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#437809 Q&A: The Masterminds Behind ...
Illustration: iStockphoto
Getting a car to drive itself is undoubtedly the most ambitious commercial application of artificial intelligence (AI). The research project was kicked into life by the 2004 DARPA Urban Challenge and then taken up as a business proposition, first by Alphabet, and later by the big automakers.
The industry-wide effort vacuumed up many of the world’s best roboticists and set rival companies on a multibillion-dollar acquisitions spree. It also launched a cycle of hype that paraded ever more ambitious deadlines—the most famous of which, made by Alphabet’s Sergei Brin in 2012, was that full self-driving technology would be ready by 2017. Those deadlines have all been missed.
Much of the exhilaration was inspired by the seeming miracles that a new kind of AI—deep learning—was achieving in playing games, recognizing faces, and transliterating voices. Deep learning excels at tasks involving pattern recognition—a particular challenge for older, rule-based AI techniques. However, it now seems that deep learning will not soon master the other intellectual challenges of driving, such as anticipating what human beings might do.
Among the roboticists who have been involved from the start are Gill Pratt, the chief executive officer of Toyota Research Institute (TRI) , formerly a program manager at the Defense Advanced Research Projects Agency (DARPA); and Wolfram Burgard, vice president of automated driving technology for TRI and president of the IEEE Robotics and Automation Society. The duo spoke with IEEE Spectrum’s Philip Ross at TRI’s offices in Palo Alto, Calif.
This interview has been condensed and edited for clarity.
IEEE Spectrum: How does AI handle the various parts of the self-driving problem?
Photo: Toyota
Gill Pratt
Gill Pratt: There are three different systems that you need in a self-driving car: It starts with perception, then goes to prediction, and then goes to planning.
The one that by far is the most problematic is prediction. It’s not prediction of other automated cars, because if all cars were automated, this problem would be much more simple. How do you predict what a human being is going to do? That’s difficult for deep learning to learn right now.
Spectrum: Can you offset the weakness in prediction with stupendous perception?
Photo: Toyota Research Institute for Burgard
Wolfram Burgard
Wolfram Burgard: Yes, that is what car companies basically do. A camera provides semantics, lidar provides distance, radar provides velocities. But all this comes with problems, because sometimes you look at the world from different positions—that’s called parallax. Sometimes you don’t know which range estimate that pixel belongs to. That might make the decision complicated as to whether that is a person painted onto the side of a truck or whether this is an actual person.
With deep learning there is this promise that if you throw enough data at these networks, it’s going to work—finally. But it turns out that the amount of data that you need for self-driving cars is far larger than we expected.
Spectrum: When do deep learning’s limitations become apparent?
Pratt: The way to think about deep learning is that it’s really high-performance pattern matching. You have input and output as training pairs; you say this image should lead to that result; and you just do that again and again, for hundreds of thousands, millions of times.
Here’s the logical fallacy that I think most people have fallen prey to with deep learning. A lot of what we do with our brains can be thought of as pattern matching: “Oh, I see this stop sign, so I should stop.” But it doesn’t mean all of intelligence can be done through pattern matching.
“I asked myself, if all of those cars had automated drive, how good would they have to be to tolerate the number of crashes that would still occur?”
—Gill Pratt, Toyota Research Institute
For instance, when I’m driving and I see a mother holding the hand of a child on a corner and trying to cross the street, I am pretty sure she’s not going to cross at a red light and jaywalk. I know from my experience being a human being that mothers and children don’t act that way. On the other hand, say there are two teenagers—with blue hair, skateboards, and a disaffected look. Are they going to jaywalk? I look at that, you look at that, and instantly the probability in your mind that they’ll jaywalk is much higher than for the mother holding the hand of the child. It’s not that you’ve seen 100,000 cases of young kids—it’s that you understand what it is to be either a teenager or a mother holding a child’s hand.
You can try to fake that kind of intelligence. If you specifically train a neural network on data like that, you could pattern-match that. But you’d have to know to do it.
Spectrum: So you’re saying that when you substitute pattern recognition for reasoning, the marginal return on the investment falls off pretty fast?
Pratt: That’s absolutely right. Unfortunately, we don’t have the ability to make an AI that thinks yet, so we don’t know what to do. We keep trying to use the deep-learning hammer to hammer more nails—we say, well, let’s just pour more data in, and more data.
Spectrum: Couldn’t you train the deep-learning system to recognize teenagers and to assign the category a high propensity for jaywalking?
Burgard: People have been doing that. But it turns out that these heuristics you come up with are extremely hard to tweak. Also, sometimes the heuristics are contradictory, which makes it extremely hard to design these expert systems based on rules. This is where the strength of the deep-learning methods lies, because somehow they encode a way to see a pattern where, for example, here’s a feature and over there is another feature; it’s about the sheer number of parameters you have available.
Our separation of the components of a self-driving AI eases the development and even the learning of the AI systems. Some companies even think about using deep learning to do the job fully, from end to end, not having any structure at all—basically, directly mapping perceptions to actions.
Pratt: There are companies that have tried it; Nvidia certainly tried it. In general, it’s been found not to work very well. So people divide the problem into blocks, where we understand what each block does, and we try to make each block work well. Some of the blocks end up more like the expert system we talked about, where we actually code things, and other blocks end up more like machine learning.
Spectrum: So, what’s next—what new technique is in the offing?
Pratt: If I knew the answer, we’d do it. [Laughter]
Spectrum: You said that if all cars on the road were automated, the problem would be easy. Why not “geofence” the heck out of the self-driving problem, and have areas where only self-driving cars are allowed?
Pratt: That means putting in constraints on the operational design domain. This includes the geography—where the car should be automated; it includes the weather, it includes the level of traffic, it includes speed. If the car is going slow enough to avoid colliding without risking a rear-end collision, that makes the problem much easier. Street trolleys operate with traffic still in some parts of the world, and that seems to work out just fine. People learn that this vehicle may stop at unexpected times. My suspicion is, that is where we’ll see Level 4 autonomy in cities. It’s going to be in the lower speeds.
“We are now in the age of deep learning, and we don’t know what will come after.”
—Wolfram Burgard, Toyota Research Institute
That’s a sweet spot in the operational design domain, without a doubt. There’s another one at high speed on a highway, because access to highways is so limited. But unfortunately there is still the occasional debris that suddenly crosses the road, and the weather gets bad. The classic example is when somebody irresponsibly ties a mattress to the top of a car and it falls off; what are you going to do? And the answer is that terrible things happen—even for humans.
Spectrum: Learning by doing worked for the first cars, the first planes, the first steam boilers, and even the first nuclear reactors. We ran risks then; why not now?
Pratt: It has to do with the times. During the era where cars took off, all kinds of accidents happened, women died in childbirth, all sorts of diseases ran rampant; the expected characteristic of life was that bad things happened. Expectations have changed. Now the chance of dying in some freak accident is quite low because of all the learning that’s gone on, the OSHA [Occupational Safety and Health Administration] rules, UL code for electrical appliances, all the building standards, medicine.
Furthermore—and we think this is very important—we believe that empathy for a human being at the wheel is a significant factor in public acceptance when there is a crash. We don’t know this for sure—it’s a speculation on our part. I’ve driven, I’ve had close calls; that could have been me that made that mistake and had that wreck. I think people are more tolerant when somebody else makes mistakes, and there’s an awful crash. In the case of an automated car, we worry that that empathy won’t be there.
Photo: Toyota
Toyota is using this
Platform 4 automated driving test vehicle, based on the Lexus LS, to develop Level-4 self-driving capabilities for its “Chauffeur” project.
Spectrum: Toyota is building a system called Guardian to back up the driver, and a more futuristic system called Chauffeur, to replace the driver. How can Chauffeur ever succeed? It has to be better than a human plus Guardian!
Pratt: In the discussions we’ve had with others in this field, we’ve talked about that a lot. What is the standard? Is it a person in a basic car? Or is it a person with a car that has active safety systems in it? And what will people think is good enough?
These systems will never be perfect—there will always be some accidents, and no matter how hard we try there will still be occasions where there will be some fatalities. At what threshold are people willing to say that’s okay?
Spectrum: You were among the first top researchers to warn against hyping self-driving technology. What did you see that so many other players did not?
Pratt: First, in my own case, during my time at DARPA I worked on robotics, not cars. So I was somewhat of an outsider. I was looking at it from a fresh perspective, and that helps a lot.
Second, [when I joined Toyota in 2015] I was joining a company that is very careful—even though we have made some giant leaps—with the Prius hybrid drive system as an example. Even so, in general, the philosophy at Toyota is kaizen—making the cars incrementally better every single day. That care meant that I was tasked with thinking very deeply about this thing before making prognostications.
And the final part: It was a new job for me. The first night after I signed the contract I felt this incredible responsibility. I couldn’t sleep that whole night, so I started to multiply out the numbers, all using a factor of 10. How many cars do we have on the road? Cars on average last 10 years, though ours last 20, but let’s call it 10. They travel on an order of 10,000 miles per year. Multiply all that out and you get 10 to the 10th miles per year for our fleet on Planet Earth, a really big number. I asked myself, if all of those cars had automated drive, how good would they have to be to tolerate the number of crashes that would still occur? And the answer was so incredibly good that I knew it would take a long time. That was five years ago.
Burgard: We are now in the age of deep learning, and we don’t know what will come after. We are still making progress with existing techniques, and they look very promising. But the gradient is not as steep as it was a few years ago.
Pratt: There isn’t anything that’s telling us that it can’t be done; I should be very clear on that. Just because we don’t know how to do it doesn’t mean it can’t be done. Continue reading
Posted in Human Robots
#437673 Can AI and Automation Deliver a COVID-19 ...
Illustration: Marysia Machulska
Within moments of meeting each other at a conference last year, Nathan Collins and Yann Gaston-Mathé began devising a plan to work together. Gaston-Mathé runs a startup that applies automated software to the design of new drug candidates. Collins leads a team that uses an automated chemistry platform to synthesize new drug candidates.
“There was an obvious synergy between their technology and ours,” recalls Gaston-Mathé, CEO and cofounder of Paris-based Iktos.
In late 2019, the pair launched a project to create a brand-new antiviral drug that would block a specific protein exploited by influenza viruses. Then the COVID-19 pandemic erupted across the world stage, and Gaston-Mathé and Collins learned that the viral culprit, SARS-CoV-2, relied on a protein that was 97 percent similar to their influenza protein. The partners pivoted.
Their companies are just two of hundreds of biotech firms eager to overhaul the drug-discovery process, often with the aid of artificial intelligence (AI) tools. The first set of antiviral drugs to treat COVID-19 will likely come from sifting through existing drugs. Remdesivir, for example, was originally developed to treat Ebola, and it has been shown to speed the recovery of hospitalized COVID-19 patients. But a drug made for one condition often has side effects and limited potency when applied to another. If researchers can produce an antiviral that specifically targets SARS-CoV-2, the drug would likely be safer and more effective than a repurposed drug.
There’s one big problem: Traditional drug discovery is far too slow to react to a pandemic. Designing a drug from scratch typically takes three to five years—and that’s before human clinical trials. “Our goal, with the combination of AI and automation, is to reduce that down to six months or less,” says Collins, who is chief strategy officer at SRI Biosciences, a division of the Silicon Valley research nonprofit SRI International. “We want to get this to be very, very fast.”
That sentiment is shared by small biotech firms and big pharmaceutical companies alike, many of which are now ramping up automated technologies backed by supercomputing power to predict, design, and test new antivirals—for this pandemic as well as the next—with unprecedented speed and scope.
“The entire industry is embracing these tools,” says Kara Carter, president of the International Society for Antiviral Research and executive vice president of infectious disease at Evotec, a drug-discovery company in Hamburg. “Not only do we need [new antivirals] to treat the SARS-CoV-2 infection in the population, which is probably here to stay, but we’ll also need them to treat future agents that arrive.”
There are currentlyabout 200 known viruses that infect humans. Although viruses represent less than 14 percent of all known human pathogens, they make up two-thirds of all new human pathogens discovered since 1980.
Antiviral drugs are fundamentally different from vaccines, which teach a person’s immune system to mount a defense against a viral invader, and antibody treatments, which enhance the body’s immune response. By contrast, antivirals are chemical compounds that directly block a virus after a person has become infected. They do this by binding to specific proteins and preventing them from functioning, so that the virus cannot copy itself or enter or exit a cell.
The SARS-CoV-2 virus has an estimated 25 to 29 proteins, but not all of them are suitable drug targets. Researchers are investigating, among other targets, the virus’s exterior spike protein, which binds to a receptor on a human cell; two scissorlike enzymes, called proteases, that cut up long strings of viral proteins into functional pieces inside the cell; and a polymerase complex that makes the cell churn out copies of the virus’s genetic material, in the form of single-stranded RNA.
But it’s not enough for a drug candidate to simply attach to a target protein. Chemists also consider how tightly the compound binds to its target, whether it binds to other things as well, how quickly it metabolizes in the body, and so on. A drug candidate may have 10 to 20 such objectives. “Very often those objectives can appear to be anticorrelated or contradictory with each other,” says Gaston-Mathé.
Compared with antibiotics, antiviral drug discovery has proceeded at a snail’s pace. Scientists advanced from isolating the first antibacterial molecules in 1910 to developing an arsenal of powerful antibiotics by 1944. By contrast, it took until 1951 for researchers to be able to routinely grow large amounts of virus particles in cells in a dish, a breakthrough that earned the inventors a Nobel Prize in Medicine in 1954.
And the lag between the discovery of a virus and the creation of a treatment can be heartbreaking. According to the World Health Organization, 71 million people worldwide have chronic hepatitis C, a major cause of liver cancer. The virus that causes the infection was discovered in 1989, but effective antiviral drugs didn’t hit the market until 2014.
While many antibiotics work on a range of microbes, most antivirals are highly specific to a single virus—what those in the business call “one bug, one drug.” It takes a detailed understanding of a virus to develop an antiviral against it, says Che Colpitts, a virologist at Queen’s University, in Canada, who works on antivirals against RNA viruses. “When a new virus emerges, like SARS-CoV-2, we’re at a big disadvantage.”
Making drugs to stop viruses is hard for three main reasons. First, viruses are the Spartans of the pathogen world: They’re frugal, brutal, and expert at evading the human immune system. About 20 to 250 nanometers in diameter, viruses rely on just a few parts to operate, hijacking host cells to reproduce and often destroying those cells upon departure. They employ tricks to camouflage their presence from the host’s immune system, including preventing infected cells from sending out molecular distress beacons. “Viruses are really small, so they only have a few components, so there’s not that many drug targets available to start with,” says Colpitts.
Second, viruses replicate quickly, typically doubling in number in hours or days. This constant copying of their genetic material enables viruses to evolve quickly, producing mutations able to sidestep drug effects. The virus that causes AIDS soon develops resistance when exposed to a single drug. That’s why a cocktail of antiviral drugs is used to treat HIV infection.
Finally, unlike bacteria, which can exist independently outside human cells, viruses invade human cells to propagate, so any drug designed to eliminate a virus needs to spare the host cell. A drug that fails to distinguish between a virus and a cell can cause serious side effects. “Discriminating between the two is really quite difficult,” says Evotec’s Carter, who has worked in antiviral drug discovery for over three decades.
And then there’s the money barrier. Developing antivirals is rarely profitable. Health-policy researchers at the London School of Economics recently estimated that the average cost of developing a new drug is US $1 billion, and up to $2.8 billion for cancer and other specialty drugs. Because antivirals are usually taken for only short periods of time or during short outbreaks of disease, companies rarely recoup what they spent developing the drug, much less turn a profit, says Carter.
To change the status quo, drug discovery needs fresh approaches that leverage new technologies, rather than incremental improvements, says Christian Tidona, managing director of BioMed X, an independent research institute in Heidelberg, Germany. “We need breakthroughs.”
Putting Drug Development on Autopilot
Earlier this year, SRI Biosciences and Iktos began collaborating on a way to use artificial intelligence and automated chemistry to rapidly identify new drugs to target the COVID-19 virus. Within four months, they had designed and synthesized a first round of antiviral candidates. Here’s how they’re doing it.
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STEP 1: Iktos’s AI platform uses deep-learning algorithms in an iterative process to come up with new molecular structures likely to bind to and disable a specific coronavirus protein. Illustrations: Chris Philpot
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STEP 2: SRI Biosciences’s SynFini system is a three-part automated chemistry suite for producing new compounds. Starting with a target compound from Iktos, SynRoute uses machine learning to analyze and optimize routes for creating that compound, with results in about 10 seconds. It prioritizes routes based on cost, likelihood of success, and ease of implementation.
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STEP 3: SynJet, an automated inkjet printer platform, tests the routes by printing out tiny quantities of chemical ingredients to see how they react. If the right compound is produced, the platform tests it.
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STEP 4: AutoSyn, an automated tabletop chemical plant, synthesizes milligrams to grams of the desired compound for further testing. Computer-selected “maps” dictate paths through the plant’s modular components.
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STEP 5: The most promising compounds are tested against live virus samples.
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Iktos’s AI platform was created by a medicinal chemist and an AI expert. To tackle SARS-CoV-2, the company used generative models—deep-learning algorithms that generate new data—to “imagine” molecular structures with a good chance of disabling a key coronavirus protein.
For a new drug target, the software proposes and evaluates roughly 1 million compounds, says Gaston-Mathé. It’s an iterative process: At each step, the system generates 100 virtual compounds, which are tested in silico with predictive models to see how closely they meet the objectives. The test results are then used to design the next batch of compounds. “It’s like we have a very, very fast chemist who is designing compounds, testing compounds, getting back the data, then designing another batch of compounds,” he says.
The computer isn’t as smart as a human chemist, Gaston-Mathé notes, but it’s much faster, so it can explore far more of what people in the field call “chemical space”—the set of all possible organic compounds. Unexplored chemical space is huge: Biochemists estimate that there are at least 1063 possible druglike molecules, and that 99.9 percent of all possible small molecules or compounds have never been synthesized.
Still, designing a chemical compound isn’t the hardest part of creating a new drug. After a drug candidate is designed, it must be synthesized, and the highly manual process for synthesizing a new chemical hasn’t changed much in 200 years. It can take days to plan a synthesis process and then months to years to optimize it for manufacture.
That’s why Gaston-Mathé was eager to send Iktos’s AI-generated designs to Collins’s team at SRI Biosciences. With $13.8 million from the Defense Advanced Research Projects Agency, SRI Biosciences spent the last four years automating the synthesis process. The company’s automated suite of three technologies, called SynFini, can produce new chemical compounds in just hours or days, says Collins.
First, machine-learning software devises possible routes for making a desired molecule. Next, an inkjet printer platform tests the routes by printing out and mixing tiny quantities of chemical ingredients to see how they react with one another; if the right compound is produced, the platform runs tests on it. Finally, a tabletop chemical plant synthesizes milligrams to grams of the desired compound.
Less than four months after Iktos and SRI Biosciences announced their collaboration, they had designed and synthesized a first round of antiviral candidates for SARS-CoV-2. Now they’re testing how well the compounds work on actual samples of the virus.
Out of 10
63 possible druglike molecules, 99.9 percent have never been synthesized.
Theirs isn’t the only collaborationapplying new tools to drug discovery. In late March, Alex Zhavoronkov, CEO of Hong Kong–based Insilico Medicine, came across a YouTube video showing three virtual-reality avatars positioning colorful, sticklike fragments in the side of a bulbous blue protein. The three researchers were using VR to explore how compounds might bind to a SARS-CoV-2 enzyme. Zhavoronkov contacted the startup that created the simulation—Nanome, in San Diego—and invited it to examine Insilico’s AI-generated molecules in virtual reality.
Insilico runs an AI platform that uses biological data to train deep-learning algorithms, then uses those algorithms to identify molecules with druglike features that will likely bind to a protein target. A four-day training sprint in late January yielded 100 molecules that appear to bind to an important SARS-CoV-2 protease. The company recently began synthesizing some of those molecules for laboratory testing.
Nanome’s VR software, meanwhile, allows researchers to import a molecular structure, then view and manipulate it on the scale of individual atoms. Like human chess players who use computer programs to explore potential moves, chemists can use VR to predict how to make molecules more druglike, says Nanome CEO Steve McCloskey. “The tighter the interface between the human and the computer, the more information goes both ways,” he says.
Zhavoronkov sent data about several of Insilico’s compounds to Nanome, which re-created them in VR. Nanome’s chemist demonstrated chemical tweaks to potentially improve each compound. “It was a very good experience,” says Zhavoronkov.
Meanwhile, in March, Takeda Pharmaceutical Co., of Japan, invited Schrödinger, a New York–based company that develops chemical-simulation software, to join an alliance working on antivirals. Schrödinger’s AI focuses on the physics of how proteins interact with small molecules and one another.
The software sifts through billions of molecules per week to predict a compound’s properties, and it optimizes for multiple desired properties simultaneously, says Karen Akinsanya, chief biomedical scientist and head of discovery R&D at Schrödinger. “There’s a huge sense of urgency here to come up with a potent molecule, but also to come up with molecules that are going to be well tolerated” by the body, she says. Drug developers are seeking compounds that can be broadly used and easily administered, such as an oral drug rather than an intravenous drug, she adds.
Schrödinger evaluated four protein targets and performed virtual screens for two of them, a computing-intensive process. In June, Google Cloud donated the equivalent of 16 million hours of Nvidia GPU time for the company’s calculations. Next, the alliance’s drug companies will synthesize and test the most promising compounds identified by the virtual screens.
Other companies, including Amazon Web Services, IBM, and Intel, as well as several U.S. national labs are also donating time and resources to the Covid-19 High Performance Computing Consortium. The consortium is supporting 87 projects, which now have access to 6.8 million CPU cores, 50,000 GPUs, and 600 petaflops of computational resources.
While advanced technologies could transform early drug discovery, any new drug candidate still has a long road after that. It must be tested in animals, manufactured in large batches for clinical trials, then tested in a series of trials that, for antivirals, lasts an average of seven years.
In May, the BioMed X Institute in Germany launched a five-year project to build a Rapid Antiviral Response Platform, which would speed drug discovery all the way through manufacturing for clinical trials. The €40 million ($47 million) project, backed by drug companies, will identify outside-the-box proposals from young scientists, then provide space and funding to develop their ideas.
“We’ll focus on technologies that allow us to go from identification of a new virus to 10,000 doses of a novel potential therapeutic ready for trials in less than six months,” says BioMed X’s Tidona, who leads the project.
While a vaccine will likely arrive long before a bespoke antiviral does, experts expect COVID-19 to be with us for a long time, so the effort to develop a direct-acting, potent antiviral continues. Plus, having new antivirals—and tools to rapidly create more—can only help us prepare for the next pandemic, whether it comes next month or in another 102 years.
“We’ve got to start thinking differently about how to be more responsive to these kinds of threats,” says Collins. “It’s pushing us out of our comfort zones.”
This article appears in the October 2020 print issue as “Automating Antivirals.” Continue reading
Posted in Human Robots