Vulgano Brother

Lots of folk here at the Mission could benefit. Small changes in neurotransmitters can make huge changes in behavior, and heredity and/or trauma can predispose certain people towards certain addictions. If we know what gene plays what role there is possibly that we can start preventing addictions, and crime and broken families and….

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Thursday, April 17, 2008
The $100 Genome

Forget the $1,000 genome. Some companies are looking far past that goal in the hope of creating a really inexpensive sequencing technology.

By Emily Singer



It currently costs roughly $60,000 to sequence a human genome, and a handful of research groups are hoping to achieve a $1,000 genome within the next three years. But two companies, Complete Genomics and BioNanomatrix, are collaborating to create a novel approach that would sequence your genome for less than the price of a nice pair of jeans--and the technology could read the complete genome in a single workday. "It would have been absolutely impossible to think about this project 10 years ago," says Radoje Drmanac, chief scientific officer at Complete Genomics, which is based in Mountain View, CA. The most recent figures for sequencing a human genome are $60,000 in about six weeks, as reported by Applied Biosystems last month. (That's down from $3 billion for the Human Genome Project, which was sequenced using traditional methods and finished in 2003, and about $1 million for James Watson's genome, sequenced using a newer, high-throughput approach and released last year.) But scientists are still racing to develop methods that are fast and cheap enough to allow everyone to get their genomes sequenced, thus truly ushering in the era of personalized medicine.

Most existing technologies detect the sequence of DNA a single letter at a time. But Complete Genomics aims to speed the process by detecting entire "words," each composed of five DNA letters. Drmanac likens the technology to Google searches, which query a database of text with keywords. Further speeding up the process with novel chemistry and advances in nanofabrication, the companies will develop a device that can simultaneously read the sequence of multiple genomes on a single chip. To accomplish the new sequencing, scientists first generate all possible combinations of five-letter DNA segments, given the four letters, or bases, that make up all DNA. These segments are labeled with different types of fluorescent markers and added in groups to a single-stranded molecule of DNA. When a particular segment matches a sequence on the strand of DNA to be read, it binds to that part of the molecule. A specialized camera then snaps a picture--the different fluorescent signals indicate the sequence at specific points along the strand of DNA. The process is repeated with different five-letter DNA combinations, until the entire molecule is sequenced. The approach is feasible because of the recent availability of cheap DNA synthesis, making it much more efficient to generate libraries of these DNA segments. Each DNA molecule will be threaded into a nanofluidics device, made by Philadelphia-based BioNanomatrix, lined with rows of tiny channels. The narrow width of the channels--about 100 nanometers--forces the normally tangled DNA to unwind, lining up like a train in a long tunnel and giving researchers a clear view of the molecule. "Since we can stretch out DNA, we can get a huge amount of information from each piece of DNA we look at," says Mike Boyce-Jacino, chief executive officer of BioNanomatrix. "The big difference from any other approach is that we are looking at physical location at the same time we are looking at sequence information."

Sequencing methods currently in use sequence small fragments of DNA and then piece together the location of each fragment computationally, which is more time consuming and requires repetitive sequencing. The companies still have a long road to the $100 genome. BioNanomatrix has already shown that long pieces of DNA--two million letters in length--can be threaded into the channels of existing chips. But now researchers need to develop chips with many more channels, so that multiple genomes' worth of DNA can be sequenced simultaneously. The main hurdle for Complete Genomics will be to generate fluorescent labels that can be easily and accurately detected. Most current methods get over this problem by making many copies of the same DNA molecule and sequencing them simultaneously, thus boosting the signal to noise ration. But that approach limits the length of the piece of DNA that can be sequenced, and it increases cost by increasing the amount of chemicals needed for the reaction. The project is part of the Advanced Technology Program, funded by the National Institute of Standards and Technology to spur development of novel, high-risk technologies. This year, Complete Genomics is releasing a commercial product based on similar chemistry, but the company has declined to give details on its status.

The technology necessary to achieve a $100 genome is still at least five years away, says George Church, a geneticist at Harvard Medical School, in Boston, and a member of Complete Genomics' scientific advisory board. "But [it's] coming from a company that has an almost-as-good technology coming out this year." Both Drmanac and Boyce-Jacino say that one of the biggest advantages of their technology will be the ability to sequence very long strands of DNA. The newest sequencing technologies in use today read DNA in fairly short spurts, from about 30 to 200 letters, which are then stitched together by a computer. This approach works well for some applications, such as resequencing a known genome. But a growing number of studies suggest that the small structural changes in DNA, such as deletions or inversions of short sequences, play a significant role in human variability, says Jeff Schloss, program director for technology development at the National Human Genome Research Center, in Bethesda, MD. "Those are much harder to pick up with short reads." Longer reads will also allow scientists to look at collections of genetic variations that have been inherited together, known as haplotypes. This kind of analysis can determine if a particular genetic variation has been passed down from the individual's mother or father. Recent research suggests that in some cases, maternal or paternal inheritance can impact the severity of the disease. With new tools to better track inheritance patterns, scientists may discover that this phenomenon is more common than previously thought. "That's one reason we're hoping that several of the emerging methods will allow long reads," says Schloss.


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Mapping the individual - cheaply

By 2015, babies might have their entire DNA read at birth, as costs of sequencing plunge. Charles Arthur looks at the implications for individuals and society.

Charles Arthur
The Guardian
Thursday April 24 2008



Had one of his parents been slightly less fortunate in their choice of a mate, James Watson might not have helped discover the structure of DNA in 1953. Instead, he would have been born deaf, and then lost his sight as he became a teenager. Equally, as he is, had he been less fortunate in the genetic lottery when he chose his wife, either of their sons might have had the same fate. This is because Watson's complete DNA - his genome - contains a single gene for Usher's syndrome, an inherited disorder which affects hearing and sight. Watson's must have come from one of his parents. Usher's is a "recessive" disease - you need two copies of the gene to be affected. About five people per 100,000 carry the gene, so Watson's chances of being disabled weren't large. But they were real.

Revealing the risk

We know this because the analysis of his genome was made public last week, in a groundbreaking paper in the science journal Nature that also revealed that he carries genes that may increase his risk of cancer, including one linked to breast cancer. While the sequencing of genomes for research has become almost routine - so far the genomes of dozens of species have been sequenced - Watson's was notable for how quickly and cheaply it was done.
The first full human genome sequencing, completed in 2003, took 13 years and cost $437m (£220m). Watson's sequencing, carried out by a company called 454 Life Sciences, took only two months and cost about $1m. Other companies, such as Illumina and Applied Biosystems, are relentlessly pushing the cost down.

Reading the 3bn "base pairs" in human DNA - akin to letters, encoding a total of between 20,000 and 30,000 genes that are the "words" of genetics - is getting faster as companies find quicker ways to "read" entire stretches of DNA at a time, like reading a sentence in chunks rather than letter by letter. 454's can read up to 450 bases at a time; Pacific BioSciences, one of many rivals, more than a thousand. The cost of sequencing an individual genome is thus falling exponentially - just as the cost of hard disk space or transistors on a chip did when computing took off. Plotting the numbers on a graph suggests that by 2012 it will take a few hours and cost less than $100. A few years after that it will cost perhaps $10.

That's when you should expect an explosion in personal sequencing. Jason Bobe, the director of community for the Personal Genome Project, based at Harvard Medical School, writes the Personal Genome blog and reckons that by 2015, 50 million people will have had their own DNA sequenced. He says: "My rationale is simply to assume that the trend line for the personal sequencing market might look a lot like the one experienced in the personal computer market" - which grew from a few thousand units sold in 1975 to 50m in 1995. "If the personal genome sequencing market follows suit, we might say that 2007 for personal genome sequences was like 1979 for PCs, and we've just turned the corner into 1980 where units sold remains below 1m, but growth is noticeable."

Who benefits?

Cheap, fast genome sequencing could upend how we think of disease and identity. If it's fast and cheap enough, would benefits claimants be asked to provide a DNA swab from their cheek? Would the same swab be your passport? Might police at a crime scene simply scan for DNA? The first, most obvious, use is foetal testing. Would a future James Watson and would-be spouse compare genomes? If both had single genes for Usher's syndrome, would they have children anyway, given the one-in-four chance that their child might have the full-blown syndrome? Would abortions be allowed on the basis that a child would have a disabling - but by no means life-threatening - genetic disease? The impending arrival of everyone's genome only makes this more urgent.

Watson himself, on seeing the presence of his breast cancer gene, said he would have acted on the knowledge had he had daughters: "I would tell them to immediately check if they had [that mutation]." But he also chose to withhold parts of the sequence relating to the APOE gene - associated with a higher risk of Alzheimer's disease - because he doesn't want to know if he has a genetic disposition to it. His nuanced approach will be food for thought for the House of Lords select committee on science, which this week opens an inquiry into "genomic medicine".

Mark Jobling, professor of genetics at the University of Leicester, notes that: "The problem is that many common genetic diseases are complex. It isn't a single base change. More complex diseases like schizophrenia and Alzheimer's won't be predictable." The idea of DNA profiling to collect benefits isn't new. It was suggested by the Labour MP Frank Field, then in opposition, as long ago as July 1996, "to safeguard the National Insurance system" - though he insisted that this was not "the introduction of an ID card".

He added: "A DNA test should be taken at birth along with all the other tests which are now merely a routine." The suggestions caused outrage at the time; but routinely sequencing a baby's genome at birth will be possible in a decade. Precisely that suggestion - of routine genomic sequencing of newborns - was suggested in a 2003 policy paper on the NHS, points out Dr Helen Wallace, director of Genewatch UK. "It was criticised on cost grounds," she notes, "but more particularly because most of that information [about an individual's genome] was likely to be misleading. OK, you can tell where someone has recessive genes that might lead to a known genetic illness, but the claims being made now by some of the companies offering sequencing are leading to concern and fear of disease."

Wallace suggests that they are distractions. "You share your environment and lifestyle with your family and for most of us this will be more important than our genes," she says. "Gene tests won't help to tackle major health problems such as bad diets, poverty, smoking and pollution." Genewatch generally opposes universal sequencing, on surveillance grounds.

What about crime scene tests? Jobling says: "The only reason for doing a full genome sequence would be for phenotype prediction, if you found DNA and didn't have a match. There have been some genetic variants already discovered that affect height; you might know eyes, hair ... you could produce an identikit predictive picture of your suspect. But in terms of individual ID, [DNA fingerprinting is] already perfectly adequate as it is."

Sequential growth

There's also the question of how far the price of testing will fall. Jobling points to one key difference between computers and DNA sequencers: computers are all-purpose machines. PCs are a mass technology, Jobling notes, "whereas it's difficult to see that there would be a case for having a DNA sequencer in every home. We've got a new sequencer here at the university and it cost £250,000, with an annnual maintenance contract of £25,000. And that's before we've switched it on."

So, he says: "How far down the cost [of sequencing] will go will be determined by the final size of the market and its applications." But if the whole population is sequenced from birth, and your DNA becomes your passport and benefit ID, that will expand the market - perhaps making it a self-fulfilling prediction. James Watson may be among the first. But many will follow.

The rapidly falling cost and time needed to map your DNA

2003
$437,000,000
13 years to map
2007
$10,000,000
4 years
2008
$100,000
4 weeks
2012
$100*
2 days
*Forecast

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