Multiplying DNA One Drop at a Time
As the cost of DNA sequencing continues to fall and scientists discover a growing number of genes linked to different diseases, the field of genetic diagnostics is preparing for a boom. Rather than the single-gene tests common today, clinical genetics laboratories are developing tests that simultaneously detect tens or even hundreds of genetic mutations linked to cancer and other diseases, as well as conditions such as mental retardation.
However, with these more complex tests, diagnostic developers need to be able efficiently and accurately select specific portions of the genome for analysis. “Now the cost of sequencing is so cheap you don’t have to look at just one or two genes, you can look much more broadly,” says Alexis Borisy, entrepreneur in residence at Third Rock Ventures and acting chief executive of Foundation Medicine, a Cambridge, MA-based startup developing genetic tests for analyzing cancer. “But the whole genome or exome [the portion of the genome that codes for proteins] is still too expensive to be clinically useful, so you have to focus the search.”
RainDance, a startup based in Lexington, MA, aims to fill that gap with its droplet-based microfluidics technology. Founded in 2004, the company uses picoliter-sized droplets as tiny test tubes to carry out chemical reactions at very small volumes. Precisely sized droplets are created on a microfluidics chip by surrounding aqueous liquid with small volumes of oil. The droplets, generated at a rate of 10 million per hour, can be tightly packed and injected with different reagents, including strands of DNA. To catalyze a reaction, an electrical signal triggers droplets containing different reagents to merge.
While the droplet system can be adapted to perform a number of chemical analyses, the company’s first commercial technology is its RainStorm device, designed to amplify specific sections of DNA. Drops are filled with short strands of DNA designed to mark the section of the target DNA molecule to be amplified. A second set of droplets holds a single target DNA molecule along with the enzyme needed to perform the polymerase chain reaction (PCR), a chemical reaction used to copy DNA. Merging the two droplets creates a tiny test tube primed for the reaction; under the correct temperature conditions, the enzyme binds to the marker molecules and copies only the target segment of DNA. Company president S. Roopom Banerjee says the small volumes and high throughput capacity of the device–it can perform 1 to 2 million PCR reactions at a time–make it cheaper than traditional methods.
RainDance is not currently developing its own genetic diagnostics. Rather, the company sells its amplification technology to clinical genetics laboratories, which then create the tests. Madhuri Hegde, senior director of the Emory Genetics Laboratory, in Atlanta, is one of the first people to incorporate the technology into clinical testing. Today her lab individually sequences 300 genes, “but combining some of these into panels will be much cheaper than individual gene tests,” she says. Her group has used the device to develop a test for mental retardation linked to the x-chromosome, which can result from mutations in a number of genes. The test analyzes 1,600 fragments of DNA encompassing 93 genes. The Emory lab has developed similar tests for congenital disorders of glycosylation, rare conditions that strike in infancy and result in severe developmental delay, and congenital muscular dystrophies, a group of degenerative muscle diseases that also strike near birth.
“I think [the RainDance technology] holds lots of promise in a clinical setting,” says Hegde, who has been working with the technology for the last two years. But she also notes its cost. “The machine is very expensive,” she says, in the range of $200,000 to $250,000.
RainDance’s microdroplet technology is just one of a number of methods under development for selecting relevant genes within the genome. The Emory lab, for example, is also working with a technology from Fluidigm, another microfluidics company. It remains to be seen which will prove most effective in different situations.
One market that RainDance aims to dominate is cancer diagnostics, such as analyzing tumors for specific mutations that make them more likely to respond to certain drugs. Analyzing cancer DNA presents a unique challenge; the technology must be able to detect mutations in the tumor, which may occur in only a small subset of cells. Typical amplification methods expand both normal and cancerous pieces of DNA together, meaning the cancer mutation can get lost. One advantage of RainDance’s droplet technology is that it amplifies only one piece of DNA per droplet.
Foundation Medicine’s Borisy says the company will likely explore RainDance’s technology when developing its cancer genetic test. However, he cautions that cancer diagnostics need to be able to accurately amplify DNA from a very small sample. “For routine oncology, you need to be able to work from 100 nanograms or less,” he says.
RainDance is also working on a number of other applications, such as analysis of single cells, which could be used for drug toxicity testing. For example, drug companies could encapsulate single cells into droplets, expose the cells to experimental compounds, and then add fluorescent tags designed to bind to markers of cell death.
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