What if determining your blood type took a few seconds and a few dozen red blood cells instead of several minutes and milliliters of blood? To that end, one company is building on a two-decades-old invention that harnesses laser radiation to noninvasively trap and manipulate submicroscopic particles.
Arryx Inc, which is developing the new assay, is among a handful of companies that have begun to commercialize optical tweezers. An invention by Bell Labs physicists, optical tweezers are best known for their role in determining DNA’s elasticity and other benchmark single-molecule studies. Those experiments were done with custom-built instruments with diffraction-limited resolution, and some with subpiconewton sensitivity. Now new commercial optical tweezers are being targeted to researchers and medical institutions that don’t want to build their own.
The AFM analogy
In an optical tweezer system, a particle is pushed by the momentum from a tightly focused laser beam and trapped by the gradient forces of the beam’s refracted light. The trapping force acts against thermal fluctuations, light scattering forces, or—in the case of some single-molecule force measurements—motile biological specimens that are tethered to an optically trapped spherical substrate. In addition to an IR laser source, chosen to minimize photodamage to biomolecules, modern optical tweezers are often fitted with high-powered optical microscopes, electro/acousto-optic feedback devices, software controls, and microfluidic chambers.
Up until the 1990s, many people were still building atomic force microscopes by themselves, says physicist Torsten Jähnke, chief technology officer of Germany-based JPK Instruments AG. The company makes AFMs and also optical tweezers designed for particle-tracking and force measurements. Jähnke adds that the reason people are buying AFMs now is because “they are flexible, modular, and easy to use,” which, he says, is now happening with optical tweezers.
“There’s been quite some competition coming up in the tweezers market in the last two or so years,” says Michael Gögler, a product manager at German microscope manufacturer Carl Zeiss AG. Coupled with a UV laser, Zeiss’s optical tweezers can, among other things, guide sperm to egg for in vitro fertilization. A similar instrument was available in the 1990s from now defunct Cell Robotics Inc. The demise of that company, says GöUgler, may be blamed in part on its premature entry into an unprepared market. Back then, optical tweezers were a tool almost exclusive to physicists, he says. “But with the growing popularity of interdisciplinary research, a lot more techniques get to be known to the biology community.”
The current market for optical tweezers is in biological research, says Kishan Dholakia, a biophysicist at Scotland’s University of St. Andrews. At this stage, Dholakia says he thinks optical tweezers are “a top-end research tool.” His own optical tweezers patent uses acousto-optic modulators to generate multiple traps. He says that single-molecule force measurements and the building of tissue scaffolds are among the applications for the instrument, which has been commercialized by UK-based equipment provider Elliot Scientific Ltd.
“Truly exciting new results about the dynamics of complex biochemical systems have emerged from the use of optical tweezers in the last three to five years,” says Carlos Bustamante, a biochemist at the University of California, Berkeley and a pioneer of optical tweezer studies of DNA and RNA. Bustamante is looking to commercialize a mini-tweezers system that is “about the size of a coffee pot” and says making optical tweezers widely available “would be terrific for science.” For his research, though, he doubts that current commercial tweezers can do the job. “Traps are easy to make. But it’s not that easy to achieve what I call analytical precision.”
The next level for optical tweezer applications is medical diagnostics, says Arryx co-founder and New York University biophysicist David Grier. Arryx’s holographic tweezers, which use spatial light modulators to create up to 200 three-dimensional optical traps, can determine blood type in “only 5 to 10 seconds” from simultaneous force measurements on several dozen red blood cells, says Grier. And recently added to the company’s pipeline is licensed NIST technology to detect blood pathogens at femtomolar concentrations.
Research-grade sensitivity is not the only challenge facing commercial optical tweezers. Optical traps in general are not very selective, says NIH staff scientist Keir Neuman, who studied transcription processes with optical tweezers research pioneer Steven Block. “Anything that can fall into a trap will fall into a trap, if it has a larger index of refraction than the surrounding media,” he says. NIST researcher Kristian Helmerson, one of the inventors of the recently-licensed blood pathogen detection technology, says optical tweezers are “extremely sensitive” biosensors, but are relatively slow for cell-sorting applications. Cost is also a concern: Most of the commercial systems run between $100 000 and $350 000. Grier, however, notes that systems are becoming cheaper with the availability of low-cost lasers and inexpensive, high-quality consumer electronics.
Retired Bell Labs physicist Arthur Ashkin, who led the first demonstration of optical tweezers in 1986, says he’s happy about progress being made to commercialize the technology. “I never thought it would be practical, because I thought the laser would destroy living things,” he says. Energy secretary Steven Chu, a coauthor with Ashkin of the 1986 paper, had been conducting single-molecule biological research with optical tweezers at UC Berkeley prior to his recent appointment. “The focus [in the 1980s] was on trapping atoms,” says Chu, who shared a Nobel Prize with William D. Phillips and Claude Cohen-Tannoudji for that work. “But Art [Ashkin] just continued to play with the single-focus laser beams to move bacteria and his [latex] beads.”
Is there another Nobel Prize in store for optical trapping? “I would not be surprised,” says Chu. “In the coming decade there could be a truly great discovery using optical tweezers, or some other single-molecule technique.”
But JPK application specialist Joost van Mameren says that optical tweezers must be made more broadly available and the benchmark single-molecule experiments with optical tweezers should be successfully repeated with commercial systems to convince researchers to buy them. “Spending two or three years to build a system from scratch was enjoyable,” says van Mameren, who worked with optical tweezers for his PhD. “But that does not produce many papers.”