Complete Genomics, which has received $46 million in venture funding to date and has largely stayed under the radar, plans to launch with a bang and anticipates the capacity to sequence 1,000 genomes in 2009 and 20,000 in 2010. That would represent a massive jump: with a price tag of $100,000 to $1 million over the past two years, only a handful of human genomes have been sequenced to date.

"Suddenly, these guys are talking about sequencing hundreds to thousands of genomes in the next couple of years," says Chad Nusbaum, codirector of the Genome Sequencing and Analysis program at the Broad Institute, in Cambridge, MA. "That opens up tremendous vistas for the kind of science we want to do. It's really by generating hundreds of human-genome sequences that you can start to ask hard questions about human genetics."

Complete Genomics says that it has already sequenced a human genome, although it has not yet released the data for independent review. "'Stunning' is not too strong a word, if they can do it in the very near term," says Jeffrey Schloss, program director for technology development at the U.S. National Human Genome Research Institute, on the possibility of a $5,000 genome. "But I haven't seen any data and I don't know anyone who has, which is of course critical."

J. Craig Venter, founder of the J. Craig Venter Institute, in Rockville, MD, is working with Complete Genomics to validate its technology, comparing the sequence that it generates with a reference sequence of his own genome.

Complete Genomics says that its cheap price tag comes thanks to two innovations: a way to densely pack DNA, developed by Rade Drmanac, the company's chief scientific officer, and a method to randomly read DNA letters, based on sequencing technology developed at George Church's lab at Harvard.

To start with, an 80-base-pair piece of DNA is inserted into a circular piece of synthetic DNA and replicated 1,000 times with a specialized enzyme. That large aggregate of DNA spontaneously compresses into a tightly packed ball, thanks to chemical characteristics engineered into the synthetic DNA. These DNA "nanoballs" are then packed onto specially fabricated arrays with unprecedented density--about a billion balls fit on a chip the size of a microscope slide. The high density of DNA allows large volumes to be sequenced quickly with few reagents, one of the most costly components of the process.

Next, as with other approaches, Complete Genomics determines the sequence of the target DNA using a series of fluorescently labeled DNA strands designed to bind to corresponding letters. But while advanced sequencing technologies currently in use--including those from Illumina, Applied Biosystems, and 454--read the sequence sequentially, letter by letter, Complete Genomics's labels bind to the target DNA randomly. Both the labels and the DNA circle are designed to allow scientists to deduce the position of each highlighted base--information that is then used to computationally reconstruct the sequence of the target DNA. (With both Complete Genomics's and other companies' methods, the short strands are computationally stitched together to generate the entire genome sequence.)

Because the identification of each base in the sequence does not depend on the correct identification of the previous one, individual errors have less impact on the overall result, generating a more accurate sequence with less repeat sequencing. (For a more detailed explanation and schematic of Complete Genomics's sequencing process, click here.)

A $5,000 genome is likely to open new arenas in genetic study of common disease. Most studies to date have analyzed carefully selected portions of individuals' genomes, linking common variations to risk of common ailments, such as diabetes and heart disease. However, even studies of thousands of patients have uncovered genetic variations that account for only a small percentage of the risk for disease. Scientists say that the ability to sequence many people's genomes will allow them to search for rare variations that likely account for remaining genetic risk. "I'd love to get my hands on [this technology] and think about how I can solve new problems with it," says Phil Sharp, MIT Institute Professor and winner of the 1993 Nobel Prize in Physiology or Medicine.

Beyond its unique technology, Complete Genomics has also chosen an unusual business model: rather than selling instruments, as most sequencing companies have done, it plans to offer sequencing services through a commercial-scale genome center. Cliff Reid, the company's president and chief executive officer, hopes that both the service model and the price tag will appeal to those who don't want to do their own sequencing, such as pharmaceutical companies. "They don't want to purchase an instrument; they want to purchase data," says Reid. In an effort to further pharmacogenomics--the ability to prescribe the right drug at the right dose to a patient based on his or her individual genetic profile--genomics is a growing component of clinical trials.

The company is now building a massive data center to manage the immense volume of information it expects to generate; it's planning to have a computer cluster containing 60,000 processors online by 2010. "No one has ever put together a data processing center this size for sequencing--because no one has ever been able to sequence this many genomes," says Reid. Complete Genomics will focus entirely on human-genome sequencing, unlike other companies, which use their technology for a variety of sequencing projects. And unlike Knome, a personal-genomics startup that offers individuals a complete genome sequence and personalized analysis for $350,000, Complete Genomics provides only the genome sequence.

The company has already made its first deal: to sequence 100 genomes in 2009 and 2,000 genomes in 2010 for Leroy Hood at the Institute for Systems Biology, in Seattle. Hood, who in the 1980s developed the first automated sequencing machine, sits on the Complete Genomics advisory board. Hood's project will comprise about ten percent of the facilities sequencing capacity in the first two years.

Even if Complete Genomics faces up to its promises, "they face a lot of competition," says J. Craig Venter. For example, Applied Biosystems, a veteran in the sequencing industry, recently announced a next-generation technology that it believes will be able to sequence genomes for $10,000.

Copyright Technology Review 2008.

Substances harvested from cannabis plants could soon outshine conventional antibiotics in the escalating battle against drug-resistant bacteria. The compounds, called cannabinoids, appear to be unaffected by the mechanism that superbugs like MRSA use to evade existing antibiotics. Scientists from Italy and the United Kingdom, who published their research in the Journal of Natural Products last month, say that cannabis-based creams could also be developed to treat persistent skin infections.

Cannabis has long been known to have antibacterial properties and was studied in the 1950s as a treatment for tuberculosis and other diseases. But research into using cannabis as an antibiotic has been limited by poor knowledge of the plant's active ingredients and by the controversy surrounding its use as a recreational drug.

Now Giovanni Appendino of the Piemonte Orientale University, in Italy, and Simon Gibbons of the School of Pharmacy at the University of London, U.K., have revisited the antibiotic power of marijuana by systematically testing different cannabinoids' ability to kill MRSA.

MRSA, short for methicillin-resistant Staphylococcus aureus, is a bacterium that can cause difficult-to-treat infections since it does not respond to many antibiotics. Many healthy people carry S. aureus on their skin, but problems arise when multi-drug-resistant strains infect people with weak immune systems through an open wound. In the worst cases, the bug spreads throughout the body, causing a life-threatening infection.

To make matters worse, resistance to antibiotics is rapidly increasing, and some strains are now even immune to vancomycin, a powerful antibiotic that is normally used only as a last resort when other drugs fail.

But when Appendino, Gibbons, and their colleagues applied extracts from five major cannabinoids to bacterial cultures of six strains of MRSA, they discovered that the cannabinoids were as effective at killing the bugs as vancomycin and other antibiotics.

"The cannabinoids even showed exceptional activity against the MRSA strain that makes extra amounts of the proteins that give the bugs resistance against many antibiotics," says Gibbons. These proteins, he explains, allow the bacteria to "hoover up unwanted things from inside the cell and spit them out again."

Conveniently, of the five cannabinoids tested by the researchers, the two most effective ones also happen to be nonpsychoactive, meaning that they cannot cause a high. "What this means is, we could use fiber hemp plants that have no use as recreational drugs to cheaply and easily produce potent antibiotics," says Appendino.

In an attempt to discover how the cannabinoids kill MRSA, the team manipulated several chemical groups within the compounds. Most of the changes did not affect the antibiotic activity at all, and those that did seemed to influence only how well the cannabinoid is taken up by the bacterial cells.

"Everything points towards these compounds having been evolved by the plants as antimicrobial defenses that specifically target bacterial cells," says Gibbons. "But the actual mechanism by which they kill the bugs is still a mystery. We've tested whether the cannabinoids affect common antibiotic targets like fatty acid synthesis or the [DNA-bending enzyme] DNA gyrase, but they don't. I really cannot hazard a guess how they do it, but their high potency as antibiotics suggests there must be a very specific mechanism."

Appendino and Gibbons say that cannabinoids could quickly be developed as treatments for skin infections, provided the nonpsychoactive varieties are used. "The most practical application of cannabinoids would be as topical agents to treat ulcers and wounds in a hospital environment, decreasing the burden of antibiotics," says Appendino.

Whether the cannabinoids could also be delivered in the form of an injection or in pills is less clear, the pair says, because they may be inactivated by blood serum.

Frank Bowling of the University of Manchester, who has had success treating MRSA-infected wounds with maggots, says that "any alternative treatment that removes MRSA from the wound and prevents it from spreading into the body is fantastic and preferable to using antibiotics that have strong side effects and against which resistance is already developing." He cautions, however, that the researchers still need to show that the cannabinoids are safe to use.

This is not something that Appendino is too concerned about: "The topical use of cannabis preparations has a long tradition in European medicine, and no allergies have been reported."

Mark Rogerson of GW Pharmaceuticals, a U.K.-based company that develops cannabinoid-based drugs to treat severe pain caused by multiple sclerosis and cancer, says that the discovery that cannabinoids kill MRSA "really underlines the potentially great diversity of medical applications that cannabis-based medicine can have. You can almost think of the cannabis plant as a mini pharma industry in its own right." But Rogerson says that it is unlikely that existing cannabis-based medicines could be used to treat MRSA because the exact effect will depend on the correct combination and dosage of cannabinoids.

Meanwhile, Appendino and Gibbons hope that antibacterial effectiveness could also make cannabinoids suitable preservatives for cosmetics and toiletries. "The golden standards of preservatives are parabens and chlorinated phenols," says Appendino, but these compounds do not degrade well in the environment and are strongly suspected to be hormonal modifiers. He also argues that, since all major cannabinoids are similarly effective, complete purification of a single compound isn't necessary. So semipurified cannabinoid mixtures extracted from nonpsychoactive plants could make a cheap and easy alternative to conventional preservatives.

Copyright Technology Review 2008.

Source: http://www.technologyreview.com/Biotech/21366/