We all carry our DNA around with us—in every cell of our bodies—but some biotech trailblazers are toting their genomes with them, too. In a recent talk Jay Flatley, president and CEO of sequencing giant Illumina, recalled being asked by his doctor to get a certain genetic test. But Flatley was able to pull up his full genome on his iPad then and there instead of sending a spit sample off to the lab.

Although most people are not yet able—or willing—to obtain or share their own personal genome sequence, many already see a genome-empowered future dawning. In the quest to better know one's self, however, more and more people are turning to genome sequencing to uncover information about their ancestral histories, impending health risks, and disorders of potential progeny. After the U.S. Food and Drug Administration (FDA) prevented Pathway Genomics' direct-to-consumer DNA kits from reaching drugstore shelves in May, however, the technology—and companies who offer it—have come under finer scrutiny from the public as well as the government.

Despite the completion of the generalized human genome draft a decade ago, connections between diseases and genetic variations have proved to be evermore complex and elusive.

"We naively thought that there would be a few genes involved in risks for a variety of common disorders," says Barbara Bernhardt, an associate professor of medicine and genetic counselor at the Hospital of the University of Pennsylvania (Penn).

Some conditions, such as cystic fibrosis (pinpointed even before the completion of the human genome), are caused by single gene mutations, and clinical genetic tests for these types of diseases have been useful diagnostic tools. But other diseases, such as Alzheimer's, have no uniform genetic signature—or clear way of avoiding them—leaving many to wonder about the science and utility behind the results many genome scans offer casual consumers. Other information gleaned from sequences—for example, the drug metabolic-rate estimates for medications such as the blood-thinner Warfarin—could be used directly for medical treatment decisions.

"They certainly do provide medical information to people," Bernhardt says of the direct-to-consumer genomic tests. "From that perspective, they do need to be regulated as medical devices."

The FDA, which had provided relatively loose rules for consumer genetic testing, is now revaluating the industry's methods and will begin asking companies to provide data about how they interpret the scans for customers.

In a 2006 Scientific American article, Harvard Medical School geneticist George Church called for genome sequencing for all. But four years later, is the technology ready for the mass market?

Testing the market
The first complete individual human genome was finished less than three years ago and cost hundreds of millions of dollars. Now many companies offer a similar service, which promises a personalized laundry list of disease risks assessed from a simple cheek swipe or spit test, available online for thousands—and in some cases, for less complete scans, hundreds—of dollars.

Despite the drastic decline in price and increase in availability, direct-to-consumer genome sequencing has been relatively slow to catch on. The Google-backed sequencing company 23andMe has gone through two rounds of staff cuts in the past several months, and the Iceland-based deCODE genetics was delisted from public trading on Nasdaq earlier this year after its market value dropped.

Additionally, a mishap earlier this month at a lab under contract with 23andMe resulted in as many as 96 customers receiving the wrong genetic reports.

"The consumer market for whole genome sequencing and interpretation has yet to evolve," says Nathan Pearson, director of research at Knome, a company that offers full genome sequencing. Recent studies have also found other applications for genetic tests, such as ancestry profiles, to be rather unreliable. And many consumers are reluctant to submit their DNA for private sequencing—let alone inclusion in genetic studies—fearing privacy issues.

Even so, research shows that genetic insight into health risks is in high demand in some consumer groups. In an ongoing study of attitudes toward genetic testing at Penn's School of Medicine, Bernhardt and her colleagues have found that their subjects generally embraced and understood their genetic test results and risk levels. Their volunteers were primarily people who took an active interest in their health, she notes, and results were presented only for a single condition for which preventive actions could be taken (such as risk for heart disease), rather than a fuller scan of multiple risks that many of the direct-to-consumer tests offer.

But for conditions in which there is currently no cure or effective prevention there is concern that just downloading a personal genetic risk profile at home might cause undue stress or even depression. Bernhardt and others recommend that consumers meet with a genetic counselor before tests to prepare for what information might come back—and for how it should be used.

The family doctor, however, might not be ready to help in interpreting genetic test results. Bernhardt notes that a lot of general practitioners often do not know what to do with this genetic information.

Recoding the code
Even for genetic tests that offer just a snapshot of relatively common disease-linked variations, the amount of data such a scan generates is immense and requires distillation before relevant information can be presented to consumers. This process of interpretation, however, is one place where the science can get murky.

Most companies offer genetic data in terms of relative risk for particular conditions. Some, including Knome, provide links to scientific studies about genetic variants that appear in your genome, allowing a customer to judge what a particular difference might mean for them. Their personal scans, however, have primarily been limited to a few dozen "healthy and wealthy" customers who are motivated to dive into the literature and explore health implications for themselves.

"Dealing with the huge haystack of data that you get is a really difficult task," Pearson says. And that service is not likely to disappear, even as sequencing prices drop. "When sequencing is free or nearly free, there will always be room for expert interpretation," he says. "That's our stock and trade," he says of his work with Knome.

That approach could have limitations for much of the public who might not be interested in sifting through a decade of scientific literature about a particular mutation they carry. "They're going to get overwhelmed," Pearson notes about consumers who get inundated with mountains of data about their 3.3-billion base-pair genome. Finding ways to convey results "judiciously, securely and wisely" will be a long-term challenge for the industry, Pearson says.

2 Comments

1. 1. nexstepone 05:05 PM 6/29/10

   I agree with the general content of the article, however I will suggest that attempting to define the "success of gene testing" in concrete terms is by it's very nature inherently flawed. We all want our healthcare professional to provide us with definitives. Give my problem a name and an ICD9 code. However human kind represents a dynamic, multi-factorical complexity such that the best we can provide is an increase or decrease in the probability of an outcome. Being able to take the complexity of analysis and reduce it to a reasonable analysis is the challenge. Any analysis needs to be in the hands of the TRAINED healthcare professional, not the consumer.
   
   I will suggest that the area of drug metabolism, gene analysis has the probability to improve the status quo. A study last year by MEDCO reported that $145 Billion of the $292 Billion spent on prescription drugs DID NOT WORK. The MEDCO findings indicate that the introduction of a drug into a patient protocol is at best, a toss of the coin in terms of it's probability of meeting the drug's intended target or goal.
   
   Prescription drugs that utilize hepatic pathways have been defined. I will further suggest that KNOWING the degree that a drug pathway is compromised provides for an INFORMED decision by the healthcare professional. The group of genes called CYPs (Cytochrome P450s) represent the intersection in the pathway for many drugs. CYP450s serve a dual purpose, they are part of the pathway of elimination (metabolizing) of drugs, both prescription and OTC however in some instances these genes are needed to activate the drug (Pro-drug). Some foods, nutrients, OTC drugs, exotoxins and other prescription drugs can and do impact how these genes express (produce the enzyme/protein). In effect these other substances have a probability of compromising the elimination or activation of drugs that use CYP pathways, even if the gene is "normal" in function (EM - extensive metabolizer).
   
   The diversity of function in drug metabolizing genes is an extremely important variable to consider in optimizing a patients drug protocol. CYP genes vary in function from poor metabolizers (PM - NO FUNCTION) to ultra-rapid metabolizers (URM - up to 13 duplicates) of the same gene. Knowing the function of a CYP is an important factor to consider. In my experience in analyzing this group of genes for patients, most drugs use more than one pathway for metabolism. So complexity is the norm and the possible combinations of variables exceeds even the brightest of minds.
   
   The pharmacologic and toxic effects of certain drugs are exaggerated in a significant percentage of the population due to a heritable deficiency in CYP 450 enzymes (Tucker, 1994; Meyer, 1994; Smith et al., 1998). The two major polymorphically (many forms) expressed CYP450 enzymes are CYP2D6 and CYP2C19. The incidence of the poor-metabolizer genotype varies among different ethnic groups. Five to 10 percent of individuals in Caucasian populations are of the PM (no function) CYP2D6 genotype and have deficient metabolism of debrisoquine (an antihypertentive drug metabolized by CYP2D6) and over 25 other drugs. However, less than 1 percent of Japanese subjects are defective in CYP2D6 activity. In contrast, 20 percent of Japanese subjects are poor metabolizers of S-mephenytoin (an anticonvulsant metabolized by CYP2C19), whereas less than 5 percent of Caucasians are so affected (Kaneko et al, 1999).
   
   Significant improvements in patient outcomes and sharp reductions in the cost of ineffective medications and the effects of ADRs and ADEs can be achieved by considering the effects of genetic variation and of other drugs, supplements and foods in a patients protocol.
   
   Several examples follow.
   
   Drug-gene interaction: Warfarin therapy
   
   Warfarin is an anticoagulant commonly used to prevent and control blood clots, but it is complicated to use because the optimal dose varies greatly among patients. If the dose is too strong, the risk of serious bleeding increases and if the dose is too weak, the risk of stroke increases. In a 2006 study, the AEA-Brookings Joint Center for Regulatory Studies estimated that formally integrating genetic testing into routine Warfarin therapy could allow American users to avoid 85,000 serious bleeding events and 17,000 strokes annually. They also estimated integrating genetic testing into Warfarin therapy could save $1.1 billion annually.
   
   Drug-gene and drug-drug example: Plavix and Protein Pump Inhibitors
   
   Plavix (clopidogrel) is the second largest selling drug in the world. It is commonly prescribed to reduce the risk of blood clots and potentially fatal heart attacks in patients who have received stents to open clogged coronary arteries. Researchers have found that patients with variations in the gene cytochrome CYP2C19 have a 3.6 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers.
   
   Recent studies have also created confusion about the appropriate use of Plavix and Proton Pump Inhibitors (PPIs) a group of drugs including Prilosec, Prevacid and Nexium, that produce a pronounced and long-lasting reduction of gastric acid production. The Medco Outcomes Study, a retrospective analysis of 16,690 patients taking clopidogrel for a full year following coronary stenting revealed that patients who also took a PPI for an average of nine months experienced a 70% increase in the risk of heart attack or unstable angina, a 48% increase in the risk of stroke or stroke-like symptoms, and a 35% increase in the need for a repeat coronary procedure. The proposed mechanism is that PPIs inhibit CYP2C19-mediated metabolic bioactivation of clopidogrel into its active ingredient. Clopidogrel is a pro-drug that requires the enzyme to take it's active form.
   
   Drug-food example: grapefruit and common statins
   
   Statins are the most widely prescribed cholesterol-lowering medications. Grapefruit contains the compound bergamottin, which interacts with the cytochrome P-450 and P-glycoprotein enzyme systems. These enzyme systems are responsible for breaking down statins, as well as other drugs, into more usable chemicals and transporting them in the body. When a person consumes grapefruit or grapefruit juice at or around the time of their statin dose, bergamottin prevents the enzyme systems from breaking down the drug, causing high amounts of the statin drug to accumulate in the body. This can cause a variety of very dangerous health problems, such as liver damage or severe muscle and kidney damage.
   
   So the bottom line is, there is NO simple solution. The only way for the healthcare professional to determine the viability of a drug working as intended is to KNOW how this group of CYP genes function and what other substances have influence on them. By having an understanding of how the pieces of the puzzle interact, and how our own unique puzzle is laid out, can the healthcare professional have a probability of decreasing a negative effect (side effect, ADR or ADE). Unfortunately most physicians were not trained in pharmacogenomics and the analysis is time consuming. The result is that the probability of a physicians "guess" being correct is not better than a toss of a coin. Ever heard the statement by your physician "let's try this, and if it doesn't work we will try something else?" The future in drug protocol effectiveness is based on Personalized Medicine, and in this case, Pharmacogenomics is the key to that reaching that end.

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2. 2. inbetweener 01:20 PM 7/3/10

   Scratch that, I'm blind and didn't spot that the link was in the text, but still citing it at the end clearly would be nice.

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