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In the Glow

By 1997, however, when Martin began shopping for new technologies, several groups of researchers had begun to make quantum dots brighter and more practical. With these refinements, the potential for using them in biological imaging and diagnostics was becoming increasingly evident. It began to look as if it would be possible to turn nanoparticles into sensitive probes that would hone in on specific biological targets, all the time glowing in distinctive colors that said: “Here it is!”-with the “it” being a virus, a protein of great interest, perhaps some specific DNA.

The movement toward biological applications was a long process, with no single breakthrough leading the way. But a key realization, says Paul Alivisatos, a chemist at the University of California, Berkeley, who contributed a number of important advances, is that “quantum dots are macromolecules, the size of proteins. Once you realize that the size scales are compatible, you say, “Okay, these things can go together.” Adds Moungi Bawendi, an MIT chemist who has worked on the particles for more than a decade: Biology is “not what we initially thought about. But in some sense it’s a much better application-it’s a natural.”

Such a natural, in fact, that Alivisatos and collaborator Shimon Weiss, a physicist at Lawrence Berkeley Laboratory, and graduate student Marcel Bruchez, started discussing business opportunities in the mid-1990s. “We were stumbling” around, trying to form a company to exploit the biological potential of quantum dots, says Alivisatos. Then, in 1997, they got a phone call from Joel Martin, who was wandering around Silicon Valley looking for the new new thing. In a nanosecond, Alivisatos was inviting the venture capitalist-and his million dollar check-to the Berkeley lab for a visit.

The potential of quantum dots was confirmed in late 1998 by the publication of two breakthrough papers in the journal Science demonstrating that the nanoparticles could be made compatible with living systems and used as bio-probes. One paper was by Alivisatos and his Berkeley co-workers, the other by Indiana University chemist Shuming Nie. Both groups of researchers had learned how to dissolve the nanoparticles in water and coat the tiny crystals with an outer layer to which they could readily bind biomolecules capable of recognizing proteins or DNA. The research confirmed the potential of quantum dot probes for sensitive diagnostic tests, even genetic analysis.

As part of the research, the scientific teams demonstrated ways to detect proteins inside and on the surface of a cell, suggesting a tantalizing possibility-it might be possible to attach a single glowing nanodot to, say, a protein, as a way to watch cellular events. Such observations could provide a far greater understanding of how cells work-and what can go wrong-providing valuable clues in the development of future pharmaceuticals and therapeutics.

A month after the Science papers, Quantum Dot was started. Martin and Manian signed leading nanodot researchers to the company’s scientific advisory board and gave them a financial stake in the outfit’s success. That meant making partners out of long-time rivals Alivisatos, Bawendi, Nie and Paul Mulvaney, a chemistry professor at the University of Melbourne. For good measure, the startup hired Bruchez and Stephen Empedocles, newly minted PhDs from Alivisatos’ and Bawendi’s chemistry labs, as staff scientists. The company licensed key technologies from the universities, garnering an intellectual property portfolio covering the use of quantum dots in biology.

Martin says that while the scientific value of the technology “clicked” the first time he saw it, the path to commercialization was not as obvious. Clearly, the startup didn’t want to compete directly with diagnostics and analytical instrument giants such as Roche and Perkin-Elmer, and just as clearly it didn’t want to merely supply quantum dots as commodity items. The answer, says Martin, was a business model imitating Intel. The chip maker aims to put its microprocessors in everyone’s computer; Quantum Dot would try to make its nanoparticles an essential piece of diagnostics kits and analytical instruments. The strategy was to make the large manufacturers customers, not competitors.

Quantum Dot’s business plan calls for the company to begin shipping test quantities of dots to potential customers this winter to allow them to assess the value of the nanoparticles in diagnostic testing and drug discovery. Deals with instrument makers will come later, says Martin. He estimates the startup has enough cash to survive for another year but says it plans to raise more money this spring.

The company expects to have a commercial product by mid-year, and Martin says initial applications will likely come in drug research. But for the longer term, one killer app stands out. Quantum Dot is working on biological “bar codes”-polymer beads packed with a known combination of thousands or even millions of quantum dots. Each of these beads would have a known color signature-a spectral bar code. Instead of using a quantum dot to tag a biomolecule by binding to it, the scientists aim to build assays for genetic analysis on the surface of the beads. “Labs on a chip” are one of the hottest new approaches to genetic analysis, and Quantum Dot hopes its “lab on a bead” could be an easier way to recognize gene sequences. The researchers attach a particular sequence of DNA to the surface of each type of bead. Because you could readily form thousands, even millions, of beads each with a distinct DNA probe (and readily identify each probe using the bar code), the technique could provide a quick way to simultaneously identify a large number of gene sequences in, say, a blood sample, providing a valuable diagnostic and research tool.

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