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/

Think twice about buying ‘squashed-faced’ breeds, vets urge dog-lovers

British Veterinary Association launches #breedtobreathe campaign to highlight serious health issues breeds such as pugs and French bulldogs are prone to

Vets have urged dog-lovers to think twice about buying squashed-faced dogs such as pugs and French bulldogs, after many would-be owners were found to be unaware of the health problems such breeds often experience.

According to data from the Kennel Club, registrations of squashed-faced, or brachycephalic, breeds have shot up in recent years: while just 692 French bulldogs were registered in 2007, registrations reached 21,470 in 2016.

Certain DNA variations in dogs are linked to a short skull shape. The animals baby-like faces with large, round, wide-set eyes and flat noses are known to be a key factor in why owners choose such breeds: over time those traits have been bred for, and in some cases have been taken to extremes.

This selective breeding and prioritising appearance over health has left the breeds prone to skin disorders, eye ulcers and breathing difficulties among other problems.

Now the British Veterinary Association (BVA) has launched a campaign dubbed #breedtobreathe to draw attention to the issues, revealing that a new survey of 671 vets found 75% of owners were unaware of the health problems of brachycephalic breeds before they chose their squashed-faced dog. Moreover the vets said just 10% of owners could spot health problems related to such breeds, with many thinking that problems including snorting were normal for such dogs.

Brachycephalic dogs graph

The survey also revealed that 49% of vets thought advertising and social media were among the reasons behind the surge in ownership of these dogs, while 43% said celebrity ownership was one of the driving factors.

We find that our veterinary surgeons are finding increasing numbers of flat-faced dogs are coming into their practices with problems which are related to the way these animals are made, said John Fishwick, president of the BVA. One of the things that is causing this increase that we have seen over the last few years appears to be celebrity endorsements and their use in advertising.

Among those criticised by the BVA are pop star Lady Gaga, who is often photographed with her French bulldogs, and YouTube star Zoella, whose pug features in her videos. Big brands are also targeted; the organisation revealed that Heinz, Costa and Halifax have all agreed to avoid using squashed-faced dogs in future advertising.

Q&A

What sort of health problems do brachycephalic dogs have?

Breeds such as pugs, bulldogs, French bulldogs and boxers are prone to a range of health problems, many of which are related to their short skulls and other characteristic features.

Breathing problems

Brachycephalic breeds often have narrow nostrils, deformed windpipes and excess soft tissues inside their nose and throat all of which can lead to difficulties with breathing, which can also lead to heart problems. The dogs are also prone to overheating.

Dental problems

The shortened upper jaws of squashed-faced dogs means their teeth are crowded, increasing the risk of tooth decay and gum disease.

Skin disorders

The deep folds around the dogs faces, such as the characteristic wrinkles of a bulldog, also bring problems as they are prone to yeast and bacterial infections.

Eye conditions

The head shape and prominent eyes of brachycephalic breeds means the dogs are at risk of eye conditions including ulcers. Among the causes of eye ulcers is that brachycephalic dogs often cannot blink properly and have problems with tear production, while eyelashes or nasal folds can also rub the surface of their eyes.

Birth problems

Brachycephalic breeds can have difficulties giving birth naturally because of the disproportionate size of the puppies heads, meaning that caesarean sections are often necessary. According torecent researchmore than 80% of Boston terrier, bulldog and French bulldog puppies in the UK are born in this manner.

The BVA is urging people to send letters to brands asking them not to use such dogs in promotional material. The campaign also aims to raise awareness of potential health problems of squashed-face breeds, and stresses the need for vets, owners, dog-show judges, breeders, researchers and others to work together to make sure the breeds are healthy.

They are lovely breeds of dog, they are very friendly and they make good pets, said Fishwick. The problem is a lot of them are really struggling, and we really want to make sure people understand this and encourage them to think about either going for another breed or a healthier version of these breeds ones which have been bred to have a longer snout or possibly even cross breeds.

The BVA warned that without action, the number of corrective surgeries needed on such animals will soar.

Caroline Kisko, secretary of the Kennel Club urged owners to do their homework before buying a squashed-faced dog. As soon as you get a market drive then the puppy farms just say ooh well breed those now, she said.

But Dr Rowena Packer of the Royal Veterinary College (RVC) said the problem is not confined to new owners, with recent research from the RVC finding that more than 90% of pug, French bulldog and English bulldog owners said they would own another such dog in the future. It is not just going to be a flash in the pan that we see this huge surge and then it goes away, she said.

It has been suggested that vets may be unwilling to speak out for fear that owners will simply take their pets elsewhere, damaging business.

But Packer disagrees, saying: I dont think any vet went into [the job] hoping that their salary would be paid by the suffering of dogs who have been bred to effectively have problems.

Dr Crina Dragu, a London-based veterinary surgeon, noted that not all squashed-faced dogs have problems. You see the ones that have happy lives, normal lives, and you see the ones that the minute they are born they spend their entire lives as though [they are being smothered] with a pillow all day, every day, she said.

Packer said prospective owners should be aware squashed-faced dogs can be an expensive commitment: I think they need to be aware of both the emotional and financial hardship that they could be putting themselves and their dogs through for potentially five to 10 years.

Read more: https://www.theguardian.com/lifeandstyle/2018/jan/05/think-twice-about-buying-squashed-faced-breeds-vets-urge-dog-lovers

Google Is Giving Away AI That Can Build Your Genome Sequence

Today, a teaspoon of spit and a hundred bucks is all you need to get a snapshot of your DNA. But getting the full picture—all 3 billion base pairs of your genome—requires a much more laborious process. One that, even with the aid of sophisticated statistics, scientists still struggle over. It’s exactly the kind of problem that makes sense to outsource to artificial intelligence.

On Monday, Google released a tool called DeepVariant that uses deep learning—the machine learning technique that now dominates AI—to assemble full human genomes. Modeled loosely on the networks of neurons in the human brain, these massive mathematical models have learned how to do things like identify faces posted to your Facebook news feed, transcribe your inane requests to Siri, and even fight internet trolls. And now, engineers at Google Brain and Verily (Alphabet’s life sciences spin-off) have taught one to take raw sequencing data and line up the billions of As, Ts, Cs, and Gs that make you you.

And oh yeah, it’s more accurate than all the existing methods out there. Last year, DeepVariant took first prize in an FDA contest promoting improvements in genetic sequencing. The open source version the Google Brain/Verily team introduced to the world Monday reduced the error rates even further—by more than 50 percent. Looks like grandmaster Ke Jie isn’t be the only one getting bested by Google’s AI neural networks this year.

DeepVariant arrives at a time when healthcare providers, pharma firms, and medical diagnostic manufacturers are all racing to capture as much genomic information as they can. To meet the need, Google rivals like IBM and Microsoft are all moving into the healthcare AI space, with speculation about whether Apple and Amazon will follow suit. While DeepVariant’s code comes at no cost, that isn’t true of the computing power required to run it. Scientists say that expense is going to prevent it from becoming the standard anytime soon, especially for large-scale projects.

But DeepVariant is just the front end of a much wider deployment; genomics is about to go deep learning. And once you go deep learning, you don’t go back.

It’s been nearly two decades since high-throughput sequencing escaped the labs and went commercial. Today, you can get your whole genome for just $1,000 (quite a steal compared to the $1.5 million it cost to sequence James Watson’s in 2008).

But the data produced by today’s machines still only produce incomplete, patchy, and glitch-riddled genomes. Errors can get introduced at each step of the process, and that makes it difficult for scientists to distinguish the natural mutations that make you you from random artifacts, especially in repetitive sections of a genome.

See, most modern sequencing technologies work by taking a sample of your DNA, chopping it up into millions of short snippets, and then using fluorescently-tagged nucleotides to produce reads—the list of As, Ts, Cs, and Gs that correspond to each snippet. Then those millions of reads have to be grouped into abutting sequences and aligned with a reference genome.

That’s the part that gives scientists so much trouble. Assembling those fragments into a usable approximation of the actual genome is still one of the biggest rate-limiting steps for genetics. A number of software programs exist to help put the jigsaw pieces together. FreeBayes, VarDict, Samtools, and the most well-used, GATK, depend on sophisticated statistical approaches to spot mutations and filter out errors. Each tool has strengths and weaknesses, and scientists often wind up having to use them in conjunction.

No one knows the limitations of the existing technology better than Mark DePristo and Ryan Poplin. They spent five years creating GATK from whole cloth. This was 2008: no tools, no bioinformatics formats, no standards. “We didn’t even know what we were trying to compute!” says DePristo. But they had a north star: an exciting paper that had just come out, written by a Silicon Valley celebrity named Jeff Dean. As one of Google’s earliest engineers, Dean had helped design and build the fundamental computing systems that underpin the tech titan’s vast online empire. DePristo and Poplin used some of those ideas to build GATK, which became the field’s gold standard.

But by 2013, the work had plateaued. “We tried almost every standard statistical approach under the sun, but we never found an effective way to move the needle,” says DePristo. “It was unclear after five years whether it was even possible to do better.” DePristo left to pursue a Google Ventures-backed start-up called SynapDx that was developing a blood test for autism. When that folded two years later, one of its board members, Andrew Conrad (of Google X, then Google Life Sciences, then Verily) convinced DePristo to join the Google/Alphabet fold. He was reunited with Poplin, who had joined up the month before.

And this time, Dean wasn’t just a citation; he was their boss.

As the head of Google Brain, Dean is the man behind the explosion of neural nets that now prop up all the ways you search and tweet and snap and shop. With his help, DePristo and Poplin wanted to see if they could teach one of these neural nets to piece together a genome more accurately than their baby, GATK.

The network wasted no time in making them feel obsolete. After training it on benchmark datasets of just seven human genomes, DeepVariant was able to accurately identify those single nucleotide swaps 99.9587 percent of the time. “It was shocking to see how fast the deep learning models outperformed our old tools,” says DePristo. Their team submitted the results to the PrecisionFDA Truth Challenge last summer, where it won a top performance award. In December, they shared them in a paper published on bioRxiv.

DeepVariant works by transforming the task of variant calling—figuring out which base pairs actually belong to you and not to an error or other processing artifact—into an image classification problem. It takes layers of data and turns them into channels, like the colors on your television set. In the first working model they used three channels: The first was the actual bases, the second was a quality score defined by the sequencer the reads came off of, the third contained other metadata. By compressing all that data into an image file of sorts, and training the model on tens of millions of these multi-channel “images,” DeepVariant began to be able to figure out the likelihood that any given A or T or C or G either matched the reference genome completely, varied by one copy, or varied by both.

But they didn’t stop there. After the FDA contest they transitioned the model to TensorFlow, Google's artificial intelligence engine, and continued tweaking its parameters by changing the three compressed data channels into seven raw data channels. That allowed them to reduce the error rate by a further 50 percent. In an independent analysis conducted this week by genomics computing platform, DNAnexus, DeepVariant vastly outperformed GATK, Freebayes, and Samtools, sometimes reducing errors by as much as 10-fold.

“That shows that this technology really has an important future in the processing of bioinformatic data,” says DNAnexus CEO, Richard Daly. “But it’s only the opening chapter in a book that has 100 chapters.” Daly says he expects this kind of AI to one day actually find the mutations that cause disease. His company received a beta version of DeepVariant, and is now testing the current model with a limited number of its clients—including pharma firms, big health care providers, and medical diagnostic companies.

To run DeepVariant effectively for these customers, DNAnexus has had to invest in newer generation GPUs to support its platform. The same is true for Canadian competitor, DNAStack, which plans to offer two different versions of DeepVariant—one tuned for low cost and one tuned for speed. Google’s Cloud Platform already supports the tool, and the company is exploring using the TPUs (tensor processing units) that connect things like Google Search, Street View, and Translate to accelerate the genomics calculations as well.

DeepVariant’s code is open-source so anyone can run it, but to do so at scale will likely require paying for a cloud computing platform. And it’s this cost—computationally and in terms of actual dollars—that have researchers hedging on DeepVariant’s utility.

“It’s a promising first step, but it isn’t currently scalable to a very large number of samples because it’s just too computationally expensive,” says Daniel MacArthur, a Broad/Harvard human geneticist who has built one of the largest libraries of human DNA to date. For projects like his, which deal in tens of thousands of genomes, DeepVariant is just too costly. And, just like current statistical models, it can only work with the limited reads produced by today’s sequencers.

Still, he thinks deep learning is here to stay. “It’s just a matter of figuring out how to combine better quality data with better algorithms and eventually we’ll converge on something pretty close to perfect,” says MacArthur. But even then, it’ll still just be a list of letters. At least for the foreseeable future, we’ll still need talented humans to tell us what it all means.

Read more: https://www.wired.com/story/google-is-giving-away-ai-that-can-build-your-genome-sequence/

Jennifer Doudna: I have to be true to who I am as a scientist

Crispr inventor Jennifer Doudna talks about discovering the gene-editing tool, the split with her collaborator and the complex ethics of genetic manipulation

Jennifer Doudna, 53, is an American biochemist based at the University of California, Berkeley. Together with the French microbiologist Emmanuelle Charpentier, she led the discovery of the revolutionary gene-editing tool, Crispr. The technology has the potential to eradicate previously incurable diseases, but also poses ethical questions about the possible unintended consequences of overwriting the human genome.

Were you nerdy as a child? What got youhooked on science?
Yes, I was nerdy. My father was a professor of American literature in Hawaii and he loved books. One day I came home from school and he haddropped a copy of The Double Helixon the bed, by Jim Watson. Onerainy afternoon I read it and Iwasjust stunned. I was blown awaythat you could do experiments about what a molecule looks like. I was probably 12 or 13. I think that wasthebeginning ofstarting to think,Wow, that could be an amazingthing to work on.

Youve spent most of your career uncovering the structure of RNA and never set out to create a tool to copy andpaste human genes. How did you endup working on Crispr?
I think you can put scientists into two buckets. One is the type who dives very deeply into one topic for their whole career and they know it better than anybody else in the world. Then theresthe other bucket, where I wouldput myself, where its like youre at a buffet table and you see an interesting thing here and do it for a while, and that connects you to another interesting thing and you take a bit of that. Thats how I came to be working on Crispr it was a total side-project.

But when you first started your collaboration with Emmanuelle Charpentier, did you have a hunch youwere on to something special?
We met at a conference in San Juan, Puerto Rico, and took a walk around the old town together. She was so passionate, her excitement was very infectious. I still remember walking down this street with her and she said: Well Im really glad you want to work with us on the mysterious [Cas9 the enzyme that snips DNA at the chosen location in the editing process]. It was this kind of electrifying moment. Even then I just had this gut feeling that this was something really interesting.

How important is personal chemistry inscience collaborations?
Its essential. Working in a lab is analogous to being in a high-school play: youre rehearsing long hours, itscrowded, there are stressful things that come up. Its the same thing in science. Things never work as you think they will, experiments fail and so to have people around that really get along with each other is super important. Many collaborations dont work out, usually just because peoples interests arent aligned or people dont really like working together.

The real frenzy around your work started in 2012, when you showed that Crispr-Cas9 could be used to slice up DNA at any site [of the DNA molecule] you wanted. Did you realise this was abig deal gradually orimmediately?
It wasnt a gradual realisation, it was one of those OMG moments where you look at each other and say holy moly. This was something we hadnt thought about before, but now we could see how it worked, we could see it would be such a fantastic way to do gene editing.

After you demonstrated Crispr could edit bacterial DNA, two rival labs (Harvard and the Broad Institute) got there first in human cells. How come they beat you to it?
They were absolutely set up to do that kind of experiment. They had all the tools, the cells growing, everything was there. For us, they were hard experiments to do because its not thekind of science we do. What speaksto the ease of the system was that a lab like mine could even do it.

The Broad Institute won the latest round of an ongoing legal battle over patent rights they claim that it wasnt obvious that Crispr could be used to edit human cells too. Where do you stand?
People have asked me over and over again: Did you know it was going to work? But until you do an experiment you dont know thats science. Ive been lambasted for this in the media, but I have to be true to who I am as a scientist. We certainly had a hypothesisand it certainly seemed likea very good guess that it would.

Theres the patent dispute and you and Emmanuelle Charpentier also ended up pursuing rival projects to commercialise the technology. Are you all still friends?
If theres a sadness to me about all of this and a lot of its been wonderful and really exciting its that I wouldve loved to continue working with Emmanuelle, scientifically. For multiple reasons that wasnt desirable to her. Im not blaming her at all she had her reasons and I respect her a lot.

The media loves to drive wedges, but we are very cordial. I was just with her in Spain and she was telling me about the challenges [of building her new lab in Berlin]. I hope on her side, certainly on my side, we respect each others work and in the end were all init together.

In your book you describe a nightmare youhad involving Hitler wearing a pig mask, asking to learn more about your amazing technology. Do you still have anxiety dreams about where Crispr mightleave the human race?
I had the Hitler dream and Ive had a couple of other very scary dreams, almost like nightmares, which is quite unusual for an adult. Not so much lately, but in the first couple of years after I published my work, the field was moving so fast. I had this incredible feeling that the science was getting out way ahead of any considerations about ethics, societal implications and whether we should be worrying about random people in various parts of the world using this for nefarious purposes.

In 2015, you called for a moratorium on the clinical use of gene editing. Where do you stand on using Crispr to edit embryos these days?
It shouldnt be used clinically today, but in the future possibly. Thats a big change for me. At first, I just thought why would you ever do it? Then I started to hear from people with genetic diseases in their family this is now happening every day for me. Alot of them send me pictures of their children. There was one that Icant stop thinking about, just sent to me in the last 10 days or so. A mother who told me that her infant son was diagnosed with a neurodegenerative disease, caused by a sporadic rare mutation. She sent me a picture of thislittle boy. He was this adorable little baby, he was bald, in his little carrier and so cute. I have a son and myheart just broke.

What would you do as a mother? You see your child and hes beautiful, hes perfect and you know hes going to suffer from this horrible disease and theres nothing you can do about it. Its horrible. Getting exposed to that, getting to know some of these people, its not abstract any more, its very personal. And you think, if there were away to help these people, we should do it. It would be wrong not to.

What about the spectre of designerbabies?
A lot of it will come down to whether the technology is safe and effective, are there alternatives that would be equally effective that we should consider, and what are the broader societal implications of allowing gene editing? Are people going to start saying I want a child thats 6ft 5in and has blue eyes and so on? Do we really want to go there? Would you do things that are not medically necessary but are just nice-to-haves, for some people?Its a hard question. There area lot of grey areas.

Are you worried about cuts to science funding, including to the National Institutes of Health (NIH) budget?
I am very concerned. Science funding is not a political football but in fact a down payment on discovery, the seed money to fund a critical step toward ending Alzheimers or curing cancer.

Researchers currently working on projects aimed at improving numerous aspects of our agriculture, environment and health may be forced to abandon their work. The outcome is that people will not receive the medical treatments they need, our struggle to feed our exploding population will deepen, and our efforts to manage climate change will collapse.

Over the long term, the very role of fundamental science as a means to better our society may come into question. History and all evidence points to the fact that when we inspire and support our scientific community we advance our way of life and thrive.

Were you disturbed when Trump tweeted, If U.C. Berkeley does not allow free speech and practices violence on innocent people with a different point of view NO FEDERAL FUNDS? in response to a planned alt-right speaker being cancelled due to violent protests on campus?
Yes. It was a confusing tweet since the university was clearly committed to ensuring that the event would proceed safely and first amendment rights were supported. Few expected the awful actions of a few to be met with a willingness from the highest office to deprive more than 38,000 students access to an education.

Youve spoken at Davos, shared the $3m2015 Breakthrough prize, been listedamong the 100 most influential people in the world by Time magazine. Areyou still motivated about heading intothe lab these days?
Yesterday I was getting ready to go to a fancy dinner. I was in a cocktail gown and had my makeup on and my hair done, but I wanted to talk to a postdoc in my lab about an experiment he was doing, so I texted him saying can we Skype? It was 8am in California, I was over here [in the UK] in my full evening gown, talking abouttheexperiment.Thats how nerdy I am.

A Crack in Creation: The New Power to Control Evolution by Jennifer Doudna and Sam Sternberg is published by The Bodley Head (20). To order a copy for 17 go to bookshop.theguardian.com or call 0330 333 6846. Free UK p&p over 10, online orders only. Phone orders min p&p of 1.99

Read more: https://www.theguardian.com/science/2017/jul/02/jennifer-doudna-crispr-i-have-to-be-true-to-who-i-am-as-a-scientist-interview-crack-in-creation