The Best American Science and Nature Writing 2020

by Michio Kaku

  As for the precise nature of those interactions, Buck and Axel could only theorize. They posited a sort of lock-and-key relationship between the olfactory receptors in our noses and the molecules in the air. But the number of receptors they discovered instantly posed a mathematical problem. Humans have about 400 kinds of olfactory receptors (far fewer than mice), but we can smell about 10,000 distinct odors. So Buck and Axel theorized that smell was combinatorial. Each receptor, their research showed, is uniquely primed to react to a few different molecules, and our noses sense distinct odors when many receptors fire at the same time. John Kauer, then a researcher at Tufts University, relates the idea to playing chords on a piano. “The piano only has eighty-eight notes,” he says. “If you were only able to use one note per odor, you could only detect eighty-eight different odors.” If odors are more like chords, then the math suddenly works out.

  Inspired by Buck and Axel, who won the Nobel Prize in 2004 for their work, Mershin and other scientists conceived of odors as simply lists of molecules. If you want to understand the smell of a clove of garlic, the thinking went, the answer lies in its chemical components. “Somewhere in these molecules,” Mershin believed through the mid-2000s, “the smell of garlic is written.”

  After Buck and Axel released their major findings, it didn’t take long before the first major efforts to build an artificial nose got under way. DARPA wanted to replace dogs as a tool for finding land mines, so beginning in 1997, it poured $25 million into a program called Dog’s Nose. The agency funded scientists across the country to build a bunch of would-be sniffing machines and then brought them to a field in Missouri for testing. The ground was sown with every manner of land mine, from small antipersonnel devices the size of tuna fish tins to hefty antitank munitions. Although stepping on the mines could no longer set them off—​the fuses had been removed—​the buried explosive ordnance could still be set off by, say, a lightning strike. “As soon as there was any hint of a thunderstorm,” says Kauer, who participated in the program, “we evacuated.”

  Kauer had built a gray, shoebox-sized device that he eventually christened the ScenTrak. His gadget wasn’t equipped with actual olfactory receptors. Instead, it was packed with long strands of molecules called polymers that Kauer knew would react to DNT, a molecule common in most land mines. When the ScenTrak came across an explosive, the DNT bound to the polymers, causing the ScenTrak to set off an alert. “Land mine!” the box cried.

  At least, that’s how it worked in ideal conditions. ScenTrak was able to pick out nearby traces of DNT in the air of an otherwise odorless lab. Out in the field, though, when Kauer scanned the ScenTrak back and forth over a patch of ground, it became confused. The polymers would react to DNT, but also to the weather, to plants, or to certain kinds of soil.

  Other devices in the competition, including one called Fido and another called Cyranose, were based on roughly the same theory. They all used polymers sensitive to specific compounds. And they all proved somewhat narrowly functional. (Fido is now used at military checkpoints to scan for explosives at close range.) But these devices don’t really smell, any more than, say, a carbon monoxide sensor can smell. They often misfire in scent-rich environments where odors—​apparently made of some of the same compounds—​may waft in from various nonexplosive sources.

  In part, that’s because the theory these devices were built on was too reductive. Today, most scientists believe that the lock-and-key theory of olfactory bonding is far too simple. In some cases, it turns out, molecules with very similar shapes have completely different odors; in others, very differently shaped compounds smell alike. A molecule’s shape, in other words, is not synonymous with its smell. Instead, many receptors bind to many different molecules and vice versa. But each receptor has what some scientists call a distinct “affinity” for each molecule. It’s that special affinity, the theory now goes, along with the combinatorial nature of olfactory reactions, that accounts for unique scents. The piano doesn’t just have eighty-eight keys that can form chords; it also has pedals and dynamics. “You hit piano keys at different strengths, heavy and light and so on,” Zhang says. “Heavy, you get one sound; light, you get another sound.” Or to put it another way: the theory of smell just gets more complicated.

  * * *

  Mershin and Zhang are an odd yet harmonious pair. Mershin rarely takes the same path twice. When we lose our way walking from the MIT cafeteria to his office, he confesses that he frequently gets lost—​“in my thoughts too, intellectually as well as geographically,” he says. By his own account, he is dyslexic, synesthetic, pink/gray color-blind, face-blind, and has attention deficit disorder. Sometimes he will forget his own address. He is also insatiably, compulsively curious. He once devised a game for his children that involved having them soak a cotton ball in perfume, blindfold themselves, and then try to find the cotton ball after it had been hidden. In addition to noses, he is building houses in Namibia out of mushrooms and working with a postdoctoral fellow on ways to remove heavy metals from water. “For my life, it doesn’t fit to do just one thing,” he says. “But I do like to work with people who are very focused and do one thing really well.”

  Zhang is that person. Where Mershin is restless, Zhang, who runs his own research group called the Laboratory of Molecular Architecture, is deliberate and slow. He believes you have to go deep on one project, one question. “For science to be successful you have to focus,” he says. “You cannot be distracted by other things.” In 2003, Zhang was looking for a new project, and he zeroed in on olfactory receptors. Even after Buck and Axel’s pioneering work, no one had ever been able to get an actual look at one—​either under a microscope or by using X-ray crystallography. That’s part of the reason olfaction is such an enigma. At the most basic level, we can’t directly observe what those tiny receptors are doing. Are they in fact binding with molecules? How? Do other factors like humidity or other compounds affect how those receptors respond? No one knows. Zhang wanted to change that—​by figuring out some way to see an olfactory receptor. “We decided to work on something mysterious and take some years to figure it out,” he says.

  Here’s what Zhang knew, going into his quest: Olfactory receptors are membrane proteins, and they are complicated, alien little structures. Each receptor is shaped like a long string that winds back and forth through the thin membrane that separates a cell from the outside world. If that complicated winding pattern is ever interrupted or changed, the receptor won’t work. And if the receptor is tilted or upside down? It won’t work either.

  About half of any olfactory receptor sits outside the cell, ready to interact with molecules. Then a middle section sits inside the cell membrane, and the rest resides inside the cell. When the exterior part of the receptor binds to a molecule, it changes shape, and the cell sends a message to your brain. While the heads and tails of an olfactory receptor—​the parts that sit inside and outside the cell—​love water, its middle section is hydrophobic, like the cell membrane that encases it. That means that when you take the receptors out of a cell and put them in water, they tend to clump together instead of dissolving, which makes them nearly impossible to isolate and work with.

  Zhang has been toiling away at his goal since 2003. At one point, he spent eight years simply trying to create water-soluble receptors. (“And it’s solved,” he says. “It’s done.”) But even still, he has never succeeded at seeing a receptor. Nor has anyone else. They are simply too small. Zhang describes that basic interaction between the odor molecule and the receptor as a “total black box.”

  Still, Zhang’s work did prove to be very useful when, in 2007, DARPA launched a second smell project, called RealNose. Spurred by the wars in Iraq and Afghanistan, RealNose had a new mission and a new sense of urgency. Instead of searching for land mines, the mechanical noses needed to be able to identify IEDs, which were laying waste to American troops. And this time, scientists couldn’t use polymers or other synthetic devices to mimic what the receptor
s did. They had to use mammalian olfactory receptors as their sensors.

  Zhang had a big advantage over other scientists competing for those DARPA grants. Thanks to his work, he had one of the only labs in the world that had experience growing olfactory receptors in embryonic cells and then working with them in the lab. But Mershin wasn’t thrilled about DARPA’s requirements. “For many, many, many months I rebelled,” he says. He didn’t want to bother with those finicky olfactory receptors, and he tried to convince DARPA that its requirement was a bad idea. Why did they need to use the actual, biological structure when it would be easier to use something synthetic? Something that wouldn’t stop working just because it was tilted or upside down? “Sure, we want to fly like birds, but we don’t build jet engines out of feathers,” he thought. “We want something better than birds!” Mershin just wanted a sensor that could tell you what molecules were present in a room. But he didn’t want to miss out on the funding, so he conceded.

  Mershin and Zhang decided they would grow a bunch of olfactory receptors in their lab and then essentially smear them onto a circuit board. They figured, statistically speaking, that if they slathered on enough receptors, they’d wind up with enough of them oriented in the right direction. Then they would connect the circuit boards to an electrical current. When the receptors interacted with volatile compounds, they would change their shape, just like they do in a regular nose. But instead of sending a message to a brain, the interaction would be recorded as a simple blip in electrical current.

  On a clear day in early spring, Mershin leads me into his lab and rifles through some cardboard boxes and equipment until he unearths a container of old artificial nose prototypes. In one hand, he pulls out a plastic bottle with two metal nozzles haphazardly held in place with epoxy. From his other hand, a thin plastic chip dangles from some electrical wires. “This here is the first nose,” he says.

  It was a failure. The receptors seemed to work, but the bottle was too big; smells would linger too long for the scientists to get a clear reading. So they followed it up with more prototypes, experimenting with different ways to deliver the right odiferous blast of air to the chip, and to different numbers of chips.

  From his hopper of prototypes, Mershin eventually pulls out the device, called the Nano-Nose, that he and Zhang ultimately submitted to DARPA. The whole contraption is about the size of an extra-large roasting pan and is emblazoned with the words “Property of the US Federal Government.” “Because it was for DARPA,” Mershin says, “we had to make it look bulletproof.”

  After all their prototypes, they had eventually homed in on a design that used an array of eight circuit boards, each about the size of a credit card. Inside that bulletproof metal housing, each board sat in a separate airtight bay, capable of receiving its own puff of odor and responding with its own electrical pattern. Smells could be sent into the box, and directed to each board, by an air pump that mimics taking a deep sniff.

  Zhang and Mershin built the device in a fifteen-month sprint, and it still wasn’t finished when DARPA’s deadline arrived. When it came time to show their work, Mershin loaded up a large van with the contents of nearly an entire lab—​hoses, tubes, pipes, syringes, a 300-pound optical table, and a frequency generator worth $70,000—​and drove it from Boston to Baltimore. He even brought their own odor delivery system: a modified inkjet printer called the StinkJet.

  Mershin had originally envisioned putting a supercomputer underneath the Nano-Nose that would dig through databases listing thousands of compounds and print out those the nose registered. But they’d never gotten around to that part. Instead, they resorted to what Mershin thought of as a hack.

  DARPA had given them a list of odorants that their machine would be asked to recognize. So first off, Mershin and Zhang sent those odorants through the Nano-Nose and recorded its responses; the idea was to train the nose, with the help of a laptop and a pattern-matching algorithm, on what it was supposed to be smelling for. Then, in the actual test, they would sample each mystery odorant eight times—​once through each of the eight bays—​and run it through a gauntlet of varying electrical conditions. This amounted to a process of elimination, meant to help the pattern-matching algorithm filter out false positives. It wasn’t as sophisticated as a data-mining supercomputer, but they thought it might work.

  The DARPA tests were highly controlled. Mershin and his team were not allowed to be in the room with their machine while the trial was running, and Mershin wasn’t even allowed to go to the bathroom without a security escort. During lunch breaks, the team would rush the nose back to their hotel room, soldering pieces onto it to keep improving it while ordering room service.

  In the end, the mad dash paid off. The Nano-Nose passed the sniff-off and was able to sense isolated odors in the lab. It even beat dogs in a controlled environment, sniffing out odors in lower concentrations than canines could detect. And it didn’t need a supercomputer. In fact, Mershin says, the Nano-Nose was better without it. To him, the project revealed a fundamentally important aspect of olfaction: our noses are not analytical tools. They don’t analyze the components of a scent. “The molecule is what carries the message,” Mershin says, but you can’t understand what our perception will be just from knowing the molecule. “We thought that when you sniff something, a list of molecules and concentrations comes up,” he says. “Not the case.”

  As it turned out, Mershin’s hack actually mirrors how mammals process smells. Instead of giving equal computational attention to all the compounds we inhale, our brains hierarchically sort information based on what’s important to us. We can tune out smells in a room if we’re not interested. Our receptors are still sensing compounds, but our brains aren’t paying attention. Conversely, if we narrow our attention on the signals our receptors are sending, we can pick out the subtle scent of shallots or fennel in a pasta sauce brimming with the competing scents of tomato, peppers, and garlic.

  Mershin realized that to understand smell and to use it as a tool, he didn’t need a list of molecules. He needed to know what something smelled like, not what it was made of, and those are fundamentally different things. “It was the biggest lesson I’ve ever had in my entire scientific career,” he says. “We thought we understood how noses worked. We didn’t know anything about how noses worked.”

  * * *

  On a warm Sunday in September, I go searching for bones with a German shepherd named Kato, who has been trained to find human remains. Kato and his owner, Peggy Thompson, volunteer with law enforcement agencies. They help look for lost hikers, wildfire casualties, and victims of crimes.

  We shut Kato in the house and set up a crime scene in Thompson’s picturesque one-acre yard, perched on a hillside overlooking San Jose. Out of her garage she pulls a bag of bones, a jar of teeth, and some bloody gauze. “Every time I have a procedure I ask if I can keep the dressings,” she says without a hint of humor. “It’s legal in California to possess human remains.” She pushes a clump of desiccated human skin under my nose. It smells musty and human in an inexplicable but unsettling way. We scatter a few bones and teeth across her gravel driveway, under some bushes, and on the lawn. She wedges the skin into the knot of a small tree.

  When we let Kato out and Thompson tells him to “search,” the formerly friendly pup is suddenly all business. He weaves his way back and forth, moving deliberately, nose to the ground. He finds the skin within five minutes. The rest of the bones and teeth take another ten at most.

  As impressive as the Nano-Nose is, it will take more than a boxful of blipping circuit boards to replicate everything Kato does when he’s tracking a scent. Paul Waggoner, a scientist who studies canine olfaction at Auburn University, estimates we are “decades away” from creating machines that could successfully compete with natural olfactory abilities. Waggoner, who also has his own patented training program for detection dogs, argues that machines break down early in the smelling process. “It all starts with the sampling,” he says. Essentially, ma
chines don’t sniff very well. Dogs inhale and exhale about five times every second, through nostrils that route the intake and outward flow of breath through different channels. All that snorting creates a pressure differential—​a kind of smell vortex—​that helps them pull a rich, new sample into their nose with each sniff. And while the Nano-Nose might be able to narrow its focus on a target scent, a dog’s ability to do so over great distances is stunning.

  What happens in Kato’s brain when he finally catches that scent? Well, no one knows. The higher up the chain we go, from olfactory receptors to how the brain processes and understands that information, “the darker and darker it gets,” Waggoner says.

  Still, dogs are not perfect sniffers themselves. On a second visit with Thompson, I watched another dog, a three-year-old Malinois named Annie, completely lose focus on tracking down a bone when she encountered several pigs in a nearby field. “When dogs aren’t used to stuff, it’s very difficult,” Thompson explains. Dogs get frustrated and tired. They feed off their owners’ emotions. And of course, dogs don’t scale. Highly trained bomb- and disease-sniffing dogs are in short supply and expensive, as much as $25,000 per pooch. Already, the U.S. security sector doesn’t have enough dogs to cycle through all the different agencies—​from the TSA and local law enforcement to the military—​that need them. Medical detection dogs are even trickier: not only are there very few of them, they don’t exactly plug easily into a medical setting. Despite all of the incredible findings in the past several years—​the 90 to 100 percent accuracy rates at detecting early cancer—​medical detection dogs have not been widely adopted as diagnostic helpers.