3-D Seer

Nadrian C. (Ned) Seeman: Margaret and Herman Sokol Professor of Chemistry, New York UniversityMICHAEL SUMMERS To hear Ned Seeman tell it, the worst part about doing crystallography is: all that crystallization. “It’s arguably the dumbest experiment in modern science,” says Seeman, who received his doctorate in the subject from the University of Pittsburgh in 1970. “Basically you’re trying to get molecules to line up in a crystalline arrangement. What interactions are you trying to promote? Who knows? If you don’t get crystals, what went wrong? Who knows? I don’t have the patience for it, and I’m not quite enough of a jerk to force my students to do that kind of experiment for me.” To cut straight to the crystals, Seeman came up with his own method for making molecules get in line. By taking advantage of complementary base pairing, he encourages DNA molecules to self-assemble into crystalline arrangements of his own devising. Using this approach, Seeman has constructed nanoscale materials and mechanical devices and launched the burgeoning field of DNA nanotechnology. His methods have moved him closer to his goals of “controlling the structure of matter at the finest possible scale” and unraveling the “logic of life—and the molecules that encompass that logic.” Best of all, he’s managed to avoid spending his life “doing ‘piss-in-a-pot-and-pray’ crystallization experiments.” Others have followed suit. “For the first 20 years that we were doing this structural DNA nanotech, we were the only game in town,” he says. “Now there are maybe 60 or 70 labs working on this stuff. So I’m not the only crazy person out there anymore.” Crazy or not, here he tells tales of his exile in Albany, his Escher epiphany, and his epicurious adventures. SEEMAN SETS SAIL Finding a home. “In my first academic position, I made the mistake of being housed in a biology department—because I was a crystallographer who tilted toward biology. That was a scientific death sentence. The graduate-student complement in that department was largely math-phobic, failed premeds. So I went seven years before I got my first graduate student. That was not an auspicious beginning to my career.” He remained at SUNY Albany for 11 years before joining the chemistry department at New York University in 1988, where he became “a more central character.” “For the first 20 years that we were doing this structural DNA nanotech,we were the only game in town.” Beer + Art = Inspiration. Seeman came up with the approach to self-assembling crystals while sitting in the campus pub. He’d been fooling around with Holliday junctions—branched structures formed by a pair of double helices when they come together during recombination. By manipulating the local DNA sequence, Seeman reckoned he could stabilize one of these junctions long enough to examine its structure in detail. Then he got to wondering whether he could make a junction with even more branches. “One day I went over to the pub to think about what six-armed junctions might look like when I realized that they’d be just like the flying fish in Escher’s woodcut Depth,” he says. “The fish have heads and tails, top and bottom fins, and left and right fins. And they’re arranged like the molecules in a crystal.” Further, he saw that if he could get his six-armed DNA molecules to interact with one another—to lie next to each other like the fish in Escher’s woodcut—they would assemble into a crystalline array all on their own. A sticky solution. The way Seeman planned to get his multi-armed molecules to interact was via their sticky ends—nucleotide sequences at the tip of a single-stranded DNA molecule that complement the sequences on another single-stranded chain. “It’s the ideal interaction because you can program it,” he says. “There are a lot of affinity-based interactions in biological molecules: antigens and antibodies, and so on. But sticky ends is the only one of which I’m aware where, a priori, you can predict the local structure of the product. Whether it’s a CCC up against a GGG or an TTT against a AAA, the structure you’re going to form is B-DNA—the classic Watson and Crick structure. The idea is not to rediscover the structure of DNA, but to use the DNA as scaffolding to help us build things that we want.” Making lemonade. Having to cohabit with biologists and their students made Seeman aware of sticky ends. “One of the few good things about being in the biology department at Albany was that I had to listen to everybody else’s students give their research talks. Once a week, I heard about how they’d taken this sticky end and that sticky end and stuck together their plasmids. It was relentlessly repetitive and relentlessly boring—but at least I did know what a sticky end was.” Time to make the DNA. The first step toward self-assembling DNA crystals was to make some DNA. “Today, you just make a phone call and tomorrow you have the DNA. But in those days it was a really big deal to get a specific engineered sequence of DNA.” In the summer of ’82, Seeman spent time in a lab in Leiden learning how to string nucleotides together. But back in Albany, he couldn’t seem to churn out a consistently high-quality product. “Then one weekend I went to a luncheon sponsored by the Applied Biosystems people. They were in the business of making DNA synthesis machines—and I was always willing to accept a free lunch. They described their chemistry and gave you a little manual that was really, really precise: ‘Build this little apparatus, and at this point you open the stopcock, at this point you turn on the vacuum.’ I said to myself, ‘Maybe this chemistry is better than mine.’ So I decided to try it with my own little paws.” The technique worked, says Seeman, “and I never looked back. The nice thing about that era is, the people who were making the synthesis machines were very macho. ‘We can make it longer, we can make it better, we can make more of it.’ Which is exactly what I needed.” Where’s the biology? Early on, Seeman and his colleagues made a variety of different structures. One was a two-dimensional, planar crystal that had little DNA hairpins poking up from it at regular intervals, like carefully placed blades of grass—a feature that forms a stripe when viewed by atomic force microscopy. That lattice appeared in Nature in 1998, nearly a decade after their first cubelike construction. “The cubelike molecule was the first thing we’d made of any note. We sent it to one of the top-scale journals and got two reviews back. One said ‘This is founding a new field,’ the other said, ‘Where’s the biology?’ I said, ‘There isn’t any.’ So they rejected the paper. The other journal didn’t take that position.” Although a handful of Seeman’s papers have since appeared in Nature, he says that getting published in top-tier journals is harder now than it was when he started. “As more and more people entered the field, this stuff stopped being quite so novel,” he says. Since winning the Kavli Prize in Nanoscience in 2010, Seeman says, “I’ve been rejected without review by the editors of three of the baby Natures.” Untying knots. In the middle ’90s, Seeman and team showed that DNA topoisomerase III could untangle knotted RNA. “It’s one of our least cited papers and I don’t know why. Sometimes in science, things are trendy or not trendy. I guess nobody thought that RNA topoisomerization was going to be important, so nobody paid attention. A lot of my work that’s not as good has gotten a lot more notice.” SEEMAN SAYS “I’ve always regarded DNA as a very long four-letter word— and not really very interesting when it’s linear. The 3-D nature of what we do is just far, far more exciting.” Anywhere but here. Seeman was not a big fan of life in Upstate New York. “I still talk about my 4,000 days up the river,” he laughs. “Well, 3,983. I rounded off. There was a bus that went between downtown, where I lived, and campus. You had to wait for that bus if your car broke down. You’d be standing there—by Exit 24 off the Thruway—looking at snow 3 or 4 feet deep, as far as the eye could see, thinking: ‘Is this what my life has become? Stuck in the middle of nowhere by a highway exit?’ When my friends and I got together, it was sort of like something you’d see in those World War II POW movies. All we talked about was: how the hell are we going to get out of this dump? It may be a better place now. But Albany and I antiresonated. I took the job because it was the only offer I had. And because, after all that training, I didn’t want to wind up being a cab driver, which was the only other option that was open to me.” Hung up on novelty. “I believe students and postdocs should be allowed to phumpher around for a couple weeks to see if they can solve their own problems. But there’s not a lot of point in reinventing the wheel. So I make sure everybody in the lab knows what everybody else is doing. That way, if somebody is doing something that’s fundamentally stupid—struggling with a problem for which someone else already knows the solution—they can find out right away. Then they can move on to making mistakes on problems that we don’t already know how to solve.” Doctorate in masochism. “One of the hard things about science is the constant level of abuse. Your grants are rejected, your papers are turned down—people crap all over you for one reason or another. It’s not an easy business. You have to like it enough to put up with all that and keep going. To be frank, it takes a certain amount of grit.” 24/7/365. “Used to be, back in the era of snail mail, I’d go down to the mailbox Friday afternoon, look at whatever was in there, and then say, ‘OK, I’ve got until Monday morning without anything else coming in to disturb me.’ That gave me two and a half full days to work. Now, vacations, weekends, two in the morning—there’s always something coming in over the Internet to waste your time. Things you can’t ignore. I’m not talking about spam. Spam is great. I love spam. Delete! That’s the easy part. The hard part is when something comes in that you feel a responsibility to take care of. Or at least to reply. For me, at least, the Internet has created more work than it saves.” Natural selection. “Anybody who starts off being a scientist in their 20s should expect that by the time they’re 40 or 45, the field has changed so much that the skills they knew and mastered in their youth are going to be obsolete. And if they’ve grown only the minimum amount that’s absolutely necessary, sooner or later they’re going to be wiped out.” The Seeman session. “When I go to meetings, I don’t spend much time in talks. To me a meeting happens in the hallway. I like talking with people rather than listening to them.” Adding it up. “The thing I tell somebody who’s about to become an assistant prof is: add up all the things you think a PI does: teach classes, do research, write grants, write papers, direct a group, sit on committees, whatever. If all of those discrete tasks take up 40 percent of your time, you’re doing well. The other 60 percent of your time will get frittered away in ways you just can’t imagine. And you’ve got to learn to live with that.” You can keep yer omics. “Frankly, I’ve always been kind of bored with omics of every flavor. It’s data gathering. I’ve always regarded DNA as a very long four-letter word—and not really very interesting when it’s linear. To me, the 3-D nature of what we do is just far, far more exciting. So if I were just starting out today, I’m not sure I would go into the biological sciences.” SIMPLY SEEMAN Nicotine antidote. Synthesizing loads of DNA meant that Seeman was surrounded by organic solvents all day. “That’s how I was able to quit smoking,” he says. He couldn’t risk lighting up in the lab. Music hath limited charms. “I don’t really respond very well to music. It’s like watching a sunset on a black-and-white TV. It’s not very interesting. Those areas of my brain must never have developed.” Visual stimulation. “For all my 3-D-ness, I’m not really a statue guy. I prefer brightly colored paintings—Magritte, Hieronymus Bosch. People who are a little crazy or who sometimes work on the border between two and three dimensions. I like stuff that makes me think, or that gives me ideas for things to do.” Picky eater? “I’ll eat pretty much anything except for a few raw vegetables. Raw celery, raw carrots: don’t put ’em in the same room with me. I’ll eat pizza but that’s as close as I get to a tomato. I like invertebrates. Sea cucumber is good. There’s a great night market in Beijing where they have a whole bunch of different bugs on a stick. My favorite is scorpion, if they season them properly. Much better than grasshopper.” Tuning out. “I haven’t had a television since 1972. That might make me strange right there.” Won’t go without a fight. “I’m expecting to be carried feet first out of my office one day. Why would I ever want to retire? This is too much fun.” SEEMAN’S GREATEST HITS • Demonstrated that DNA molecules can be engineered to self-assemble into three-dimensional crystalline arrays—an accomplishment that launched the field of DNA nanotechnology. • Was the first to coax synthetic strands of DNA into forming a variety of geometric and topological structures, including cubes, Borromean rings, and branched junctions with up to 12 arms. • Has built various nanomechanical devices made of DNA, including walkers, robots, and perhaps the world’s smallest assembly line. • Founded synthetic single-stranded DNA topology. • Determined that DNA topoisomerase III can also untie knots in single-stranded RNA. • Discovered that a four-stranded DNA molecule (called PX DNA) can relax supercoiled DNA containing homologous sequences. • With Donald Eigler of IBM’s Almaden Research Center, shared the 2010 Kavli Prize in Nanoscience for the development of “methods to control matter on the nanoscale”—an adventure Eigler said should be dubbed “two control freaks go to Oslo.”

3-D Seer

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Karen Hopkin

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August 2011

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