New DNA reader to bring promise, perils of genetics to clinics

NEW YORK, (Reuters) – After years of  predictions that the “$1,000 genome” – a read-out of a person’s  complete genetic information for about the cost of a dental  crown – was just around the corner, a U.S. company is announcing  that it has achieved that milestone and taken the  technology several steps ahead.

The new genome-sequencing machine from Ion Torrent, a  division of Life Technologies Corp., in Guilford,  Connecticut, is 1,000 times more powerful than existing  technology, says CEO and chairman Jonathan Rothberg.

Taking up about as much space as an office printer, it can  sequence an entire genome in a single day rather than six to  eight weeks required only a few years ago. The new sequencer,  says cardiologist Eric Topol, chief academic officer of private  California hospital and doctor network Scripps Health,   “represents an exceptional advance and can change medicine.”

Ion Torrent will sell the tabletop machine, called the Ion  Proton Sequencer, for $99,000 to $149,000, making it affordable  for large medical practices or clinics; existing sequencers cost  up to $750,000. The computer chip and biochemicals to sequence a  genome will cost $1,000, compared to, for example, $3,000 to  test for mutations just in the BRCA genes that raise the risk of  breast and ovarian cancer and $5,000 for a complete genome  sequencing by Ion Torrent competitor Illumina Inc.

For a graphic on the shrinking cost of genome sequencing,  see: http://link.reuters.com/xys85s

For now, Rothberg expects research labs to be his main  customers, using Proton to obtain the complete genome sequence  of people with cancer or autism, for instance, and thereby  elucidate a disease’s underlying genetic causes as well as  possible ways to treat it. The company has signed on Baylor  College of Medicine, Yale School of Medicine and the Broad  Institute as its first customers.

Other scientists and physicians, however, say the  long-awaited arrival of the $1,000 genome opens the door to  widespread whole-genome sequencing even of people who are not  ill. And that raises ethical, legal, and medical issues that  experts are only beginning to grapple with.

“I’m a big proponent of bringing genetics into the clinic,”  says Thomas Quertermous, chief of the division of cardiovascular  medicine at Stanford University and an expert in the genetics of  heart disease. “But it has to be done in a timely way, and not  before its time.”

Babies might be first in line for whole-genome sequencing.  Every state requires newborns to be screened for at least 29  genetic diseases.

“If the cost of whole-genome sequencing gets sufficiently  low, you could sequence all the genes in a newborn” for less  than the individual tests and follow-ups required when one comes  back positive, says Richard Lifton, chairman of the genetics  department at Yale University. “I’m increasingly confident  that’s going to happen. But we need to be careful how we utilize  this information. Do you tell a newborn’s parents his apoE  status” — that is, whether he has the form of a gene that  raises the risk of Alzheimer’s disease?
The cost of whole-genome sequencing will continue to  plummet. Lifton foresees a “zero-dollar genome,” making it  likely that “we will just do it as part of routine clinical  care” for children and adults. A Yale team led by Murat Gunel  has already used partial genome sequencing of the 1.5 percent of  the genome, called the exome, that codes for proteins to  determine the cause of a mysterious and still unnamed genetic  disease that results in severe brain malformations.

Because no genes had been identified as causing the  malformation, it was not possible to do a standard genetic test,  which reveals whether a particular gene is normal or mutated.  But exome sequencing showed that a previously unknown gene on  chromosome 19 is responsible, he and colleagues reported in  2010. “The new Proton instrument is a big step up,” says Lifton.  “It promises to markedly increase the speed and reduce the cost  of genome-level sequencing.”

 TSUNAMI OF DATA

The discovery of the mutation behind the mysterious genetic  disorder demonstrated the advantage of whole-genome sequencing  compared to single-gene tests, as scientists can’t test for a  gene they don’t know exists. Beyond such uses, say experts,  whole-genome sequencing might not be the medical miracle that  proponents forecast.

One problem is that the costs only start with the actual  sequencing. “The cost of understanding the sequence will be  much, much higher,” says bioethicist Hank Greely of Stanford  University. He participated in a 2010 project that sequenced the  full genome of Stanford bioengineer Stephen Quake. The  sequencing cost $48,000.

But because it found 2.6 million DNA misspellings and 752  other genetic glitches, says Greely, “it took a few hundred  thousand dollars worth of labor from Ph.D. students and faculty  working 4,000 to 5,000 hours to understand what the sequence  meant” — that Quake had a higher-than-average risk of sudden  cardiac death, a lower risk of Alzheimer’s, and a higher risk of  prostate cancer.

Another challenge is that whole-genome sequencing generates  a tsunami of data. It would take a genetic counselor some five  hours to explain what a typical genome means, further adding to  the true cost. The United States has about 2,500 genetic  counselors, not nearly enough to meet the need if whole-genome  sequencing becomes widespread. Might doctors take up the slack?  “Surveys show that 90 percent of patients trust their physician  to explain genomics data to them,” says Scripps’ Topol. “And 90  percent of physicians say they don’t feel comfortable with  genomics data.”

Although many bioethicists focus on the psychological harm  patients might suffer when DNA tests show an elevated risk of  cancer, diabetes, Parkinson’s, and other diseases, genomics  information could also threaten patients’ physical health if it  is misconstrued. A woman whose DNA sequencing shows she does not  carry BRCA mutations that raise her risk of breast cancer “might  say, great, I don’t need mammograms,” says Stanford’s Greely.  “But a negative BRCA test reduces her risk of breast cancer from  12 percent to 11.96 percent. My dread is less that patients will  be damaged psychologically and more that they will misunderstand  (genome sequence data) and do stupid things.”

Unlike tests that detect glitches in genes that a patient or  physician asks to have checked (those that raise the risk of,  say, colon cancer if that disease runs in the family), and  unlike the dozens of genes that “personal genetics” companies  test for, whole-genome sequencing reveals every bit of  information the genome contains about diseases or traits.

Given the ubiquity of mutations, everyone carries genes that  predispose them to more than one serious or lethal disease.   Bioethicists are only beginning to study how that knowledge  might affect someone’s decisions, from marrying or having  children to saving for retirement.

Another challenge is that although a person’s genome doesn’t  change, its meaning will. As scientists uncover more DNA  variants that protect against disease and variants that make it  more likely, a genome sequence that meant one thing in 2012 will  have a different meaning in 2013, not to mention 2020.

A DNA variant that was once thought to be dangerous “might  turn out to be benign if countered by another,” says Greely.  “Whose responsibility will it be to tell you that, years later?”  Today’s DNA testing companies offer subscriptions that give  customers regular updates like that.

Geneticists are also still struggling with the fact that  most of the risk genes raise the likelihood that the person will  develop the disease only slightly. “The bottom line is, the  effect size is so small it’s virtually insignificant  clinically,” says Quertermous. “So how should doctors  incorporate that knowledge into their armamentarium? They won’t  be able to look at 6 billion data bits” – the amount in a  whole-genome scan – “and evaluate what it means for patients.”

Knowing a patient’s whole-genome sequence, even if it raises  the risk of diseases by only a few percent, might lead  malpractice-wary doctors to order follow-up tests. If someone’s  genome suggests an elevated risk of heart disease, for instance,  a physician might feel compelled to order regular cardiac CT  angiograms, which cost $1,500 or more.

That would not only raise health-care costs, but might put  patients through a physically and psychologically onerous ordeal  unnecessarily. “There is no evidence that ‘positive’ (DNA)  tests, based only on the screening for common genetic  variations, will justify a specific medical follow-up and  procure a medical benefit to individuals,” argues geneticist  Thierry Frebourg of University Hospital in Rouen, France in a  commentary in an upcoming issue of the European Journal of Human  Genetics. Instead, whole-genome sequencing might join the ranks  of diagnostics, such as PSA tests for prostate cancer, that cost  tens of millions of dollars a year but do not benefit patients,  let alone save lives.

 INEFFECTIVE    DRUGS

Full-genome sequencing could provide real benefits in  determining which patients will benefit from a drug. For  instance, only half the hepatitis C patients who take Pegasys, a  $50,000-a-year drug from Roche Holding AG’s Genentech,  and half the rheumatoid arthritis patients who take  $26,000-a-year Enbrel from Amgen Inc and Pfizer Inc  , benefit from them, notes Scripps’ Topol, who analyzes  the potential benefits of genomic medicine in his upcoming book,  The Creative Destruction of Medicine.

Using genomic data to identify which patients will and will  not benefit could save patients and insurers tens of billions of  dollars a year now spent on ineffective drugs.

If genetic information causes patients to take better care  of themselves – eating more healthfully if they carry genes that  raise the risk of diabetes or heart disease, for instance – they  can improve health. One 2010 study found that of people who  bought direct-to-consumer genetic testing by companies such as  23andme, 34 percent said the results made them more careful  about their diet and 14 percent exercised more.

Others incorrectly see DNA as destiny, and interpret an  increased genetic risk of, say, obesity as a license to overeat,  thinking they are fated to be fat. “Good” genes might lead to  equally dangerous behavior. “A patient with hypertension might  be told by his doctor, ‘I’ve looked at your DNA and you’re  clean!’,” says Stanford’s Quertermous. “He might think, great, I  don’t need to check my blood pressure anymore or even take my  medication.”

As the science advances, however, the value of whole-genome  sequencing to patients will grow. The common DNA variants that  have been identified “account for only a small part of the  heritability of disease,” says Kari Stefansson, founder,  chairman, and CEO of deCode Genetics of Reykjavik, Iceland.

“The expectation is that a significant part of the missing  heritability lies in rare variants, and to find those you have  to do whole-genome sequencing.” deCode is sequencing the  complete genomes of 3,750 Icelanders, and has so far identified  rare variants with large effects on the risk of ovarian cancer,  glioma, gout, and heart conditions that require a pacemaker.  Those discoveries would have been difficult or impossible  without whole-genome sequencing.

Whole-genome sequencing also promises to address one of the  most troubling problems with current DNA tests, which probe some  of the 1,500 or so genes that have been associated with disease  out of a total of 22,000 human genes. But scientists do not know  how disease risk is raised or lowered by “moderator genes,”  which affect other genes. “Do we know how combinations of genes  affect risk?” Stanford’s Quertermous asks. “The answer is  completely no.” As a result, the disease risk that is calculated  from current genetic tests might be inaccurate. With millions of  whole-genome sequences, biologists believe, they can begin to  work out those crucial combined effects.

One upcoming study shows how important gene combinations can  be. In research scheduled for publication in the journal Human  Molecular Genetics, scientists led by Charis Eng of the  Cleveland Clinic examined the incidence of breast, thyroid, and  other cancers in patients carrying a mutation in a gene called  PTEN. Such mutations are typically interpreted as raising the  risk of cancer. But Eng found that the presence or absence of  mutations in another gene, called SDHx, can alter that risk.

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