Personalized Medicine: Proceed With Caution

Here at HealthBeat, we often write about medical technology—the overuse of expensive imaging tests, unscrupulous relationships between doctors and medical device makers and the way these practices inevitably drive up the cost of health care. Our current health care system operates on the “build it and they will come” mentality—from spinal fusion devices to digital mammography to drug-eluting stents, we have seen demand ramp up in direct proportion to supply. Under health reform, this will clearly change as comparative-effectiveness and cost-effectiveness studies inform the government’s scrutiny of new technologies.

So how will this work in practice? An early test case may be the emerging technology of whole genome sequencing, the process of translating and cataloging an individual’s entire genetic code—all 3 billion base pairs that make up the “instructions” for life. Genome sequencing is a key component of “personalized medicine,” the Holy Grail for medical researchers who envision administering treatment that is targeted specifically to individual patients.

A handful of venture-capital-backed companies are developing nimble machines that can now sequence an individual’s genome in just a matter of weeks. This raw information—a kind of biotech version of tea leaves—is then sent to genetics researchers on a hard-drive, along with a list of identified single gene variations that might be involved in a patient’s cancer or other disease. These gene variations could also be harbingers of medical problems he or his family members might face decades from now. Although this is powerful technology offers great promise, right now whole genome sequencing is capable of offering practical help to only a very select group of patients.

Still, commercial demand for these machines and their services is growing. Rapid genome-sequencing technology was thrust into the spotlight this month when the Pulitizer Prize for explanatory journalism was awarded to the authors of a remarkable series in the Milwaukee Wisconsin Journal Sentinel entitled, “One In A Billion: A boy's life, a medical mystery.” The series recounts the story of 6-year-old Nicholas Volker, a little boy with a deadly yet mysterious illness who endured an excruciating 100 surgeries and countless hospital admissions over his brief life. With doctors at a loss as to how to treat him, scientists at the Medical College of Wisconsin and Children's Hospital of Wisconsin took a leap and agreed to perform a complete sequencing of Nicholas’s DNA. What they found was literally a needle in a haystack—an extremely rare, possibly unique mutation in a gene for a particular controller protein. Armed with this information, his doctors realized that their best chance to help Nic was to perform a bone-marrow transplant. After the transplant Nic faced life-threatening setbacks, but he ultimately survived and continues to improve.

Now, the Wisconsin researchers are besieged with requests from desperate parents of other seriously ill children to perform similar feats. David Dimmock, a pediatric genetic specialist who helped analyze Nic Volker's DNA, told the Journal Sentinel last month that “the success of the case led to ‘a queue of people at our door saying 'My child next, my child next.' "

So far, The Medical College and Children's Hospital have received 30 referrals from doctors and they’ve established a process for reviewing and choosing medical cases that could benefit from sequencing. A new 10-member committee of doctors, ethicists and genetic counselors has “approved sequencing for at least a handful” of children, according to the Journal Sentinel. In one case, an unnamed insurer has even reportedly agreed to foot the bill for the sequencing.

A few other research projects are also enrolling participants for whole genome sequencing. According to the Journal Sentinel, one program at Duke University Medical School, is offering to sequence the genomes of very ill babies or unborn fetuses who have been diagnosed at their 20-week ultrasounds with unknown structural defects.

“‘Our goal is to provide a clinical diagnosis by birth,’” Nicholas Katsanis, a professor of cell biology and pediatrics at Duke University Medical School tells the Journal Sentinel, “‘This is designed to give us a chance to understand what we are dealing with when we are faced with a very sick baby.’”

The article adds, “Already about six babies have been approved for sequencing and Katsanis said the program's goal is between 60 and 100 per year.”

Illumina, a San Diego-based company that sequenced Nic Volker’s DNA, is hawking its services to other doctors with seriously ill patients. According to Xconomy, a technology news site, “The company is offering a discounted price of $9,500 for people with serious medical conditions who could potentially benefit from having their genomes decoded.” The article continues, “Illumina also is offering a discounted price of $14,500 to groups of five or more from the same physician.”

In fact, human genome sequencing is becoming almost “blasé” according to a Nature article, with an “estimated 30,000 human genomes expected to be sequenced worldwide this year.”

This is an astonishing idea to those of us who followed the 13 years it took to sequence the first human genome. As a science reporter with a background in molecular biology, I kept up with the progress and dedication of the far-flung teams of scientists who tackled the mountain of the laboratory work and data crunching to reach that landmark achievement. I also remember the breathless stories we wrote along the way; predicting that genetic discoveries would lead to targeted new therapies for a wide range of diseases—common yet complex problems like heart disease, as well as rare conditions caused by single gene mutations that strike just one in 10,000 or more children. Since then, gene therapy has been a huge disappointment and most common diseases have proven to have such complex causes—both genetic and environmental—that gene-based cures remain elusive. We are still waiting for the era of “personalized medicine.”

Although there are several genetic screening and diagnostic tests (like the BRCA-1 test for a common breast cancer gene) in commercial use, doctors continue to struggle with ethical questions of what to do with this information once we have it. In some cases, genetic testing can lead to more tailored therapies—for example, women who test positive for multiple copies of the HER2 gene in their breast tumors can benefit from Herceptin, a drug designed to target this particular cancer. But in the absence of many targeted treatments, knowing that we have faulty genes can become a burden, not a panacea for most people. At best, it signals the need for early and frequent testing or in the case of breast or ovarian cancer, prophylactic surgery.

Not only is the speed of whole genome sequencing progressing at a breakneck pace, the technology is also dropping precipitously in price. As the chart below shows, it cost upwards of $100 million to decode a human genome in 2001. By January 2011, commercial sequencers (like Illumina) with proprietary machines could do it at the same level of accuracy for about $21,000. Recent reports put that number even lower; between $10,000 and $15,000.

Source: National Human Genome Research Institute

But it’s unlikely that complete genome sequencing will be offered at a price that is palatable to most consumers any time soon. In his blog at Forbes, Matthew Herper explains, “Why You Can’t Have Your $1,000 Genome;”

“Research genomes are not accurate enough for medical use. Getting better accuracy requires sequencing the DNA more times, which drives the cost back up. I’d think if we’re talking about actual medical use, $10,000 is a more accurate number.”

The other problem is that beyond providing the DNA sequencing information, practical applications require genetics experts to run advanced screening and data analysis to identify gene mutations that might play a role in disease. Although researchers—like those in Wisconsin who discovered Nic Volker’s rare mutation—are developing software to speed up this process, commercial applications are still several years off.

Still, with the technology improving so rapidly, it’s important to look at whole genome sequencing through the new lens of the health reform law. Already parents of seriously ill children and cancer patients are clamoring for the chance to undergo this expensive (and labor-intensive) procedure. Reports in medical journals describe patients with mysterious forms of melanoma, leukemia and breast cancer who have had their tumor cells sequenced and then compared to the sequence of their complete genome, resulting in the identification of the nefarious gene mutation or mutations at the root of their disease. In these cases, knowledge gleaned from the sequencing has sometimes guided doctors in treatment—but most often offers important research information without the promise of a cure.

Still, the hope for a new era of “personalized medicine”—at least in cancer treatment—is very much alive. In an April 20 editorial describing two complete genome sequencing cases in the Journal of the American Medical Association, the authors write, “Today, sequencing a tumor genome is still expensive and requires an infrastructure that is incompatible with a clinical setting, but the trend suggests that we are a lot closer to cost-effective, clinical genomics than most physicians realize.”

“The ability to sequence an individual's entire genome as well as the patient's tumor genome is now a feasible enterprise at a cost and speed that was unthinkable even 5 years ago. In less than 3 years, DNA sequencing costs have decreased by more than 100-fold. The rate of improvement exceeds the advancement in computational power over the same time period, which predicts an oncoming wave of genomic data."

They continue, “New innovations in DNA sequencing are expected to increase the speed of data collection and decrease the costs by another order of magnitude in the next 2 years. Clearly, the technology will no longer be the major impediment to widespread clinical use of these tools, and the main challenges will soon move to the clinical implementation and interpretation of genomic data. Numerous regulatory and reimbursement issues remain.”

Here’s where it gets tricky. If the FDA limits the use of  whole genome sequencing machines for commercial purposes only in the cases of hard-to-treat cancers and seriously ill babies, many of the ethical, regulatory and cost issues associated with the technology could be avoided. But how will we handle these issues when doctors—as they did with drug-eluting stents, for example—start offering sequencing to people outside these narrow parameters. What if healthy people or those less seriously ill start requesting the tests; those same folks who embraced “full-body scanning” and found out that they have a tiny spot on their liver that may or may not be a harbinger of disease to come in 20 years?

It is likely that patients whose family history puts them at elevated risk of cancer will start demanding coverage for genome sequencing—just as they have for digital mammography, thermography and other higher-tech diagnostic procedures like spiral CT scanning for lung cancer.  How do we reconcile the benefits of this expensive technology with ethical concerns about patients receiving frightening results without being offered any medical solution? It’s also easy to imagine that whole genome sequencing could, like other diagnostic tests, lead to a rise in over-treatment. Will companies be able to offer this service to anyone willing to pay? The FDA is still trying to regulate do-it-yourself genetic testing kits that the “worried well” readily purchase even though they have little practical value other than to determine paternity, prompt diet changes or increase overall anxiety.

In the end, the case of whole-genome sequencing is important because it is an innovative, potentially game-changing technology that also raises questions about costs, benefits and yes, rationing of care. In terms of medical progress, stories like the one of Nic Volker are inspiring, reviving the idea that American ingenuity and risk-taking are the only weapons needed to conquer all diseases. Super-fast genome sequencing will usher in the promised era of personalized medicine! Personalized prevention! Saving the lives of gravely ill babies and children…cure cancer!

The truth is that yes, fostering innovation is important if we want to achieve life-saving treatments. It must be encouraged, not snuffed out, by health reform. But it is also true that we are drowning in health care costs and just getting started on the enormous task of figuring out which expensive technologies are really effective and game-changing and which ones are just costly versions of the same old mousetrap. Newer, as we’ve learned, is not always better. We are also grappling with serious ethical issues raised by new genetic technologies—especially concerns about diagnosing future illness without offering treatment.

Devising a sensible and fair method for evaluating future new technologies is an important but little discussed aspect of health reform. The days are over when Medicare or even private insurers agree to cover every new diagnostic or imaging test. In this era of health reform, new technologies will have to prove to be beneficial as well as cost-effective. Analyzing someone’s entire genome doesn’t make sense for the majority of Americans, at least for the foreseeable future. There just isn’t enough known about the relationship between disease (and risk of disease) and individual genetic anomalies. Supporters of this technology gush about the new era of personalized medicine—but aside from those patients suffering from a handful of cancers or extremely rare ills, whole-genome sequencing has yet to prove real benefit in treatment.

Nicholas Volker’s is a heart-rending, hopeful story that encourages the uniquely American belief that embracing new medical technology—not implementing boring cost-cutting measures and changes in service delivery—will be the key to reforming health care. Health reform is not synonymous with squelching innovation; but its insistence on comparative effectiveness and cost-effectiveness mean that pulling out all the stops—as doctors did in this case—must remain a one-in-a-billion experience.

12 thoughts on “Personalized Medicine: Proceed With Caution

  1. A clinical researcher told me some time ago that the use of RT-PCR and DNA microarrays in personalized oncology is analogous to the introduction of the personal computer. Dazzling hardware in search of a killer application. So what research scientists in universities and cancer centers have been doing for the past ten years is to try and figure out a way to use this dazzling technology to look for patterns of gene expression which correlate with and predict for the activity of anticancer drugs.
    Academics are besides themselves over the promise of genome sequencing. It seems so cool that it simply must be good for something. How about in the area of identifying drugs which will work in individual patients? All DNA or RNA-type tests are based on ‘population’ research. They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really ‘personalized’ medicine, but a refinement of statistical data.
    The particular sequence of DNA that an organism possesses (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.
    The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. A challenge facing pharmacogenetics is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine.
    In cancer medicine, teasing out the genetic patterns associated with particular drug responses could involve some intricate and time-consuming scientific detective work. Human beings are demonstrably more than the sum of their genes. Cancer biology and the study of cancer therapy are many things, but simple is not one of them. Complex problems require solutions that incorporate all of their complexities, however uncomfortable this may be for genomic investigators.

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  3. Thanks for the comment Greg. You are right that genome sequencing is an incredible technology in search of more practical applications. If used in research to expand what we know about tumor biology and to move toward more targeted treatments that would be fantastic. But cancer biology, as you said, is not simple. Aside from a few directly heritable disorders, the genetics of disease–both physical and behavioral–lag far behind our ability to parse individual gene mutations.

  4. My view of “personalized medicine” is accepted with a strong dose of skepticism. Hey all good medical practice needs to be personalized? (nothing new about that?)
    In addition to every person having their own genome every person has their own individualized behaviors, environmental exposures and, probably most importantly, their own stories which is called narrative in good medical practice
    Dr. Rick Lippin

  5. The particular sequence of DNA that an organism possesses (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.

  6. One likely outcome of genetic profiling is its use to undermine comparative effectiveness research, As Dr, Lippin points out, doctors want to individualize therapy. They decry any generalized findings they don’t agree with as “cookbook medicine”. They will identify any piece of atypicality in a patient’s genetic profile that has a minimally plausible connection to a patient’s illness to justify ignoring any reearch they don’t agree with.

  7. I think the story here is about patient involvement. Unlike whole body imaging, and the prosaic applications of phamacogenomics, genomic information does not require physician interpretation to be interesting and occasionally useful. High quality genomic data is processed by computers and highly specialized researchers while doctors struggle to keep up.
    This gap between technology and traditional medical practice will become increasingly clear to patients starting, as Maggie clearly points out, with rare pediatric diseases and cancer. Policy makers that ignore patient access to primary information (and therefore hamper patient access to technology) while charting health reform can expect push-back. Our generation of patients may not wait patiently for the doctors to catch up.

  8. This article is timely and spot on in its cautionary tone.
    Meanwhile, the latest issue of the Annals of Internal medicine provides a different view of what might be done with both clinical effectiveness and “personalized medicine” . Eddy and colleagues, using sophisticated modeling techniques and real-life data from a longitudinal study showed that it is possible to save millions of dollars and/or thousands of lives by taking a standardized protocol for treating hypertension and customizing it to each patient, using data about known risk factors such as cholesterol levels, body weight, etc. It is by no means a flashy technology, nor will it generate income for an entrepeneurial physician. But, this kind of analysis is just what we need to improve the health of the population while actually lowering costs.
    My guess is that genetic testing will spread through society faster than the findings of this paper–unless we begin to ask more rigorous questions about what really makes a difference in health care.

  9. Thanks for the comment Greg. You are right that genome sequencing is an incredible technology in search of more practical applications. If used in research to expand what we know about tumor biology and to move toward more targeted treatments that would be fantastic. But cancer biology, as you said, is not simple. Aside from a few directly heritable disorders, the genetics of disease–both physical and behavioral–lag far behind our ability to parse individual gene mutations.