicians to provide substandard care to LGBT patients—or abstain from treating them altogether. Indeed, in a statement to WIRED, an HHS spokesperson said the department would not interpret prohibitions on sex discrimination in health care to cover gender identity, citing its adherence to a 2016 court order that excluded transgender people from certain anti-discrimination protections.

That's obviously bad for the health and wellbeing of LGBT people, who may feel less comfortable sharing their sexual orientation or gender identity going forward—but it's bad for science, medicine, and policy, as well.

At its core, the new HHS office threatens data and understanding. Collecting facts and figures on sexual orientation and gender identity fills valuable gaps in the medical community's comprehension of LGBT patients and their public health needs, and progress on that front has accelerated in recent years. "Gathering these details has tremendous potential to improve care for LGBT people," says psychologist Ed Callahan, who in 2015 helped orchestrate the addition of fields for sexual orientation and gender identity—aka "SO/GI"—to electronic health records at UC Davis, the first academic system in the country to do so. The more data doctors and policymakers have on LGBT people, the better they can understand the institutional hurdles, social challenges, and public health risks they face as sexual minorities.

The creation of the new HHS division is but the latest development in an ongoing battle over whether and how that data is collected. As of this year, the Office of the National Coordinator of Health Information Technology requires outpatient clinics to use software that collects SO/GI information if they receive federal incentive payments for using government-certified electronic health care records. The Bureau of Primary Health Care requires health centers to report the sexual orientation and gender identity of their patients. And the Centers for Disease Control and Prevention and the Centers for Medicare & Medicaid Services continue to encourage data collection on SO/GI.

"There’s actually been a lot of good work happening at the Veterans Health Administration," says Sean Cahill, director of health policy research at the Fenway Institute, a Boston-based center for research, training, and policy development on LGBT-related health issues. Since 2012, the VA has encouraged the collection of SO/GI data and issued directives that ensure respectful, equitable, culturally competent care for LGBT veterans. And by the end of Obama's presidency, the number of federal surveys and studies measuring sexual orientation had increased to 12, seven of which also measured gender identity or transgender status. "So the good news is that the shift to gathering these data has been underway for several years, and does continue," Cahill says.

But data collection has slowed under the Trump administration. In the past 13 months, surveys collecting data on participation in Older Americans Act-funded programs and Administration for Community Living-supported disability services have removed questions pertaining to sexual orientation and gender identity. In the same time span, numerous political maneuvers have sown uncertainty and distrust throughout the LGBT community. A July 2017 directive from President Trump attempted to ban transgender people from enlisting in the military, and in December policy analysts were presented with a list of banned words—including "transgender"—not to be used in official CDC budget documents.

In short: Under the Trump administration, the country is simultaneously collecting less data and promoting conditions that leave LGBT patients wary of their healthcare providers. "These patients already face significant obstacles to accessing medical care, and I fear implementation of these measures will only make these obstacles worse," says Stanley Vance, a pediatrician at University of California San Francisco and an expert in the care of gender nonconforming youth. "I also worry that these measures will be an institutionalized form of discrimination against patients who have been identified as a sexual minority or transgender who freely come out to their providers or through information previously entered in electronic medical records."

Even when physicians don’t overtly discriminate against gay and transgender patients, negative health care experiences are routine. Many physicians simply don't think to consider a patient's SO/GI—information they can use to not only respect their patients, but screen them for family rejection, which studies show increases the risk for depression, suicide, and high-risk sexual behaviors. Failing to acknowledge a patient's SO/GI can compound the ill effects of social stigma and inaccessibility to care like hormone therapy or gender affirmation surgery. "Across the board, LGBT patients are the group least likely to come back for further care," Callahan says. "And that often happens because of ways they are dismissed as not existing."

Of course, the reality is that LGBT people do exist, they're entitled to equitable services and care, and they deserve to be counted—sometimes literally. "It really shouldn't be political, you know? It shouldn't be a partisan issue," Cahill says. "It's about science and data and providing quality care to all patients."

Read more: https://www.wired.com/story/how-the-religious-freedom-division-threatens-lgbt-healthand-science/

The Second Coming of Ultrasound

Before Pierre Curie met the chemist Marie Sklodowska; before they married and she took his name; before he abandoned his physics work and moved into her laboratory on Rue Lhomond where they would discover the radioactive elements polonium and radium, Curie discovered something called piezoelectricity. Some materials, he found—like quartz and certain kinds of salts and ceramics—build up an electric charge when you squeeze them. Sure, it’s no nuclear power. But thanks to piezoelectricity, US troops could locate enemy submarines during World War I. Thousands of expectant parents could see their baby’s face for the first time. And one day soon, it may be how doctors cure disease.

Ultrasound, as you may have figured out by now, runs on piezoelectricity. Applying voltage to a piezoelectric crystal makes it vibrate, sending out a sound wave. When the echo that bounces back is converted into electrical signals, you get an image of, say, a fetus, or a submarine. But in the last few years, the lo-fi tech has reinvented itself in some weird new ways.

Researchers are fitting people’s heads with ultrasound-emitting helmets to treat tremors and Alzheimer’s. They’re using it to remotely activate cancer-fighting immune cells. Startups are designing swallowable capsules and ultrasonically vibrating enemas to shoot drugs into the bloodstream. One company is even using the shockwaves to heal wounds—stuff Curie never could have even imagined.

So how did this 100-year-old technology learn some new tricks? With the help of modern-day medical imaging, and lots and lots of bubbles.

Bubbles are what brought Tao Sun from Nanjing, China to California as an exchange student in 2011, and eventually to the Focused Ultrasound Lab at Brigham and Women’s Hospital and Harvard Medical School. The 27-year-old electrical engineering grad student studies a particular kind of bubble—the gas-filled microbubbles that technicians use to bump up contrast in grainy ultrasound images. Passing ultrasonic waves compress the bubbles’ gas cores, resulting in a stronger echo that pops out against tissue. “We’re starting to realize they can be much more versatile,” says Sun. “We can chemically design their shells to alter their physical properties, load them with tissue-seeking markers, even attach drugs to them.”

Nearly two decades ago, scientists discovered that those microbubbles could do something else: They could shake loose the blood-brain barrier. This impassable membrane is why neurological conditions like epilepsy, Alzheimer’s, and Parkinson’s are so hard to treat: 98 percent of drugs simply can’t get to the brain. But if you station a battalion of microbubbles at the barrier and hit them with a focused beam of ultrasound, the tiny orbs begin to oscillate. They grow and grow until they reach the critical size of 8 microns, and then, like some Grey Wizard magic, the blood-brain barrier opens—and for a few hours, any drugs that happen to be in the bloodstream can also slip in. Things like chemo drugs, or anti-seizure medications.

This is both super cool and not a little bit scary. Too much pressure and those bubbles can implode violently, irreversibly damaging the barrier.

That’s where Sun comes in. Last year he developed a device that could listen in on the bubbles and tell how stable they were. If he eavesdropped while playing with the ultrasound input, he could find a sweet spot where the barrier opens and the bubbles don’t burst. In November, Sun’s team successfully tested the approach in rats and mice, publishing their results in Proceedings in the National Academy of Sciences.

“In the longer term we want to make this into something that doesn’t require a super complicated device, something idiot-proof that can be used in any doctor’s office,” says Nathan McDannold, co-author on Sun’s paper and director of the Focused Ultrasound Lab. He discovered ultrasonic blood-brain barrier disruption, along with biomedical physicist Kullervo Hynynen, who is leading the world’s first clinical trial evaluating its usefulness for Alzheimer’s patients at the Sunnybrook Research Institute in Toronto. Current technology requires patients to don special ultrasound helmets and hop in an MRI machine, to ensure the sonic beams go to the right place. For the treatment to gain any widespread traction, it’ll have to become as portable as the ultrasound carts wheeled around hospitals today.

More recently, scientists have realized that the blood-brain barrier isn’t the only tissue that could benefit from ultrasound and microbubbles. The colon, for instance, is pretty terrible at absorbing the most common drugs for treating Crohn’s disease, ulcerative colitis, and other inflammatory bowel diseases. So they’re often delivered via enemas—which, inconveniently, need to be left in for hours.

But if you send ultrasound waves waves through the colon, you could shorten that process to minutes. In 2015, pioneering MIT engineer Robert Langer and then-PhD student Carl Schoellhammer showed that mice treated with mesalamine and one second of ultrasound every day for two weeks were cured of their colitis symptoms. The method also worked to deliver insulin, a far larger molecule, into pigs.

Since then, the duo has continued to develop the technology within a start-up called Suono Bio, which is supported by MIT’s tech accelerator, The Engine. The company intends to submit its tech for FDA approval in humans sometime later this year.

Ultrasound sends pressure waves through liquid in the body, creating bubble-filled jets that can propel microscopic drug droplets like these into surrounding tissues.
Suono Bio

Instead of injecting manufactured microbubbles, Suono Bio uses ultrasound to make them in the wilds of the gut. They act like jets, propelling whatever is in the liquid into nearby tissues. In addition to its backdoor approach, Suono is also working on an ultrasound-emitting capsule that could work in the stomach for things like insulin, which is too fragile to be orally administered (hence all the needle sticks). But Schoellhammer says they have yet to find a limit on the kinds of molecules they can force into the bloodstream using ultrasound.

“We’ve done small molecules, we’ve done biologics, we’ve tried DNA, naked RNA, we’ve even tried Crispr,” he says. “As superficial as it may sound, it all just works.”

Earlier this year, Schoellhammer and his colleagues used ultrasound to deliver a scrap of RNA that was designed to silence production of a protein called tumor necrosis factor in mice with colitis. (And yes, this involved designing 20mm-long ultrasound wands to fit in their rectums). Seven days later, levels of the inflammatory protein had decreased sevenfold and symptoms had dissipated.

Now, without human data, it’s a little premature to say that ultrasound is a cure-all for the delivery problems facing gene therapies using Crispr and RNA silencing. But these early animal studies do offer some insights into how the tech might be used to treat genetic conditions in specific tissues.

Even more intriguing though, is the possibility of using ultrasound to remotely control genetically-engineered cells. That’s what new research led by Peter Yingxiao Wang, a bioengineer at UC San Diego, promises to do. The latest craze in oncology is designing the T-cells of your immune system to better target and kill cancer cells. But so far no one has found a way to go after solid tumors without having the T-cells also attack healthy tissue. Being able to turn on T-cells near a tumor but nowhere else would solve that.

Wang’s team took a big step in that direction last week, publishing a paper that showed how you could convert an ultrasonic signal into a genetic one. The secret? More microbubbles.

This time, they coupled the bubbles to proteins on the surface of a specially designed T-cell. Every time an ultrasonic wave passed by, the bubble would expand and shrink, opening and closing the protein, letting calcium ions flow into the cell. The calcium would eventually trigger the T-cell to make a set of genetically encoded receptors, directing it it to attack the tumor.

“Now we’re working on figuring out the detection piece,” says Wang. “Adding another receptor so that we’ll known when they’ve accumulated at the tumor site, then we’ll use ultrasound to turn them on.”

In his death, Pierre Curie was quickly eclipsed by Marie; she went on to win another Nobel, this time in chemistry. The discovery for which she had become so famous—radiation—would eventually take her life, though it would save the lives of so many cancer patients in the decades to follow. As ultrasound’s second act unfolds, perhaps her husband’s first great discovery will do the same.

Read more: https://www.wired.com/story/the-second-coming-of-ultrasound/

A Familys Race to Cure a Daughters Genetic Disease

One July afternoon last summer, Matt Wilsey distributed small plastic tubes to 60 people gathered in a Palo Alto, California, hotel. Most of them had traveled thousands of miles to be here; now, each popped the top off a barcoded tube, spat in about half a teaspoon of saliva, and closed the tube. Some massaged their cheeks to produce enough spit to fill the tubes. Others couldn’t spit, so a technician rolled individual cotton swabs along the insides of their cheeks, harvesting their skin cells—and the valuable DNA inside.

One of the donors was Asger Vigeholm, a Danish business developer who had traveled from Copenhagen to be here, in a nondescript lobby at the Palo Alto Hilton. Wilsey is not a doctor, and Vigeholm is not his patient. But they are united in a unique medical pursuit.

Wilsey’s daughter, Grace, was one of the first children ever diagnosed with NGLY1 deficiency. It’s a genetic illness defined by a huge range of physical and mental disabilities: muscle weakness, liver problems, speech deficiencies, seizures. In 2016, Vigeholm’s son, Bertram, became the first child known to die from complications of the disease. Early one morning, as Bertram, age four, slept nestled between his parents, a respiratory infection claimed his life, leaving Vigeholm and his wife, Henriette, to mourn with their first son, Viktor. He, too, has NGLY1 deficiency.

Grace and her mother, Kristen Wilsey.

BLAKE FARRINGTON

The night before the spit party, Vigeholm and Wilsey had gathered with members of 16 other families, eating pizza and drinking beer on the hotel patio as they got to know each other. All of them were related to one of the fewer than 50 children living in the world with NGLY1 deficiency. And all of them had been invited by the Wilseys—Matt and his wife Kristen, who in 2014 launched the Grace Science Foundation to study the disease.

These families had met through an online support group, but this was the first time they had all come together in real life. Over the next few days in California, every family member would contribute his or her DNA and other biological samples to scientists researching the disease. On Friday and Saturday, 15 of these scientists described their contributions to the foundation; some studied the NGLY1 gene in tiny worms or flies, while others were copying NGLY1 deficient patients’ cells to examine how they behaved in the lab. Nobody knows what makes a single genetic mutation morph into all the symptoms Grace experiences. But the families and scientists were there to find out—and maybe even find a treatment for the disease.

That search has been elusive. When scientists sequenced the first human genome in 2000, geneticist Francis Collins, a leader of the Human Genome Project that accomplished the feat, declared that it would lead to a “complete transformation in therapeutic medicine” by 2020. But the human genome turned out to be far more complex than scientists had anticipated. Most disorders, it’s now clear, are caused by a complicated mix of genetic faults and environmental factors.

And even when a disease is caused by a defect in just one gene, like NGLY1 deficiency, fixing that defect is anything but simple. Scientists have tried for 30 years to perfect gene therapy, a method for replacing defective copies of genes with corrected ones. The first attempts used modified viruses to insert corrected genes into patients’ genomes. The idea appeared elegant on paper, but the first US gene therapy to treat an inherited disease—for blindness—was approved just last year. Now scientists are testing methods such as Crispr, which offers a far more precise way to edit DNA, to replace flawed genes with error-free ones.

Certainly, the genetics revolution has made single-mutation diseases easier to identify; there are roughly 7,000, with dozens of new ones discovered each year. But if it’s hard to find a treatment for common genetic diseases, it’s all but impossible for the very rare ones. There’s no incentive for established companies to study them; the potential market is so small that a cure will never be profitable.

Which is where the Wilseys—and the rest of the NGLY1 families—come in. Like a growing number of groups affected by rare genetic diseases, they’re leapfrogging pharmaceutical companies’ incentive structures, funding and organizing their own research in search of a cure. And they’re trying many of the same approaches that Silicon Valley entrepreneurs have used for decades.

At 10:30 on a recent Monday morning, Grace is in Spanish class. The delicate 8-year-old with wavy brown hair twisted back into a ponytail sits in her activity chair—a maneuverable kid-sized wheelchair. Her teacher passes out rectangular pieces of paper, instructing the students to make name tags.

Grace grabs her paper and chews it. Her aide gently takes the paper from Grace’s mouth and puts it on Grace’s desk. The aide produces a plastic baggie of giant-sized crayons shaped like cylindrical blocks; they’re easier for Grace to hold than the standard Crayolas that her public school classmates are using.

Grace’s NGLY1 deficiency keeps her from speaking.

BLAKE FARRINGTON

At her school, a therapist helps her communicate.

BLAKE FARRINGTON

The other kids have written their names and are now decorating their name tags.

“Are we allowed to draw zombies for the decorations?” one boy asks, as Grace mouths her crayons through the baggie.

Grace’s aide selects a blue crayon, puts it in Grace’s hand, and closes her hand over Grace’s. She guides Grace’s hand, drawing letters on the paper: “G-R-A-C-E.”

Grace lives with profound mental and physical disabilities. After she was born in 2009, her bewildering list of symptoms—weak muscles, difficulty eating, failure to thrive, liver damage, dry eyes, poor sleep—confounded every doctor she encountered. Grace didn’t toddle until she was three and still needs help using the toilet. She doesn’t speak and, like an infant, still grabs anything within arm’s reach and chews on it.

Her father wants to help her. The grandson of a prominent San Francisco philanthropist and a successful technology executive, Matt Wilsey graduated from Stanford, where he became friends with a fellow undergraduate who would one day be Grace’s godmother: Chelsea Clinton. Wilsey went on to work in the Clinton White House, on George W. Bush’s presidential campaign, and in the Pentagon.

But it was his return to Silicon Valley that really prepared Wilsey for the challenge of his life. He worked in business development for startups, where he built small companies into multimillion-dollar firms. He negotiated a key deal between online retailer Zazzle and Disney, and later cofounded the online payments company Cardspring, where he brokered a pivotal deal with First Data, the largest payment processor in the world. He was chief revenue officer at Cardspring when four-year-old Grace was diagnosed as one of the first patients with NGLY1 deficiency in 2013—and when he learned there was no cure.

At the time, scientists knew that the NGLY1 gene makes a protein called N-glycanase. But they had no idea how mistakes in the NGLY1 gene caused the bewildering array of symptoms seen in Grace and other kids with NGLY1 deficiency.

Wilsey’s experience solving technology problems spurred him to ask scientists, doctors, venture capitalists, and other families what he could do to help Grace. Most advised him to start a foundation—a place to collect money for research that might lead to a cure for NGLY1 deficiency.

As many as 30 percent of families who turn to genetic sequencing receive a diagnosis. But most rare diseases are new to science and medicine, and therefore largely untreatable. More than 250 small foundations are trying to fill this gap by sponsoring rare disease research. They’re funding scientists to make animals with the same genetic defects as their children so they can test potential cures. They’re getting patients’ genomes sequenced and sharing the results with hackers, crowdsourcing analysis of their data from global geeks. They’re making bespoke cancer treatments and starting for-profit businesses to work on finding cures for the diseases that affect them.

“Start a foundation for NGLY1 research, get it up and running, and then move on with your life,” a friend told Wilsey.

Wilsey heeded part of that advice but turned the rest of it on its head.

In 2014, Wilsey left Cardspring just before it was acquired by Twitter and started the Grace Science Foundation to fund research into NGLY1 deficiency. The foundation has committed $7 million to research since then, most of it raised from the Wilseys’ personal network.

Many other families with sick loved ones have started foundations, and some have succeeded. In 1991, for instance, a Texas boy named Ryan Dant was diagnosed with a fatal muscle-wasting disease called mucopolysaccharidosis type 1. His parents raised money to support an academic researcher who was working on a cure for MPS1; a company agreed to develop the drug, which became the first approved treatment for the disease in 2003.

But unlike Dant, Grace had a completely new disease. Nobody was researching it. So Wilsey began cold-calling dozens of scientists, hoping to convince them to take a look at NGLY1 deficiency; if they agreed to meet, Wilsey read up on how their research might help his daughter. Eventually he recruited more than 100 leading scientists, including Nobel Prize-winning biologist Shinya Yamanaka and Carolyn Bertozzi, to figure out what was so important about N-glycanase. He knew that science was unpredictable and so distributed Grace Science’s funding through about 30 grants worth an average of $135,000 apiece.

Two years later, one line of his massively parallel attack paid off.

Matt Wilsey, Grace’s father.

BLAKE FARRINGTON

Bertozzi, a world-leading chemist, studies enzymes that add and remove sugars from other proteins, fine-tuning their activity. N-glycanase does just that, ripping sugars off from other proteins. Our cells are not packed with the white, sweet stuff that you add to your coffee. But the tiny building blocks of molecules similar to table sugar can also attach themselves to proteins inside cells, acting like labels that tell the cell what to do with these proteins.

Scientists thought that N-glycanase’s main role was to help recycle defective proteins, but many other enzymes are also involved in this process. Nobody understood why the loss of N-glycanase had such drastic impacts on NGLY1 kids.

In 2016, Bertozzi had an idea. She thought N-glycanase might be more than just a bit player in the cell’s waste management system, so she decided to check whether it interacts with another protein that turns on the proteasomethe recycling machine within each of our cells.

This protein is nicknamed Nerf, after its abbreviation, Nrf1. But fresh-made Nerf comes with a sugar attached to its end, and as long as that sugar sticks, Nerf doesn’t work. Some other protein has to chop the sugar off to turn on Nerf and activate the cellular recycling service.

Think of Nerf’s sugar like the pin in a grenade: You have to remove the pin—or in this case, the sugar—to explode the grenade and break down faulty proteins.

But nobody knew what protein was pulling the pin out of Nerf. Bertozzi wondered if N-glycanase might be doing that job.

To find out, she first tested cells from mice and humans with and without working copies of the NGLY1 gene. The cells without NGLY1 weren’t able to remove Nerf’s sugar, but those with the enzyme did so easily. If Bertozzi added N-glycanase enzymes to cells without NGLY1, the cells began chopping off Nerf’s sugar just as they were supposed to: solid evidence, she thought, that N-glycanase and Nerf work together. N-glycanase pulls the pin (the sugar) out of the grenade (the Nerf protein) to trigger the explosion (boom).

The finding opened new doors for NGLY1 disease research. It gave scientists the first real clue about how NGLY1 deficiency affects patients’ bodies: by profoundly disabling their ability to degrade cellular junk via the proteasome.

As it turns out, the proteasome is also involved in a whole host of other diseases, such as cancer and brain disorders, that are far more common than NGLY1 deficiency. Wilsey immediately grasped the business implications: He had taken a moon shot, but he’d discovered something that could get him to Mars. Pharmaceutical companies had declined to work on NGLY1 deficiency because they couldn’t make money from a drug for such a rare disease. But Bertozzi had now linked NGLY1 deficiency to cancer and maladies such as Parkinson’s disease, through the proteasome—and cancer drugs are among the most profitable medicines.

Suddenly, Wilsey realized that he could invent a new business model for rare diseases. Work on rare diseases, he could argue, could also enable therapies for more common—and therefore profitable—conditions.

In early 2017, Wilsey put together a slide deck—the same kind he’d used to convince investors to fund his tech startups. Only this time, he wanted to start a biotechnology company focused on curing diseases linked to NGLY1. Others had done this before, such as John Crowley, who started a small biotechnology company that developed the first treatment for Pompe disease, which two of his children have. But few have been able to link their rare diseases to broader medical interests in the way that Wilsey hoped to.

He decided to build a company that makes treatments for both rare and common diseases involving NGLY1. Curing NGLY1 disease would be to this company as search is to Google—the big problem it was trying to solve, its reason for existence. Treating cancer would be like Google’s targeted advertising—the revenue stream that would help the company get there.

But his idea had its skeptics, Wilsey’s friends among them.

One, a biotechnology investor named Kush Parmar, told Wilsey about some major obstacles to developing a treatment for NGLY1 deficiency. Wilsey was thinking of using approaches such as gene therapy to deliver corrected NGLY1 genes into kids, or enzyme replacement therapy, to infuse kids with the N-glycanase enzyme they couldn’t make on their own.

But NGLY1 deficiency seems particularly damaging to cells in the brain and central nervous system, Parmar pointed out—places that are notoriously inaccessible to drugs. It’s hard to cure a disease if you can’t deliver the treatment to the right place.

Other friends warned Wilsey that most biotech startups fail. And even if his did succeed as a company, it might not achieve the goals that he wanted it to. Ken Drazan, president of the cancer diagnostics company Grail, is on the board of directors of Wilsey’s foundation. Drazan warned Wilsey that his company might be pulled away from NGLY1 deficiency. “If you take people’s capital, then you have to be open to wherever that product development takes you,” Drazan said.

But Wilsey did have some things going for him. Biotechnology companies have become interested of late in studying rare diseases—ones like the type of blindness for which the gene therapy was approved last year. If these treatments represent true cures, they can command a very high price.

Still, the newly approved gene therapy for blindness may be used in 6,000 people, 100 times more than could be helped by an NGLY1 deficiency cure. Wilsey asked dozens of biotechnology and pharmaceutical companies if they would work on NGLY1 deficiency. Only one, Takeda, Japan’s largest drug company, agreed to conduct substantial early-stage research on the illness. Others turned him down flat.

If no one else was going to develop a drug to treat NGLY1 deficiency, Wilsey, decided, he might as well try. “We have one shot at this,” he says. “Especially if your science is good enough, why not go for it?”

“Matt was showing classic entrepreneurial tendencies,” says Dan Levy, the vice president for small business at Facebook, who has known Wilsey since they rushed the same Stanford fraternity in the 1990s. “You have to suspend a little bit of disbelief, because everything is stacked against you.”

At 11 am, Grace sits in a classroom with a speech therapist. Though Grace doesn’t speak, she’s learning to use her “talker,” a tablet-sized device with icons that help her communicate. Grace grabs her talker and presses the icons for “play” and “music,” then presses a button to make her talker read the words out loud.

The "talker" used for Grace’s therapy.

BLAKE FARRINGTON

“OK, play music,” her therapist says, starting up a nearby iPad.

Grace watches an Elmo video on the iPad for a few moments, her forehead crinkled in concentration, her huge brown eyes a carbon copy of her dad’s. Then Grace stops the video and searches for another song.

Suddenly, her therapist slides the iPad out of Grace’s reach.

“You want ‘Slippery Fish,’” her therapist says. “I want you to tell me that.”

Grace turns to her talker: “Play music,” she types again.

The therapist attempts one more time to help Grace say more clearly which particular song she wants. Instead, Grace selects the symbols for two new words.

“Feel mad,” Grace’s talker declares.

Grace working with a therapist in one of their therapy rooms.

BLAKE FARRINGTON

There’s no denying how frustrating it can be for Grace to rely on other people to do everything for her, and how hard her family works to meet her constant needs.

Matt and Kristen can provide the therapy, equipment, medicines, and around-the-clock supervision that Grace needs to have a stable life. But that is not enough—not for Grace, who wants "Slippery Fish," nor for her parents, who want a cure.

So last summer, Wilsey raised money to bring the Vigeholms and the other NGLY1 families to Palo Alto, where they met with Grace’s doctors and the Grace Science Foundation researchers. One Japanese scientist, Takayuki Kamei, was overjoyed to meet two of the NGLY1 deficiency patients: “I say hello to their cells every morning,” he told their parents.

And because all of these families also want a cure, each also donated blood, skin, spit, stool, and urine to the world’s first NGLY1 deficiency biobank. In four days, scientists collected more NGLY1 deficiency data than had been collected in the entire five years since the disease was discovered. These patient samples, now stored at Stanford University and at Rutgers University, have been divvied up into more than 5,000 individual samples that will be distributed to academic and company researchers who wish to work on NGLY1 deficiency.

That same month, Wilsey closed a seed round of $7 million to start Grace Science LLC. His main backer, a veteran private equity investor, prefers not to be named. Like many in Silicon Valley, he’s recently become attracted to health care by the promise of a so-called “double bottom line”: the potential to both to make money and to do good by saving lives.

Wilsey is chief executive of the company and heavily involved in its scientific strategy. He’s looking for a head scientist with experience in gene therapy and in enzyme replacement therapy, which Mark Dant and John Crowley used to treat their sick children. Gene therapy now seems poised to take off after years of false starts; candidate cures for blood and nervous system disorders are speeding through clinical trials, and companies that use Crispr have raised more than $1 billion.

Wilsey doesn’t know which of these strategies, if any, will save Grace. But he hopes his company will find an NGLY1 deficiency cure within five years. The oldest known NGLY1 deficient patient is in her 20s, but since nobody has been looking for these patients until now, it’s impossible to know how many others—like Bertram—didn’t make it that long.

“We don’t know what Grace’s lifespan is,” Wilsey says. “We’re always waiting for the other shoe to drop.”

But at 3 pm on this one November day, that doesn’t seem to matter.

School’s out, and Grace is seated atop a light chestnut horse named Ned. Five staff members lead Grace through a session of equine therapy. Holding herself upright on Ned’s back helps Grace develop better core strength and coordination.

Grace on her horse.

BLAKE FARRINGTON

Grace and Ned walk under a canopy of oak trees. Her face is serene, her usually restless legs still as Ned paces through late-afternoon sunshine. But for a little grace, there may be a cure for her yet.

Read more: https://www.wired.com/story/a-familys-race-to-cure-a-daughters-genetic-disease/

How Did President Trump Do on His Physical? Its Complicated

The numbers don’t lie, unless they do. After much resistance and under increasing pressure, President Trump’s White House this week allowed Rear Admiral Ronny Jackson, the White House doctor, to release results from a physical examination.

How’d Trump do? Well, that’s tricky to answer. Trump’s opposition and the media have been asking two fundamentally impolite questions for years: Is he fat? And is he nuts? As a candidate and as president, Trump has accused his opponents of mental and physical illness. Normal presidencies tend to release medical records to journalists who cover that beat. But last year wasn’t a normal campaign, and this hasn’t been a normal presidency.

Whether the president is healthy has consequences on the stability of the nation, but that knowledge has been hard to come by. Complicating things further, the answers to those impolite but salient questions aren’t, it turns out, straightforward—for anyone, not just a president.

At a long press briefing on Tuesday, Rear Admiral Ronny Jackson ran down the numbers and took some squirmy questions. Trump, 71 years old, is 6 feet and 3 inches tall, Jackson said, and weighs 239 pounds. That’s … convenient. Doctors have a suite of responses teed up for an overweight man in his 70s, but those numbers muddy the swamp. Apparently Trump reported a height of 6’2” at one point, but the most recent height and weight give him a Body Mass Index just one tick below “obese.” Medically speaking, the president is merely quite overweight. (If you believe the numbers Jackson gave, that is. If you don’t, we’re basically done here, because there’s nothing else to evaluate.)

This week’s issue of the Journal of the American Medical Association, by coincidence, dedicates an entire special section to obesity. Its point is that those rigid standards for BMI might not tell the whole story. It might be possible, for example, to be obese, BMI-wise, but still have good cardiorespiratory fitness; conversely, someone with low CRF might be more likely to face health problems than someone with obesity. Physical activity levels and other factors confound all the data, as does age. “It’s definitely a work in progress,” says Catherine Forest, medical director at Stanford Health Care in Los Altos. “The determination is based somewhat on body mass index, but it’s more complicated. If you have elevated cholesterol and you have diabetes, your risk is multiplied. If you smoke cigarettes, your risk is multiplied. If you don’t exercise, it’s multiplied.”

OK, good questions there. The president doesn’t smoke, doesn’t drink alcohol, and he doesn’t have diabetes—Jackson reported his hemoglobin A1c, a measurement of blood sugar, as 5 percent. That’s in the normal range. Trump’s blood pressure and heart rate are in the normal range, too. The president’s EKG and heart function were normal, and tests also showed that Trump’s carotid artery had no blockage.

But: The president by most accounts doesn’t exercise—playing golf three times a week doesn’t count if you ride the cart. And his cholesterol, especially the cardiovascular disease marker low-density lipoprotein cholesterol, is above 140 even though he takes a statin drug to lower it every day. He also takes a daily low dose of aspirin, also thought to be protective of the heart. His cardiac calcium level was high, a risk factor for coronary artery disease that freaked out a few cardiologists. Jackson said the president had “nonclinical coronary atherosclerosis.” Other physicians said, basically, wait what now?

The key to figuring this out, probably, is to not get too obsessed with the technical distinction between “overweight” and “obese.” That’s a public health-type way of distinguishing among populations. But we’re not talking about a population here. “I would think that if he’s close to a BMI of 30, he probably has a significant amount of excess fat,” says Xavier Pi-Sunyer, an endocrinologist at Columbia University and co-director of the New York Obesity Nutrition Research Center. “The question is, is his excess fat subcutaneous, or does he have a lot of intra-abdominal, intramuscular adipose fat? Those are significantly more dangerous.”

In other words, if all your fat is just underneath your skin, OK, maybe that’s cool. But if it’s around your vital organs and gunking up your liver, that’s not cool. “If you want to be more personalized, you probably want to do a few more studies to see where the fat is in the individual,” Pi-Sunyer says. That’d probably mean an MRI, which Jackson didn’t mention.

Cardiovascular health was only part of what Jackson tested. He performed, controversially among the Twitterati, a test called the Montreal Cognitive Assessment. It looks dumb—a series of very basic questions, like, “can you tell which one is a lion and which is an elephant,” or “draw ten minutes to 11 on a blank clock face.” Kindergarten stuff (here’s a PDF), and Trump aced it.

To be clear, though, the point of an assessment like this one or the “mini-cog” some physicians use is to check basics, not evaluate whether someone is qualified to be president. The MoCA is a screening test—you do it to see if a person needs more testing later. “That test is specifically looking for certain types of cognitive dysfunction. It doesn’t test for depression or other kinds of mental health disorders,” says Joseph Ouslander, a geriatrician at the Schmidt College of Medicine at Florida Atlantic University and executive editor of the Journal of the American Geriatric Society.

Even if a MoCA shows mild impairment, Ouslander says he might not do anything for six months or a year, or he’d wait to see if a patient or family members complained about memory lapses or other problems. (It’s like invoking the 25th Amendment, except for family dinners.) That might not be ideal. “Actually, executive function is one of the first things that’s in decline with dementia,” says Forest. “Their memory might be OK, but their ability to make good decisions is in disrepair.”

Which does hint at a bit of a then-what. Washington conventional wisdom remains that Ronald Reagan was suffering symptoms of cognitive decline in the later years of his presidency, and was protected by his staff and his wife. No doctor or medical records have confirmed that, but even the existence of the rumor hints at the degree to which a committed White House could deal with a medically compromised president. After all, Woodrow Wilson’s wife Edith became de facto president after he suffered a stroke—though it’s hard to imagine that sort of breach of constitutional succession today.

By Jackson’s account, the president got a more than full work-up. He had a colonoscopy in 2013 that was normal—no polyps—which means that no doctor needs to go near the orifice with which the president has indicated some familiarity until 2023. His neurological screens were normal, but Jackson didn't say if he'd looked at Trump's gait and balance, but the president did get all his recommended vaccinations. The kind of screening questions that Forest and Ouslander might ask on a wellness visit about depression, connection to family and friends, elder abuse, or help with shopping or finances seem non-operative for a POTUS.

Near the end of his presentation, Jackson said something a little strange. He’d acknowledged that he was going to up Trump’s statin dose and try to talk him into more exercise and a better diet; press accounts have said Trump loves his fast food and ice cream. But then Jackson said “the president’s overall health is excellent.” He said Trump had “great genes.” (No genetic test results were disclosed.) Statins can have some uncomfortable side effects including pain and, rarely, memory loss and confusion. And lifestyle changes? Let's just say that patient compliance is often an issue even for non-presidents.

“I wouldn’t call what was described a clean bill of health. There are certainly alerts that need to be followed up,” Pi-Sunyer says. “I think his doctor is probably a very good doctor and he did whatever he had to do. And now he knows the guy is overweight, has a high LDL, is over 70, very sedentary, and seems to eat an abominable diet. He knows what he has to do.” Finding out whether it happens and whether it works will have to wait until the next time Jackson does the numbers.

Read more: https://www.wired.com/story/trump-physical-exam/

Clashes Over the Future of Gene Therapy at the US’ Biggest Biotech Meeting

For one dizzying, schmooze and booze-filled week every January, thousands of tech execs, VCs, and investment bankers grind their way through a four-day slog of panel sessions, poster presentations, networking meetings, and cocktail-drenched after-hours parties in their industry’s premier orgiastic dealmaking event. And no, we’re not talking about CES.

On Monday, the Westin St. Francis hotel in downtown San Francisco opened its doors to the 36th annual J.P. Morgan Healthcare Conference, the country’s largest biotech convention. Everyone is there either to disrupt or to be disrupted. And while some companies were there to hawk the buzziest in far-future thinking—blockchain-based everything! fully robotic operating rooms!—others came to celebrate the very real, very current progress of a field 30 years in the making: gene therapy. And the promise of a much newer technology, Crispr, to propel the long-standing field forward with even greater momentum.

After decades of setbacks, gene therapy—a loosely defined umbrella term for any technique that uses genes to treat or prevent disease—is finally here. In December, the field got its very first FDA approval with Luxturna, which corrects a defective gene in a rare, inherited retinal disease. With a half dozen more treatments in late-stage trials and an unusually open-minded FDA commissioner in Washington, the industry is expecting a flurry of new approvals this year.

Which is going to throw a wrench in the health insurance industry. Because gene therapies are one-time, curative treatments, they break the traditional insurance model, which is designed to make multiple small payments over time. “We recognize that the products in this space create reimbursement challenges to the normal way of doing business,” said Janet Lambert, CEO of the Alliance for Regenerative Medicine, during her presentation Monday on the state of of the cell and gene therapy industry.

Lambert’s lobbying roadmap for 2018 includes helping insurance companies understand what to do with a new gene therapy like Luxturna, which cures blindness with a single, $850,000 injection into the eye. Ranked by sticker price, it’s the most expensive medicine in America. Spark Therapeutics, the company that makes Luxturna, argues that the six-figure price tag isn’t actually that unreasonable, if you factor in all the costs that patients with the inherited retinal disease would have racked up in a lifetime of seeking better care.

But because their clinical trial patients haven’t been followed long enough to determine if the treatment benefits are actually durable for a whole lifetime, Spark has received significant pushback from insurers. As a result, the company is already exploring a some creative new pricing models. It announced last week that it’s offering a rebate program based on the treatment’s effectiveness at 30 to 90 days and again at 30 months with one East Coast provider, and is in talks about expanding it to other insurers, Spark CEO Jeffrey Marrazzo said at JPM. He said Spark is also in discussions with the Centers for Medicare and Medicaid Services on a multi-year installment plan option. Either of these could soon serve as a model for how gene therapies might be made available to patients without cutting the legs out from under the healthcare system.

That's a problem the Crispr companies in attendance at JPM don’t have to worry about yet. But they’re hoping gene therapy will have figured it out by the time Crispr-based medicines are patient-ready and FDA-approved. The first trial in humans isn’t expected to launch until later this year. But the Big Three—Editas Medicine, Intellia Therapeutics, and Crispr Therapeutics—had other hurdles to contend with.

Over the weekend, headlines metastasized across the internet about a new study suggesting Crispr might not work in humans at all. Published on pre-print server bioRxiv by a Stanford scientist who is also a scientific founder of Crispr Therapeutics, the non peer-reviewed study found that up to 79 percent of humans could already be immune to the most common forms of Crispr, called Crispr-Cas9, which come from two strains of Staphylococcus.

The timing was pretty terrible, and all three companies’ stocks took serious hits Monday morning, even as investors crowded into ballrooms to hear Crispr execs speak. The controversy made for one of the more tense moments of a gene therapy panel, when Sandy Macrae, CEO of rival gene editing tech company Sangamo, which uses zinc-finger nucleases, poked at Crispr Therapeutics chief scientific officer, Bill Lundberg. “That’s why we use human tools to edit humans,” he said.

The crowd of about a thousand swiftly inhaled. (This is what counts as maximum drama at JPM.) But the Crispr folks swiftly pushed back on the claims that immunity will present a barrier to their pipelines, since none of them use just plain old Cas9 like it’s found in nature. They’re all making proprietary tweaks to the enzyme system that they think will make the immunity issue, well, not an issue at all.

“We’ve actually done a lot of work ourselves on this specific topic and we don’t see this as a major issue to advancing Crispr-based medicines,” said Editas president and CEO Katrine Bosley. In a presentation to investors on Wednesday, the company revealed their plans to have five medicines in human testing within the next five years. The first diseases Editas is going after include a number of inherited eye disorders. The company is also pursuing a partnership with Juno Therapeutics to use Crispr to engineer T-cells to fight off incurable cancers.

Immunity to bacterial-based gene editors won’t be an issue for the current crop of gene therapies expected to get approvals in 2018. They represent the tail ends of a long and arduous development pipeline—one that Crispr is only just beginning to enter. It might be another 30 years before anyone is arguing about the insurance implications of one-time, cure-all Crispr meds. But at least by then, there should be some good options.

Read more: https://www.wired.com/story/clashes-over-the-future-of-gene-therapy-at-the-uss-biggest-biotech-meeting/

A Robot That Tugs on Pig Organs Could Save Human Babies

The pig looks like any other pig, only it's been wearing a backpack for a week—in the name of science. Just behind its head sits a control box, with a battery and processor, from which runs a cable that enters through the pig’s flank. Once inside, the cable attaches to a very special robot clamped onto the pig's esophagus, the pathway to the stomach. Little by little, the robot lengthens, in turn lengthening the tube.

The robot attached to a segment of esophagus.

Damian et al.

This pig doesn’t necessarily need a robot tugging on its esophagus, but children born with a section of theirs missing, a disorder known as esophageal atresia, may in the near future. What researchers detail today in the journal Science Robotics is how their robot could not only help treat this disorder, but also short bowel syndrome, in which a child loses large portions of the intestines to infection. Implantable robots, then, may help extend organs in the human body—though weirdly not by stretching, like you might assume is going on here.

Current treatment for esophageal atresia is not in the least bit simple or pleasant. Surgeons attach sutures to the two ends of the food tube and pull them out through incisions in the child’s back. “They tie these onto what looks like buttons on the kid's back,” says Boston Children's Hospital researcher Pierre Dupont, co-author of the paper. “And they apply tension to those ends in this way.” This lengthens the two disconnected bits of the esophagus, so when the surgeons put them back in the chest and sew them together, they now bridge what was once a gap.

Problem is, this lengthening can take up to a month, and the kid has to be sedated the whole time. The sutures are under a lot of tension, and if the patient moves, they could pop out. On top of that, the procedure could really be more precise: Surgeons base how much tension they’re adding on experience. “If they pull too hard they tear out,” says Dupont. “If they don't pull enough the tissue doesn't grow. But they're trying to pull as hard as they can without it tearing because they don't want to have that kid paralyzed and sedated longer than they have to.”

Ideally, you could build a more precise system that works within the body, automatically sensing how much tension it needs to apply. Which is where the pig comes in. It isn’t missing a section of its esophagus, so in this experiment the robot—which is attached by way of two rings wrapped around the esophagus and sutured an inch and a half apart—is lengthening to stretch the tube like a rubber band.

Except it’s not really stretching, as it happens. “This is what our surgeons knew from experience from looking at the tissue,” says Dupont, “but never had been able to verify." The tension that comes with the traditional surgical and robotic methods is actually encouraging new tissue to grow. The robot is inducing the esophagus to produce new cells, which leads to healthier tissue than if the tube were just stretched out. The researchers managed to get the length of the pig esophagus to increase by 75 percent in just over a week.

Theoretically, in a child with a gap in their esophagus, the robot would still make the esophagus longer—it would just bring two incomplete ends together. Surgeons would suture one ring to the top end of the esophagus and one to the bottom end. Over time, the robot would contract, bringing the two ends closer and closer, inducing those cells to grow. Eventually the gap would close enough that surgeons could stitch the two ends of the tube together, making the esophagus whole.

The robot could also potentially treat short bowel syndrome. In this case, surgeons have removed a significant length of infected intestine. “The remaining length is so short, the food goes in one end and it comes out the other end without any chance for absorption of nutrients,” says Dupont. “So if there was a way to induce lengthening of that bowel then those kids wouldn't have to be fed intravenously.” Here the robot would work more like it did in the pig, attaching to the intestine and slowly expanding to lengthen the organ.

“This is very intriguing concept that attempts to address therapy for extremely challenging group of patients,” says Nikolay Vasilyev, a researcher who has developed a robot that helps hearts pump. “It remains to be seen how the robot can be safely explanted and how the tissue responds over the longer-term.”

The solution there may be degradable materials. “What I'd love to do is make a version of my robot,” says Dupont, “that even though it's placed exterior to the bowel, it would be resorbable, so that all of the components would dissolve away and we wouldn't have to subject the kid to another surgery.” So the body would essentially digest the robot outside of the digestive system.

Before that all can happen, though, the researchers will have to shrink down a robot that works on 100-pound pigs into something that’d not only fit 3-month-old humans, but work entirely inside the body. Which doesn’t seem impossible: Robots will only get smaller and more sophisticated from here. And soon enough, machines of all kinds will be making their way into the human body—think robots made of pig intestine that you swallow, for instance. So thanks, pigs, that'll do.

Read more: https://www.wired.com/story/a-robot-that-tugs-on-pig-organs-could-save-human-babies/

The Most Promising Cancer Treatments In a Century Have ArrivedBut Not For Everyone

In 1891, a New York doctor named William B. Coley injected a mixture of beef broth and Streptococcus bacteria into the arm of a 40-year-old Italian man with an inoperable neck tumor. The patient got terribly sick—developing a fever, chills, and vomiting. But a month later, his cancer had shrunk drastically. Coley would go on to repeat the procedure in more than a thousand patients, with wildly varying degrees of success, before the US Food and Drug Administration shut him down.

Coley’s experiments were the first forays into a field of cancer research known today as immunotherapy. Since his first experiments, the oncology world has mostly moved on to radiation and chemo treatments. But for more than a century, immunotherapy—which encompasses a range of treatments designed to supercharge or reprogram a patient’s immune system to kill cancer cells—has persisted, mostly around the margins of medicine. In the last few years, though, an explosion of tantalizing clinical results have reinvigorated the field and plunged investors and pharma execs into a spending spree.

Though he didn’t have the molecular tools to understand why it worked, Coley’s forced infections put the body’s immune system into overdrive, allowing it to take out cancer cells along the way. While the FDA doesn’t have a formal definition for more modern immunotherapies, in the last few years it has approved at least eight drugs that fit the bill, unleashing a flood of money to finance new clinical trials. (Patients had better come with floods of money too—prices can now routinely top six figures.)

But while the drugs are dramatically improving the odds of survival for some patients, much of the basic science is still poorly understood. And a growing number of researchers worry that the sprint to the clinic offers cancer patients more hype than hope.

When immunotherapy works, it really works. But not for every kind of cancer, and not for every patient—not even, it turns out, for the majority of them. “The reality is immunotherapy is incredibly valuable for the people who can actually benefit from it, but there are far more people out there who don’t benefit at all,” says Vinay Prasad, an Oregon Health and Science University oncologist.

Prasad has come to be regarded as a professional cancer care critic, thanks to his bellicose Twitter style and John Arnold Foundation-backed crusade against medical practices he says are based on belief, not scientific evidence. Using national cancer statistics and FDA approval records, Prasad recently estimated the portion of all patients dying from all types of cancer in America this year who might actually benefit from immunotherapy. The results were disappointing: not even 10 percent.

Now, that’s probably a bit of an understatement. Prasad was only looking at the most widely used class of immunotherapy drugs in a field that is rapidly expanding. Called checkpoint inhibitors, they work by disrupting the immune system’s natural mechanism for reining in T cells, blood-borne sentinels that bind and kill diseased cells throughout the body. The immune cells are turned off most of the time, thanks to proteins that latch on to a handful of receptors on their surface. But scientists designed antibodies to bind to those same receptors, knocking out the regulatory protein and keeping the cells permanently switched to attack mode.

The first checkpoint inhibitors just turned T cells on. But some of the newer ones can work more selectively, using the same principle to jam a signal that tumors use to evade T cells. So far, checkpoint inhibitors have shown near-miraculous results for a few rare, previously incurable cancers like Hodgkin’s lymphoma, renal cell carcinoma, and non-small cell lung cancer. The drugs are only approved to treat those conditions, leaving about two-thirds of terminal cancer patients without an approved immunotherapy option.

But Prasad says that isn’t stopping physicians from prescribing the drugs anyway.

“Hype has encouraged rampant off-label use of checkpoint inhibitors as a last-ditch effort,” he says—even for patients with tumors that show no evidence they’ll respond to the drugs. The antibodies are available off the shelf, but at a list price near $150,000 per year, it’s an investment Prasad says doctors shouldn’t encourage lightly. Especially when there’s no reliable way of predicting who will respond and who won’t. “This thwarts one of the goals of cancer care," says Prasad. "When you run out of helpful responses, how do you help a patient navigate what it means to die well?”

Merck and Bristol-Myers Squibb have dominated this first wave of immunotherapy, selling almost $9 billion worth of checkpoint inhibitors since they went on sale in 2015. Roche, AstraZeneca, Novartis, Eli Lilly, Abbvie, and Regeneron have all since jumped in the game, spending billions on acquiring biotech startups and beefing up in-house pipelines. And 800 clinical trials involving a checkpoint inhibitor are currently underway in the US, compared with about 200 in 2015. “This is not sustainable,” Genentech VP of cancer immunology Ira Mellman told the audience at last year’s annual meeting of the Society for Immunotherapy of Cancer. With so many trials, he said, the industry was throwing every checkpoint inhibitor combination at the wall just to see what would stick.

After more than a decade stretching out the promise of checkpoint inhibitors, patients—and businesses—were ready for something new. And this year, they got it: CAR T cell therapy. The immunotherapy involves extracting a patient’s T cells and genetically rewiring them so they can more efficiently home in on tumors in the body—training a foot soldier as an assassin that can slip behind enemy lines.

In September, the FDA cleared the first CAR-T therapy—a treatment for children with advanced leukemia, developed by Novartis—which made history as the first-ever gene therapy approved for market. A month later the agency approved another live cell treatment, developed by Kite Pharma, for a form of adult lymphoma. In trials for the lymphoma drug, 50 percent of patients saw their cancer disappear completely, and stay gone.

Kite’s ascendance in particular is a stunning indicator of how much money CAR-T therapy has attracted, and how fast. The company staged a $128 million IPO in 2014—when it had only a single late-phase clinical trial to its name—and sold to Gilead Science in August for $11.9 billion. For some context, consider that when Pfizer bought cancer drugmaker Medivation for $14 billion last year—one of the biggest pharma deals of 2016—the company already had an FDA-approved blockbuster tumor-fighter on the market with $2 billion in annual sales, plus two late-stage candidates in the pipeline.

While Kite and Novartis were the only companies to actually launch products in 2017, more than 40 other pharma firms and startups are currently building pipelines. Chief rival Juno Therapeutics went public with a massive $265 million initial offering—the largest biotech IPO of 2014—before forming a $1 billion partnership with Celgene in 2015. In the last few years, at least half a dozen other companies have made similar up-front deals worth hundreds of millions.

These treatments will make up just a tiny slice of the $107 billion cancer drug market. Only about 600 people a year, for example, could benefit from Novartis’ flagship CAR-T therapy. But the company set the price for a full course of treatment at a whopping $475,000. So despite the small clientele, the potential payoff is huge—and the technology is attracting a lot of investor interest. “CAR-T venture financing is still a small piece of total venture funding in oncology, but given that these therapies are curative for a majority of patients that have received them in clinical trials, the investment would appear to be justified,” says Mandy Jackson, a managing editor for research firm Informa Pharma Intelligence.

CAR-T, with its combination of gene and cell therapies, may be the most radical anticancer treatment ever to arrive in clinics. But the bleeding edge of biology can be a dangerous place for patients.

Sometimes, the modified T cells go overboard, excreting huge quantities of molecules called cytokines that lead to severe fevers, low blood pressure, and difficulty breathing. In some patients it gets even worse. Sometimes the blood-brain barrier inexplicably breaks down—and the T cells and their cytokines get inside patients’ skulls. Last year, Juno pulled the plug on its lead clinical trial after five leukemia patients died from massive brain swelling. Other patients have died in CAR-T trials at the National Cancer Institute and the University of Pennsylvania.

Scientists don’t fully understand why some CAR-T patients experience cytokine storms and neurotoxicity and others come out cured. “It’s kind of like the equivalent of getting on a Wright Brother’s airplane as opposed to walking on a 747 today,” says Wendell Lim, a biophysical chemist and director of the UC San Francisco Center for Systems and Synthetic Biology. To go from bumping along at a few hundred feet to cruise control at Mach 0.85 will mean equipping T cells with cancer-sensing receptors that are more specific than the current offerings.

Take the two FDA-approved CAR-T cell therapies, he says. They both treat blood cancers in which immune responders called B cells become malignant and spread throughout the body. Doctors reprogram patients’ T cells to seek out a B cell receptor called CD-19. When they find it, they latch on and shoot it full of toxins. Thing is, the reprogrammed T cells can’t really tell the difference between cancerous B cells and normal ones. The therapy just takes them all out. Now, you can live without B cells if you receive antibody injections to compensate—so the treatment works out fine most of the time.

But solid tumors are trickier—they’re made up of a mix of cells with different genetic profiles. Scientists have to figure out which tumor cells matter to the growth of the cancer and which ones don’t. Then they have to design T cells with antigens that can target just those ones and nothing else. An ideal signature would involve two to three antigens that your assassin T cells can use to pinpoint the target with a bullet instead of a grenade.

Last year Lim launched a startup called Cell Design Labs to try to do just that, as well as creating a molecular on-off-switch to make treatments more controlled. Only if researchers can gain this type of precise command, says Lim, will CAR-T treatments become as safe and predictable as commercial airline flight.

The field has matured considerably since Coley first shot his dying patient full of a dangerous bacteria, crossed his fingers, and hoped for the best. Sure, the guy lived, even making a miraculous full recovery. But many after him didn’t. And that “fingers crossed” approach still lingers over immunotherapy today.

All these years later, the immune system remains a fickle ally in the war on cancer. Keeping the good guys from going double-agent is going to take a lot more science. But at least the revolution will be well-financed.

Read more: https://www.wired.com/story/cancer-immunotherapy-has-arrived-but-not-for-everyone/

The AI-Engineered, 3-D Printed Cast That Wont Drive You Crazy

When a car hit San Franciscan cyclist Seth McGinnis, he flew seven feet into the air before landing on his wrist. He broke it in two places, chipping his elbow in the process.

After weeks of wearing a traditional cast, McGinnis was miserable. It smelled. It itched. He couldnt shower. He couldnt swim. He couldnt exercise properly. He wanted something differentsomething light, breathable, comfortable.

Thats when a friend told him about a Silicon Valley firm, Autodesk, that wanted to design a new kind of cast. But McGinnis doctors were skeptical.

It was at that point I started advocating for my own health care, McGinnis said. He went against his doctors advice. He had a friend cut the cast from his arm using a handheld rotary saw, and opted for something completely untested: a cast created through a collaborative effort between man and machine.

Cue Arthur Harsuvanakit, a designer for Autodesk, whose team turned to the companys generative design software for the project. They call it computer-aided design, but its more like an artificially intelligent engineer that collaborates with a human counterpart. Harsuvanakit described the process like this: We scan the persons hand, using a 3-D scanner, and we identify where exactly it needs the most support.

He then designed a traditional-looking cast and input that into the software, noting the areas that needed the most support. In McGinnis case, that meant both sides of his left forearm and thumb.

Harsuvanakits design had to be optimized, removing material to make it lighter and more efficient without sacrificing support or structural integrity. Its a bit of a black box, Harsuvanakit said about the optimization process. More times than not, it breaks your assumptions on the solutions you think your setup will provide.

The software runs off an internal feedback loop, using sophisticated physics models to figure out the best way to achieve the goals set by the human designer. After testing hundreds of designs in less than an hour, the software presents a handful of the best. Harsuvanakit plays curator and editor.

Its kind of a back and forth between the computer and the designer, he said. Youre editing and changing design direction based on what it can give you.

The goal is to make the strongest, lightest, most functional design possible. When Harsuvanakit sees a design he likes, he pulls up the model and tells the computer to further optimize the shape and solve for a new variable.

For McGinnis, they started with the most supportive cast possible. Then, Harsuvanakit and his team solved for other variables like weight, breathability, and comforteach iteration subjected to McGinnis feedback. Early in the experimental process, each version took about a week to create. By the end, however, it was less than a day.

With every result, Harsuvanakit would make a few changes to the computers design and feed it back into the software, where the process would repeat itself. When Harsuvanakit was satisfied, he would 3-D print the finished product.

The result was a ready-to-wear, space-age looking, hard plastic cast with branching supports weaving along the top of McGinnis forearm like tree roots, connecting two natural bridges on each side. Harsuvanakit and his team included two hinges to make the cast removable, which was the only way McGinnis could use the cast since it couldnt be printed directly onto his body.

In total, the team went through seven prototypes before settling on a final design.

That's not to say the process was completely smooth. Harsuvanakit originally designed the prototypes to fit McGinnis right arm, even though the left one was the one that was broken (they didnt want to take him out of the cast before they had a functioning prototype). But the final productthey simply mirrored the cast for his broken armdidnt fit. McGinnis had to resort to electrical tape to put the traditional cast back together and wear it for one more day.

The first day I went swimming in the pool and did laps, I was blown away at how nice it felt, McGinnis said. Between waterproofing, breathability, and accessibility to any itchy areasno coat hangers required!he only wishes he couldve gotten it sooner.

McGinnis only wore the cast for the last month of his three-month healing process. Since his doctors declined to participate, we cant know for sure that its medically viablethough McGinnis physical therapists say that hes recovered well and McGinnis himself says that he healed faster because of it.

From Autodesks perspective, the experiment was a rousing success, adding to their portfolio of generatively designed products that already included furniture, power tools, and engine blocks.

Still, Harsuvanakit admits, the technology isnt ready for widespread medical use. Its more of a proof-of-concept at this point, he said. He noted that the iteration time would need to be quicker and the software needs to be more streamlined. Next steps include getting the backing of a healthcare provider for financial backing and continued experimentation for FDA trials.

Right now, its a great talking piece for the health industry, Harsuvanakit said. But he knows it will be more.

Read more: https://www.thedailybeast.com/the-ai-engineered-3-d-printed-cast-that-wont-drive-you-crazy

The FDA has approved a blood sugar monitor that doesnt require a finger prick

Further proof the U.S. Food and Drug Administration has been warming up to modern technology — it has just approved the first continuous blood sugar monitor that doesn’t require the user to prick themselves over and over for a blood sample.

Today, the FDA cleared Abbot’s FreeStyle Libre Flash Glucose Monitoring System, a device that uses a small sensor wire inserted under the skin to determine glucose levels in adult diabetics. Another wand-like device is then waved over the sensor to measure and give a readout of those glucose levels.

This is a milestone move for the FDA as diabetes affects nearly 30 million people in the United States who currently have to test their blood sugar by pricking themselves several times throughout the day and every time they eat.

However, the idea for a prickless blood sugar monitor isn’t new. Tech companies have increasingly shown an interest in the massive diabetics market over the past few years. Apple is rumored to be working on such a device and its CEO Tim Cook has even been spotted wearing a possible prototype that could connect to the Apple Watch.

Other companies endeavor to build something similar, including Glucowise, which has a device still under development.

However, it seems it’s not so easy to create a needleless blood sugar detector. Google tried to build a contact lens that could detect glucose but it seems the project has gone nowhere since drug company Novartis licensed the tech in 2014. Another FDA-approved device for glucose monitoring without the prick called the GlucoWatch was approved in the early 2000’s, but consumers found it cumbersome and it happened to cause a bad rash in some.

But there’s new hope today that the Freestyle monitor has worked out all the kinks. The device is intended for those 18 and older and, after a 12-hour start-up period, can be worn for up to 10 days, according to a statement on the FDA’s website.

“The FDA is always interested in new technologies that can help make the care of people living with chronic conditions, such as diabetes, easier and more manageable,” said FDA spokesperson Donald St. Pierre. “This system allows people with diabetics to avoid the additional step of finger stick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes—with a wave of the mobile reader.”

Read more: https://techcrunch.com/2017/09/28/the-fda-has-approved-the-first-blood-sugar-monitor-that-doesnt-require-a-finger-prick/