A Marriage of Nanotech and Biotech

Harvard chemistry professor George Whitesides' latest quest is getting tiny nonliving structures to assemble themselves

When he was a teenager in Louisville, Ky., George Whitesides spent his summers washing glassware at the chemistry lab of his father's company, which made materials used to repair concrete. All those beakers and pipettes needed to be cleaned for the next day's experiments. And amidst all the grunt work -- Whitesides remembers pouring coal tar through holes to measure how long it took to seep through -- he "got to see how technology development worked."

Eventually, that led to a career in chemistry that has spanned four decades and included numerous seminal contributions. From concrete repair, Whitesides went on to study chemistry at Harvard and get a PhD in chemistry at CalTech. Beginning at age 24, he spent 20 years teaching at Massachusetts Institute of Technology, followed by another 20 years, and counting, as a Harvard professor.


  Whitesides' accomplishments add up to a laundry list of groundbreaking contributions. They include work that formed the basis of the biotech industry itself by coming up with the first methods for bioengineering -- or altering -- the molecules in the cells of mammals. Subsequently, his research also helped start the field of microfluidics -- in which multiple chemical reactions can be performed on a single chip. This "lab on a chip" method of researching molecules is now widely used by scientists trying to create new drugs.

Over the years, Whitesides has been involved in helping to start more biotech outfits than he cares to count. They include Geltex, which was acquired by Genzyme General in 2000. Two Geltex drugs are currently on the market -- Renagel, for kidney-dialysis patients, and cholesterol-lowering agent Cholestagel. Other startups he helped found include Advanced Magnetics, which makes an magnetic resonance imaging (MRI) spectroscopy agent that enhances images, and Igen International, which makes biological detection systems used by drug researchers to test new compounds.

Those achievements alone seem enough for a lifetime, but Whitesides, at 63, is as busy as ever. His research, performed with the help of 30 or so Harvard graduate students, reaches across a broad spectrum of disciplines, from biochemistry to materials science. Much of his work remains in areas that may have implications for biotech: Self-assembling molecules used for making nanomachines, polyvalent drugs that attack a disease from multiple directions, and new analytical tools for drug discovery. He also helped invent a molecule that helps treat anthrax by interfering with the bacteria's toxic machinery.


  Whitesides describes his approach to scientific discovery as butterfly-like. "We move from flower to flower, into a problem with a fairly large number of people, work on it intensively for some years, and then move out and into some other area." One of the flowers he's now hovering over is nanotechnology -- the nascent science of developing a manufacturing technology that can inexpensively fabricate structures with molecular precision.

Nanotech is probably least developed in medicine and health, where space-age applications like tiny submarines that deliver drugs to exact spots on the surface of diseased cells are likely decades away. "The issue of where the field is going is still a matter of interesting discussion," says Whitesides.

The part of nanoresearch that most intrigues Whitesides is a manufacturing process for these tiny structures, called soft lithography. This involves a series of patterning techniques in which a "stamp" of a nanostructure can be made, then used repeatedly to imprint new structures. So far, this approach can assemble just one molecule at a time.


  To make anything of real use, techniques would have to be developed to assemble millions of molecules. That's where another of Whitesides' areas of interest comes in: self-assembly. This idea gets much of its inspiration from nature. He explains: "In biology, the right mix of biological molecules will interact on their own to form distinctive structures, such as cells, tissues, and organs."

Whitesides' goal is to find a way for nonliving things to spontaneously assemble themselves just as living things do. This would take care of many of the most minute and difficult steps involved in nanofabrication. Already, he's trying to get nonliving devices to self-assemble -- and he has started work on advanced nanosize structures that would combine self-replicating machines and the natural self-assembly that occurs in living cells.

Indeed, the ultimate feat would be to meld nonliving and living systems. For example, self-assembled artificial nerve cells could be attached to living cells and help restore the use of limbs to people who have suffered severe nerve damage. That sort of application, however, is probably decades away. The earliest marriage of nanotech and biotech may involve very small sensors that can report what's going on within cells on an continuing basis.


  In the meantime, Whiteside is trying to devise better tools for discovering new drugs. He says more than ever, the industry needs efficient and accurate devices to speed preclinical research -- the work that's done before a drug is deemed ready for testing in patients. Making smaller, faster tools might be one way of increasing the volume of screening that can be done.

Indeed, the techniques of soft lithography are the science behind the venture Surface Logix, another one that Whitesides helped start. It's trying to develop cell-based sensors for screening potential drugs. "We're interested in the use of microsystems to explore biological activities," the scientist says.

He's also involved in research on so-called polyvalent drugs. Currently, most drugs are small molecules that act as keys fitting into particular keyholes on the surface of a protein involved in disease. Polyvalent drugs would look more like a cluster of different keys that would seek out multiple matching keyholes. "The notion of multiple interaction is integral to many areas of biological control," Whitesides says. "And this idea is quite unfamiliar to the pharmaceutical industry."

No one can say yet which of these efforts may end up in commercial use. But one thing is sure: With Whitesides at the controls, there'll be no shortage of biotech ideas to explore.

By Amy Tsao in New York

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