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On a dark night, away from city lights, the stars of the Milky Way can seem uncountable. Yet from any given location no more than 4,500 are visible to the naked eye. Meanwhile, our galaxy has 100–400 billion stars, and there are even more galaxies in the universe.
The numbers of the night sky are humbling. And they give us a deep perspective…on drugs.
Yes, this includes wow-the-stars-are-freaking-amazing-tonight drugs, but also the kinds of drugs that make us well again when we’re sick. The number of possible organic compounds with “drug-like” properties dwarfs the number of stars in the universe by over 30 orders of magnitude.
Next to this multiverse of possibility, the chemical configurations scientists have made into actual medicines are like the smattering of stars you’d glimpse downtown.
But for good reason.
Exploring all that potential drug-space is as humanly impossible as exploring all of physical space, and even if we could, most of what we’d find wouldn’t fit our purposes. Still, the idea that wonder drugs must surely lurk amid the multitudes is too tantalizing to ignore.
Which is why, Alex Zhavoronkov said at Singularity University’s Exponential Medicine in San Diego last week, we should use artificial intelligence to do more of the legwork and speed discovery. This, he said, could be one of the next big medical applications for AI.
Dogs, Diagnosis, and Drugs
Zhavoronkov is CEO of Insilico Medicine and CSO of the Biogerontology Research Foundation. Insilico is one of a number of AI startups aiming to accelerate drug discovery with AI.
In recent years, Zhavoronkov said, the now-famous machine learning technique, deep learning, has made progress on a number of fronts. Algorithms that can teach themselves to play games—like DeepMind’s AlphaGo Zero or Carnegie Mellon’s poker playing AI—are perhaps the most headline-grabbing of the bunch. But pattern recognition was the thing that kicked deep learning into overdrive early on, when machine learning algorithms went from struggling to tell dogs and cats apart to outperforming their peers and then their makers in quick succession.
[Watch this video for an AI update from Neil Jacobstein, chair of Artificial Intelligence and Robotics at Singularity University.]
In medicine, deep learning algorithms trained on databases of medical images can spot life-threatening disease with equal or greater accuracy than human professionals. There’s even speculation that AI, if we learn to trust it, could be invaluable in diagnosing disease. And, as Zhavoronkov noted, with more applications and a longer track record that trust is coming.
“Tesla is already putting cars on the street,” Zhavoronkov said. “Three-year, four-year-old technology is already carrying passengers from point A to point B, at 100 miles an hour, and one mistake and you’re dead. But people are trusting their lives to this technology.”
“So, why don’t we do it in pharma?”
Trial and Error and Try Again
AI wouldn’t drive the car in pharmaceutical research. It’d be an assistant that, when paired with a chemist or two, could fast-track discovery by screening more possibilities for better candidates.
There’s plenty of room to make things more efficient, according to Zhavoronkov.
Drug discovery is arduous and expensive. Chemists sift tens of thousands of candidate compounds for the most promising to synthesize. Of these, a handful will go on to further research, fewer will make it to human clinical trials, and a fraction of those will be approved.
The whole process can take many years and cost hundreds of millions of dollars.
This is a big data problem if ever there was one, and deep learning thrives on big data. Early applications have shown their worth unearthing subtle patterns in huge training databases. Although drug-makers already use software to sift compounds, such software requires explicit rules written by chemists. AI’s allure is its ability to learn and improve on its own.
“There are two strategies for AI-driven innovation in pharma to ensure you get better molecules and much faster approvals,” Zhavoronkov said. “One is looking for the needle in the haystack, and another one is creating a new needle.”
To find the needle in the haystack, algorithms are trained on large databases of molecules. Then they go looking for molecules with attractive properties. But creating a new needle? That’s a possibility enabled by the generative adversarial networks Zhavoronkov specializes in.
Such algorithms pit two neural networks against each other. One generates meaningful output while the other judges whether this output is true or false, Zhavoronkov said. Together, the networks generate new objects like text, images, or in this case, molecular structures.
“We started employing this particular technology to make deep neural networks imagine new molecules, to make it perfect right from the start. So, to come up with really perfect needles,” Zhavoronkov said. “[You] can essentially go to this [generative adversarial network] and ask it to create molecules that inhibit protein X at concentration Y, with the highest viability, specific characteristics, and minimal side effects.”
Zhavoronkov believes AI can find or fabricate more needles from the array of molecular possibilities, freeing human chemists to focus on synthesizing only the most promising. If it works, he hopes we can increase hits, minimize misses, and generally speed the process up.
Proof’s in the Pudding
Insilico isn’t alone on its drug-discovery quest, nor is it a brand new area of interest.
Last year, a Harvard group published a paper on an AI that similarly suggests drug candidates. The software trained on 250,000 drug-like molecules and used its experience to generate new molecules that blended existing drugs and made suggestions based on desired properties.
An MIT Technology Review article on the subject highlighted a few of the challenges such systems may still face. The results returned aren’t always meaningful or easy to synthesize in the lab, and the quality of these results, as always, is only as good as the data dined upon.
Stanford chemistry professor and Andreesen Horowitz partner, Vijay Pande, said that images, speech, and text—three of the areas deep learning’s made quick strides in—have better, cleaner data. Chemical data, on the other hand, is still being optimized for deep learning. Also, while there are public databases, much data still lives behind closed doors at private companies.
To overcome the challenges and prove their worth, Zhavoronkov said, his company is very focused on validating the tech. But this year, skepticism in the pharmaceutical industry seems to be easing into interest and investment.
AI drug discovery startup Exscientia inked a deal with Sanofi for $280 million and GlaxoSmithKline for $42 million. Insilico is also partnering with GlaxoSmithKline, and Numerate is working with Takeda Pharmaceutical. Even Google may jump in. According to an article in Nature outlining the field, the firm’s deep learning project, Google Brain, is growing its biosciences team, and industry watchers wouldn’t be surprised to see them target drug discovery.
With AI and the hardware running it advancing rapidly, the greatest potential may yet be ahead. Perhaps, one day, all 1060 molecules in drug-space will be at our disposal. “You should take all the data you have, build n new models, and search as much of that 1060 as possible” before every decision you make, Brandon Allgood, CTO at Numerate, told Nature.
Today’s projects need to live up to their promises, of course, but Zhavoronkov believes AI will have a big impact in the coming years, and now’s the time to integrate it. “If you are working for a pharma company, and you’re still thinking, ‘Okay, where is the proof?’ Once there is a proof, and once you can see it to believe it—it’s going to be too late,” he said.
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Ask any neuroscientist to draw you a neuron, and it’ll probably look something like a star with two tails: one stubby with extensive tree-like branches, the other willowy, lengthy and dotted with spindly spikes.
While a decent abstraction, this cartoonish image hides the uncomfortable truth that scientists still don’t know much about what many neurons actually look like, not to mention the extent of their connections.
But without untangling the jumbled mess of neural wires that zigzag across the brain, scientists are stumped in trying to answer one of the most fundamental mysteries of the brain: how individual neuronal threads carry and assemble information, which forms the basis of our thoughts, memories, consciousness, and self.
What if there was a way to virtually trace and explore the brain’s serpentine fibers, much like the way Google Maps allows us to navigate the concrete tangles of our cities’ highways?
Thanks to an interdisciplinary team at Janelia Research Campus, we’re on our way. Meet MouseLight, the most extensive map of the mouse brain ever attempted. The ongoing project has an ambitious goal: reconstructing thousands—if not more—of the mouse’s 70 million neurons into a 3D map. (You can play with it here!)
With map in hand, neuroscientists around the world can begin to answer how neural circuits are organized in the brain, and how information flows from one neuron to another across brain regions and hemispheres.
The first release, presented Monday at the Society for Neuroscience Annual Conference in Washington, DC, contains information about the shape and sizes of 300 neurons.
And that’s just the beginning.
“MouseLight’s new dataset is the largest of its kind,” says Dr. Wyatt Korff, director of project teams. “It’s going to change the textbook view of neurons.”
MouseLight is hardly the first rodent brain atlasing project.
The Mouse Brain Connectivity Atlas at the Allen Institute for Brain Science in Seattle tracks neuron activity across small circuits in an effort to trace a mouse’s connectome—a complete atlas of how the firing of one neuron links to the next.
MICrONS (Machine Intelligence from Cortical Networks), the $100 million government-funded “moonshot” hopes to distill brain computation into algorithms for more powerful artificial intelligence. Its first step? Brain mapping.
What makes MouseLight stand out is its scope and level of detail.
MICrONS, for example, is focused on dissecting a cubic millimeter of the mouse visual processing center. In contrast, MouseLight involves tracing individual neurons across the entire brain.
And while connectomics outlines the major connections between brain regions, the birds-eye view entirely misses the intricacies of each individual neuron. This is where MouseLight steps in.
Slice and Dice
With a width only a fraction of a human hair, neuron projections are hard to capture in their native state. Tug or squeeze the brain too hard, and the long, delicate branches distort or even shred into bits.
In fact, previous attempts at trying to reconstruct neurons at this level of detail topped out at just a dozen, stymied by technological hiccups and sky-high costs.
A few years ago, the MouseLight team set out to automate the entire process, with a few time-saving tweaks. Here’s how it works.
After injecting a mouse with a virus that causes a handful of neurons to produce a green-glowing protein, the team treated the brain with a sugar alcohol solution. This step “clears” the brain, transforming the beige-colored organ to translucent, making it easier for light to penetrate and boosting the signal-to-background noise ratio. The brain is then glued onto a small pedestal and ready for imaging.
Building upon an established method called “two-photon microscopy,” the team then tweaked several parameters to reduce imaging time from days (or weeks) down to a fraction of that. Endearingly known as “2P” by the experts, this type of laser microscope zaps the tissue with just enough photos to light up a single plane without damaging the tissue—sharper plane, better focus, crisper image.
After taking an image, the setup activates its vibrating razor and shaves off the imaged section of the brain—a waspy slice about 200 micrometers thick. The process is repeated until the whole brain is imaged.
This setup increased imaging speed by 16 to 48 times faster than conventional microscopy, writes team leader Dr. Jayaram Chandrashekar, who published a version of the method early last year in eLife.
The resulting images strikingly highlight every crook and cranny of a neuronal branch, popping out against a pitch-black background. But pretty pictures come at a hefty data cost: each image takes up a whopping 20 terabytes of data—roughly the storage space of 4,000 DVDs, or 10,000 hours of movies.
Stitching individual images back into 3D is an image-processing nightmare. The MouseLight team used a combination of computational power and human prowess to complete this final step.
The reconstructed images are handed off to a mighty team of seven trained neuron trackers. With the help of tracing algorithms developed in-house and a keen eye, each member can track roughly a neuron a day—significantly less time than the week or so previously needed.
A Numbers Game
Even with just 300 fully reconstructed neurons, MouseLight has already revealed new secrets of the brain.
While it’s widely accepted that axons, the neurons’ outgoing projection, can span the entire length of the brain, these extra-long connections were considered relatively rare. (In fact, one previously discovered “giant neuron” was thought to link to consciousness because of its expansive connections).
Images captured from two-photon microscopy show an axon and dendrites protruding from a neuron’s cell body (sphere in center). Image Credit: Janelia Research Center, MouseLight project team
MouseLight blows that theory out of the water.
The data clearly shows that “giant neurons” are far more common than previously thought. For example, four neurons normally associated with taste had wiry branches that stretched all the way into brain areas that control movement and process touch.
“We knew that different regions of the brain talked to each other, but seeing it in 3D is different,” says Dr. Eve Marder at Brandeis University.
“The results are so stunning because they give you a really clear view of how the whole brain is connected.”
With a tested and true system in place, the team is now aiming to add 700 neurons to their collection within a year.
But appearance is only part of the story.
We can’t tell everything about a person simply by how they look. Neurons are the same: scientists can only infer so much about a neuron’s function by looking at their shape and positions. The team also hopes to profile the gene expression patterns of each neuron, which could provide more hints to their roles in the brain.
MouseLight essentially dissects the neural infrastructure that allows information traffic to flow through the brain. These anatomical highways are just the foundation. Just like Google Maps, roads form only the critical first layer of the map. Street view, traffic information and other add-ons come later for a complete look at cities in flux.
The same will happen for understanding our ever-changing brain.
Image Credit: Janelia Research Campus, MouseLight project team Continue reading
“We cannot be conscious of what we are not conscious of.” – Julian Jaynes, The Origin of Consciousness in the Breakdown of the Bicameral Mind
Unlike the director leads you to believe, the protagonist of Ex Machina, Andrew Garland’s 2015 masterpiece, isn’t Caleb, a young programmer tasked with evaluating machine consciousness. Rather, it’s his target Ava, a breathtaking humanoid AI with a seemingly child-like naïveté and an enigmatic mind.
Like most cerebral movies, Ex Machina leaves the conclusion up to the viewer: was Ava actually conscious? In doing so, it also cleverly avoids a thorny question that has challenged most AI-centric movies to date: what is consciousness, and can machines have it?
Hollywood producers aren’t the only people stumped. As machine intelligence barrels forward at breakneck speed—not only exceeding human performance on games such as DOTA and Go, but doing so without the need for human expertise—the question has once more entered the scientific mainstream.
Are machines on the verge of consciousness?
This week, in a review published in the prestigious journal Science, cognitive scientists Drs. Stanislas Dehaene, Hakwan Lau and Sid Kouider of the Collège de France, University of California, Los Angeles and PSL Research University, respectively, argue: not yet, but there is a clear path forward.
The reason? Consciousness is “resolutely computational,” the authors say, in that it results from specific types of information processing, made possible by the hardware of the brain.
There is no magic juice, no extra spark—in fact, an experiential component (“what is it like to be conscious?”) isn’t even necessary to implement consciousness.
If consciousness results purely from the computations within our three-pound organ, then endowing machines with a similar quality is just a matter of translating biology to code.
Much like the way current powerful machine learning techniques heavily borrow from neurobiology, the authors write, we may be able to achieve artificial consciousness by studying the structures in our own brains that generate consciousness and implementing those insights as computer algorithms.
From Brain to Bot
Without doubt, the field of AI has greatly benefited from insights into our own minds, both in form and function.
For example, deep neural networks, the architecture of algorithms that underlie AlphaGo’s breathtaking sweep against its human competitors, are loosely based on the multi-layered biological neural networks that our brain cells self-organize into.
Reinforcement learning, a type of “training” that teaches AIs to learn from millions of examples, has roots in a centuries-old technique familiar to anyone with a dog: if it moves toward the right response (or result), give a reward; otherwise ask it to try again.
In this sense, translating the architecture of human consciousness to machines seems like a no-brainer towards artificial consciousness. There’s just one big problem.
“Nobody in AI is working on building conscious machines because we just have nothing to go on. We just don’t have a clue about what to do,” said Dr. Stuart Russell, the author of Artificial Intelligence: A Modern Approach in a 2015 interview with Science.
The hard part, long before we can consider coding machine consciousness, is figuring out what consciousness actually is.
To Dehaene and colleagues, consciousness is a multilayered construct with two “dimensions:” C1, the information readily in mind, and C2, the ability to obtain and monitor information about oneself. Both are essential to consciousness, but one can exist without the other.
Say you’re driving a car and the low fuel light comes on. Here, the perception of the fuel-tank light is C1—a mental representation that we can play with: we notice it, act upon it (refill the gas tank) and recall and speak about it at a later date (“I ran out of gas in the boonies!”).
“The first meaning we want to separate (from consciousness) is the notion of global availability,” explains Dehaene in an interview with Science. When you’re conscious of a word, your whole brain is aware of it, in a sense that you can use the information across modalities, he adds.
But C1 is not just a “mental sketchpad.” It represents an entire architecture that allows the brain to draw multiple modalities of information from our senses or from memories of related events, for example.
Unlike subconscious processing, which often relies on specific “modules” competent at a defined set of tasks, C1 is a global workspace that allows the brain to integrate information, decide on an action, and follow through until the end.
Like The Hunger Games, what we call “conscious” is whatever representation, at one point in time, wins the competition to access this mental workspace. The winners are shared among different brain computation circuits and are kept in the spotlight for the duration of decision-making to guide behavior.
Because of these features, C1 consciousness is highly stable and global—all related brain circuits are triggered, the authors explain.
For a complex machine such as an intelligent car, C1 is a first step towards addressing an impending problem, such as a low fuel light. In this example, the light itself is a type of subconscious signal: when it flashes, all of the other processes in the machine remain uninformed, and the car—even if equipped with state-of-the-art visual processing networks—passes by gas stations without hesitation.
With C1 in place, the fuel tank would alert the car computer (allowing the light to enter the car’s “conscious mind”), which in turn checks the built-in GPS to search for the next gas station.
“We think in a machine this would translate into a system that takes information out of whatever processing module it’s encapsulated in, and make it available to any of the other processing modules so they can use the information,” says Dehaene. “It’s a first sense of consciousness.”
In a way, C1 reflects the mind’s capacity to access outside information. C2 goes introspective.
The authors define the second facet of consciousness, C2, as “meta-cognition:” reflecting on whether you know or perceive something, or whether you just made an error (“I think I may have filled my tank at the last gas station, but I forgot to keep a receipt to make sure”). This dimension reflects the link between consciousness and sense of self.
C2 is the level of consciousness that allows you to feel more or less confident about a decision when making a choice. In computational terms, it’s an algorithm that spews out the probability that a decision (or computation) is correct, even if it’s often experienced as a “gut feeling.”
C2 also has its claws in memory and curiosity. These self-monitoring algorithms allow us to know what we know or don’t know—so-called “meta-memory,” responsible for that feeling of having something at the tip of your tongue. Monitoring what we know (or don’t know) is particularly important for children, says Dehaene.
“Young children absolutely need to monitor what they know in order to…inquire and become curious and learn more,” he explains.
The two aspects of consciousness synergize to our benefit: C1 pulls relevant information into our mental workspace (while discarding other “probable” ideas or solutions), while C2 helps with long-term reflection on whether the conscious thought led to a helpful response.
Going back to the low fuel light example, C1 allows the car to solve the problem in the moment—these algorithms globalize the information, so that the car becomes aware of the problem.
But to solve the problem, the car would need a “catalog of its cognitive abilities”—a self-awareness of what resources it has readily available, for example, a GPS map of gas stations.
“A car with this sort of self-knowledge is what we call having C2,” says Dehaene. Because the signal is globally available and because it’s being monitored in a way that the machine is looking at itself, the car would care about the low gas light and behave like humans do—lower fuel consumption and find a gas station.
“Most present-day machine learning systems are devoid of any self-monitoring,” the authors note.
But their theory seems to be on the right track. The few examples whereby a self-monitoring system was implemented—either within the structure of the algorithm or as a separate network—the AI has generated “internal models that are meta-cognitive in nature, making it possible for an agent to develop a (limited, implicit, practical) understanding of itself.”
Towards conscious machines
Would a machine endowed with C1 and C2 behave as if it were conscious? Very likely: a smartcar would “know” that it’s seeing something, express confidence in it, report it to others, and find the best solutions for problems. If its self-monitoring mechanisms break down, it may also suffer “hallucinations” or even experience visual illusions similar to humans.
Thanks to C1 it would be able to use the information it has and use it flexibly, and because of C2 it would know the limit of what it knows, says Dehaene. “I think (the machine) would be conscious,” and not just merely appearing so to humans.
If you’re left with a feeling that consciousness is far more than global information sharing and self-monitoring, you’re not alone.
“Such a purely functional definition of consciousness may leave some readers unsatisfied,” the authors acknowledge.
“But we’re trying to take a radical stance, maybe simplifying the problem. Consciousness is a functional property, and when we keep adding functions to machines, at some point these properties will characterize what we mean by consciousness,” Dehaene concludes.
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