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/

A specific structural variation on chromosome 16 dramatically boosts the risk of autism, according to a study published today in the New England Journal of Medicine. The finding--one of the most significant to date--permits the development of new diagnostic tests to identify children at risk, and could ultimately point to specific biochemical pathways to target in drug development.

"This is one of the single largest [influences] and most frequent genetic causes for autism identified so far," says Bai-Lin Wu,director of the Genetics Diagnostic Laboratory at Children's Hospital Boston and one of the senior authors on the study.

Autism spectrum disorder--or autism, as it is commonly called--refers to a group of developmental disabilities with wide-ranging language, social, and behavioral symptoms. The disorder is known to have a strong genetic influence, with up to 90 percent of cases thought to have a genetic component. However, because the disorder is linked to a combination of genetic variations, each playing a minor role, identifying specific genetic triggers has been difficult. Now new microarray technologies, which allow scientists to screen a million or more genetic variations in thousands of patients, are enabling the much larger studies needed to pinpoint these triggers.

In the new paper, scientists say that they used microarrays to scour the DNA of more than 2,000 individuals with autism. They found that deletion or duplication of approximately 500 of the same DNA letters on chromosome 16 was strongly linked to autism, accounting for about one percent of cases. "While that doesn't sound like a huge number, the fact that these people carry the identical spontaneous deletion or duplication would be incredibly unlikely to happen by chance," says Mark Daly, a geneticist at Massachusetts General Hospital's (MGH) Center for Human Genetic Research, in Boston, and at the Whitehead Institute, in Cambridge, and one of the study's senior authors.

The results were independently identified by three different groups--at MGH; Children's Hospital Boston; and deCODE Genetics, in Iceland--that are studying three different populations, giving added weight to the work.

The findings build on previous reports that autism is linked to genetic deletions or duplications that arise spontaneously, rather than being passed down through generations. In almost all cases, parents of the affected people did not carry the chromosome 16 variation.

One of the most immediate clinical benefits of the research will be the development of inexpensive diagnostic tests. "Because the variation occurs so frequently, you could directly test for the presence or absence of a duplication or deletion as part of standardized genetic testing for autism," says James Gusella, a neurogeneticist at Harvard Medical School, in Boston, who participated in the research. For example, children who show developmental delays but are too young to undergo clinical autism testing could be screened for this variation, allowing parents and doctors to prescribe intervention for those who test positive. "We will be able to find at-risk children early on so that language and behavior problems can be treated much earlier," says Yiping Shen, director of research and development at Children's Hospital's Genetics Diagnostic Laboratory, who was also involved in the work.

Such testing could also predict if parents with one autistic child are at greater risk of having another; if their child's autism is linked to a spontaneous variation, they are at no greater risk than the general population. Researchers at Children's Hospital, which provides genetic testing to families, are already developing a clinical diagnostic test.

Scientists are also trying to pinpoint the specific gene or genes within this section of DNA that underlie the increased risk. Daly and his collaborators plan to sequence this region of the genome in another group of people with autism, in search of single-letter mutations that might disrupt the function of specific genes. "Genetics provides us with the only opportunity to gain insight into the biological mechanisms that underlie autism," says Daly. "We can look at individual gene discovery as a small first step in the overall path to develop treatments."

Previous studies have identified autism risk genes. However, these studies have focused on people with genetic disorders that often co-occur with autism, such as Fragile-X syndrome, complicating the role those genes play in the disorder. "Up until now, we haven't had the capacity to look at a single gene that is associated with pure autism," says Gusella.

The findings could point to additional spots in the human genome to search for autism risk genes. The variation on chromosome 16 lies within a genetic "hot spot," an area that is predisposed to undergoing structural duplications due to the architecture of the DNA, says Evan Eichler, a geneticist at the University of Washington in Seattle, who wrote an editorial accompanying the paper. "Every time we produce gametes, there's a finite probability of this region to duplicate," he says. In addition, the region has a high concentration of genes that are rapidly evolving in humans. While the significance of that finding is not yet clear, it may explain autism's status as a relatively young disease.

In a milestone for the emerging field of comparative genomics, an international team of scientists has carried out a comparative analysis of the genome sequences of 12 different species of fruit flies. Not only did the researchers uncover patterns in the way that genes evolve as species adapt to different environments, but they also developed a new way of identifying the functional elements of the genome--a discovery with potentially far-reaching consequences.

For more than a hundred years, the fruit-fly species Drosophila melanogaster has been instrumental in the study of genetics, developmental biology, and animal behavior. Because a significant number of human genes have fruit-fly analogues, researchers have also used the insect to study many human diseases, including cancer, diabetes, and neurodegenerative disorders such as Alzheimer's. In 2000, scientists published the genome sequence for D. melanogaster; the sequence of a second fruit-fly species followed several years later.

There are 1,500 species of fruit flies, however, and they vary in appearance, behavior, and habitat. To fully understand the fruit-fly genome and how it has evolved, a consortium of more than a hundred labs around the world sequenced an additional 10 species and compared all 12 sequences. The group details its findings in two reports published in the November 8 issue of Nature.

"If you want to get a crystal-clear picture of how genes influence what an animal will look like, what it will eat, what behavior it will exhibit, this is a completely unparalleled resource for doing that," says Leslie Vosshall, a neurogeneticist at Rockefeller University, in New York.

The researchers selected species from all over the world--from Africa, Asia, the Americas, and the Pacific Islands. Some species are widespread and feed on a range of foods, whereas others are more limited. For instance, one species lives only on the Seychelles islands off the east coast of Africa and eats only one kind of fruit.

In one of the papers, a team led by Manolis Kellis, a computational biologist at MIT, compared the 12 sequences in order to identify all the functional elements in the fruit-fly genome. These include not only genes that code for proteins, but also sequences that help regulate gene expression by, for instance, encoding small RNA molecules that bind to other parts of the genome. To find these elements, researchers typically look for sequences that are common, and therefore highly conserved, among different genomes. "The basic premise of comparative genomics is that if something is conserved over millions of years in a dozen species, it's likely to do something useful," says Kellis.

But Kellis and his colleagues were also seeking an alternative strategy. They figured that by looking only for sequences that have remained roughly the same, they would miss a large number of functional elements. For instance, protein-coding genes can undergo extensive changes and yet retain their critical functions.

By looking at all 12 genomes, the team found that each type of functional element changes in characteristic ways over time, and those patterns of change serve as evolutionary signatures. For instance, a series of three-letter DNA sequences in which the first two letters are always conserved but the third one changes is likely to be a protein-coding gene, says Kellis. So the researchers designed computer algorithms to mine the sequence data and find the evolutionary signatures for each type of functional element. "This allowed us to find things that we would never have expected to find just by looking at a single genome," says Kellis.

Kellis's team found thousands of previously unidentified functional elements, including 150 protein-coding genes and more than a hundred microRNA genes. (MicroRNAs are short segments of RNA that silence genes by binding to specific sites in the genome.) The researchers also found that some genes, during their translation into proteins, ignore certain instructions and, as a result, acquire bits of protein encoded by other genes. "This is an entirely new mechanism," says Kellis, adding that his group has since found evidence of this mechanism in the human genome as well.

The second Nature paper describes research led by Andrew Clark, a population geneticist at Cornell University, who looked at known genes to see how they vary from one species to another and how they evolve, acquiring new functions as species adapt to their changing environments. Genes involved in the immune system, for instance, appear to evolve more rapidly than genes in the rest of the genome. The same was true for genes that regulate insecticide resistance.

Taste and smell receptor genes also undergo frequent changes. When the researchers compared species of flies that are generalists with those that have more specialized food preferences, they found that the specialists lose genes for different taste receptors at a much higher rate than the generalists do. "How you smell the world influences how you eat, and this will tell us an enormous amount about how genes that encode for smell and taste influence behavior," says Vosshall.

The studies of the 12 fruit-fly genomes will no doubt help scientists better understand the human genome, says Kellis. Not only do fruit flies and humans have so many genes in common, but now researchers have a systematic way of interpreting genomes that could lead to the discovery of entirely new kinds of functional elements, he says.