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Chemical Connector

Paul Weiss ’80, SM ’80, is bringing together nanoscientists and neuroscientists to develop new tools for understanding the brain.

On a beautiful April morning, chemist Paul Weiss is darting across the campus of the University of California, Los Angeles, in red-framed Wayfarer sunglasses and a suit. He’s on his way to make himself an espresso, but even with a caffeine deficit he’s tough to keep up with. Weiss put the coffee machine in his students’ office instead of his own, to create more opportunities to check in with them and run into colleagues.

Paul Weiss

Weiss, who heads the California Nanosystems Institute, a state-sponsored research hub for all things nano, is a specialist in developing new ways of probing single molecules like neurotransmitters and those that make up the active layer in solar panels. However, with caffeine in his system, what he wants to talk about is not chemistry but community. For Weiss, 53, chemistry is a social science. “It’s about making a connection,” he says. To be able to do something useful, he says, you have to connect to other people within and outside your field, know what problems other fields like neuroscience or energy will be facing in 10 years, and start building the necessary tools today.

As far as he’s concerned, one of the most important goals for the next decade is to understand the human brain. To meet that challenge, biologists need help from chemists, physicists, engineers, and other toolmakers like him, he says. The brain has nearly 100 billion neurons networked together by an estimated 100 trillion electrical and chemical connections. How all these interactions combine to enable us to walk, talk, learn, form memories, create—and how things go wrong in diseases like Parkinson’s—is pretty much a mystery. Weiss hopes to create new tools for probing the nanoscale chemical and electrical activity of thousands to millions of neurons at once. “If we want to understand what a memory is, how we learn—this is where we think the sweet spot is,” he says.

For years, Weiss has been recruiting researchers from apparently distant fields to work on the problem—helping organize meetings of scientists to talk about it, trying to bridge the gap between neuroscientists and physical scientists. This organizing work has now borne fruit. In April, President Obama requested $100 million in federal funding for the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Private research institutions are also chipping in. The Kavli Foundation, a nonprofit in Oxnard, California, has pledged $40 million over the next 10 years. “His profound understanding of the whole field of nanotechnology made a huge difference,” says the Kavli Foundation’s vice president of science programs, Miyoung Chun, who helped coördinate the project that became the BRAIN Initiative.

Researchers working in relative isolation have already made progress on developing tools for studying the brain, including arrays of nanoscale electrodes for probing neurons and computer programs for analyzing the onslaught of data these kinds of measurements are expected to generate. By working together, Weiss believes, researchers from different fields can now accelerate advances by developing common, widely available tools.

Weiss comes to neuroscience from pretty far afield. “I took biology pass/fail,” he says. After getting a master’s in chemistry at MIT, he did a PhD at the University of California, Berkeley, with Yuan T. Lee, who won the Nobel Prize in chemistry in 1986, the year Weiss graduated. For his postdoctoral work, Weiss went to IBM, where he got to work with one of the pioneers of what would become his favorite chemistry method. At IBM, Donald Eigler was doing early experiments with the scanning tunneling microscope, which can image and manipulate individual atoms and molecules; Eigler would later use it to spell out “IBM” in xenon atoms in one of the famous early images of nanotechnology.

What was exciting at IBM was that “most of what we saw, we didn’t understand,” recalls Weiss. “We had different backgrounds and would argue about how to do experiments, since things rarely worked.” He looks back fondly on these scientific arguments and encourages that kind of debate in his own lab—and ends up having similar discussions over the dinner table with his wife and collaborator, UCLA psychiatry professor Anne Andrews.

After he became a professor at Penn State in 1989, Weiss continued working with scanning tunneling microscopy for many years, developing new variations on the technology as he pushed atoms around to study how their electrical structure gives rise to their chemistry. Then he met Andrews, a neuroscientist and chemist also at Penn State at the time, who asked him, “Why are you doing all this useless stuff?” Andrews asked Weiss to apply his expertise to help her shed light on a critical—but hard-to-measure—aspect of brain communication.

Communication in the brain is based on a combination of electrical and chemical signals that Weiss says are “entangled in interesting ways.” For information to be passed between nerve cells, electrical signals must be converted into chemical signals. The sending nerve cell releases chemical signaling molecules into the synapse, the tiny gap between cells. These neurotransmitters, as the signaling molecules are called, diffuse across the synapse and bind to a receptor on the surface of the second nerve cell, delivering the message. Neurons constantly receive and integrate multiple, sometimes conflicting, signals; when they corroborate each other, the receiving nerve cell generates its own. This electrical and chemical signaling occurs in hundreds of microseconds over spaces of mere nanometers. To understand how the brain works, Weiss says, neuroscientists need new tools to map these interactions at fine scales, in thousands or even millions of neurons at once.

It’s a relatively simple matter to track electrical signals by inserting an electrode into the brain. In fact, many researchers have applied advances in nanoelectronics to improve these electrodes, leading to seizure-soothing brain stimulators and brain-machine interfaces for prosthetics. But chemical signals, which are just as important, are much harder to track. About 100 signaling chemicals modulate activity in the brain. Neurotransmitters including serotonin and dopamine have been linked with our ability to feel pleasure; deficits or excesses of some of these have been linked with drug addiction, depression, Parkinson’s, and other maladies. But their functions and their mechanisms are poorly understood, and so is their role not just in sickness but in health. “We’re missing a lot of subtlety,” says Weiss. Better understanding of brain chemistry could reveal those nuances and help drug developers create new therapies.

One fundamental problem Weiss and Andrews are working on is that the receptor proteins neurotransmitters bind to are themselves not well understood. It’s difficult even to crystallize them to determine their structure, and because neurotransmitters are such small molecules, they’re hard to immobilize so that their interactions with these proteins can be studied: attempts to use any part of the neurotransmitter as a “handle” to pin it down can interfere with its chemical activity. But Weiss and Andrews found a way to experiment on a derivative of serotonin with an extra chemical group that can be tethered to a surface, leaving all the active parts of the neurotransmitter free.

Their broader goal is to build an artificial nerve-cell surface that can be used to sense chemical activity in the brain. As part of the BRAIN Initiative, Andrews and Weiss are now leading an effort to develop this kind of sensor at UCLA. They believe it will be possible to integrate such chemical sensors with electrical sensors in compact, biocompatible devices. But Weiss says it presents a huge engineering challenge. “Anne and I have been working on this for a decade at our own insufficient pace,” he says. (The prospect of being able to accelerate that pace was one thing that prompted their move to UCLA and the California Nanosystems Institute in 2009.)

That’s why they were so excited to participate in a meeting on the interface between nanoscience and neuroscience at the Kavli Institute in London in September 2011—a meeting that helped catalyze the BRAIN Initiative. The neuroscientists were “a little bit cliquish,” says Weiss, and more focused on studying the physical and electrical connections between cells, but he pushed them to take chemistry into account. Weiss’s dedication to bringing people together—and bringing physical sciences to bear on challenges in biology—made a big difference in getting the initiative off the ground, says Chun. “Paul is just very wise,” she says. “He can round people up and make them talk to each other.”

At press time, Weiss, Andrews, and all the other scientists involved were still waiting to find out whether Obama’s BRAIN funding request would end up in the 2014 budget, but they were optimistic. “Things will go a lot faster if this project is promoted on a national scale rather than person to person,” Weiss says.

In the meantime, he says, sitting in his office at UCLA, he has “an infinite supply of problems” that colleagues from the medical school want him to tackle, as well as stacks of submissions to review for the journal he edits, ACS Nano; grants and presentations to write; and students to check in on. “I think it’s time for another coffee,” he says.

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