New York - A new DNA reader could bring genetics to medical
clinics.
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 US company is to
announce 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 in Guilford, Connecticut, is 1 000 times more
powerful than existing technology, says CEO and chairperson 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, said 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.
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 experts are only beginning to grapple with.
"I'm a big proponent of bringing genetics into the
clinic," said 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,
said Richard Lifton, chairperson of the genetics department at Yale University.
"I'm increasingly confident that's going to happen. But
we need to be careful how we utilise 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% 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," said
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, said 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," said 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, said Greely, "it took a few hundred thousand
dollars worth of labour 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 counsellor some five hours to
explain what a typical genome means, further adding to the true cost.
The United States has about 2 500 genetic counsellors, not
nearly enough to meet the need if whole-genome sequencing becomes widespread.
Might doctors take up the slack?
"Surveys show that 90% of patients trust their
physician to explain genomics data to them," said Scripps' Topol.
"And 90% 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," said Stanford's Greely. "But a negative BRCA test
reduces her risk of breast cancer from 12% to 11.96%. 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," said 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,"
said 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 healthcare 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,"
argued 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's Genentech, and half the rheumatoid arthritis patients who take $26
000-a-year Enbrel from Amgen and Pfizer, benefit from them, noted Scripps'
Topol, who analysed 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% said the results made them more careful about
their diet and 14% exercised more.
Others incorrectly see DNA as destiny, and interpret an
increased genetic risk of, say, obesity as a licence to overeat, thinking they
are fated to be fat.
"Good" genes might lead to equally dangerous
behaviour. "A patient with hypertension might be told by his doctor, 'I've
looked at your DNA and you're clean!'," said 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", said Kari Stefansson, founder, chairperson 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.
"Current genetic testing, which looks at only a few
genes, is like trying to forecast the stock market by looking at just 26
stocks," says Eng of the Cleveland Clinic. Such limited genetic data can
be misleading.
In a separate study of 44 patients, scheduled for
publication in the European Journal of Human Genetics, Eng and colleagues find
that family medical history assessed the risk of breast, colon and prostate
cancer more accurately than DNA sequencing.
For instance, family history correctly classified eight
women as being at high risk for breast cancer. But only one of the eight was so
classified by DNA. "For now, family health history is a better predictor
of cancer risk than genomic testing, which looks at too few genes," Eng
said.
Because whole-genome sequencing is not yet being marketed to
consumers, the US Food and Drug Administration (FDA) has not taken a position
on it. But it is concerned by existing tests that are sold directly to the public
by Navigenics, Pathway Genomics and 23andme, and has invited companies that
sell them to meet with agency officials to work out ways "to provide
consumers with accurate, reliable kits", said FDA spokesperson Erica
Jefferson.
Until then, the companies are prohibited from marketing the
tests to the public. "Manufacturers have not provided scientific evidence
about the accuracy and reliability of their tests, which can lead to incorrect
treatment decisions with serious health consequences," said Jefferson.
"The risk of getting a disease depends on a set of complex
interactions", so "even people with the same genetic make-up may have
different risks of disease".
Gene-sequencing companies understand the challenges.
"Each genome has probably 24 000 mutations that we can
understand," said Ion Torrent's Rothberg. "But there are probably 400
that have never been seen before" and whose significance for health is an
enigma.
Ion Torrent is working on algorithms to determine the
medical significance of the millions of DNA glitches that will be found in
every genome. Companies such as Personalis of Palo Alto, California have sprung
up to determine the medical significance of whole-genome sequences. That will
take years.
"We recognise this is just the beginning,"
Rothberg said.