Anti-gene-testing week at N. Y. Times

First, there was Michael Crichton's guest op-ed:

YOU, or someone you love, may die because of a gene patent that should never have been granted in the first place. Sound far-fetched? Unfortunately, it's only too real.

Crichton argues that genetic information is a product of nature, not invention, and so shouldn't be patentable:

Humans share mostly the same genes. The same genes are found in other animals as well. Our genetic makeup represents the common heritage of all life on earth. You cant patent snow, eagles or gravity, and you shouldnt be able to patent genes, either. Yet by now one-fifth of the genes in your body are privately owned.

This is an old argument, and whether you consider it right or not, the U.S. courts so far have rejected it. In its favor, Crichton can cite some fairly egregious outcomes, including the story of Canavan disease:

When the gene was identified in 1993, the families got the commitment of a New York hospital to offer a free test to anyone who wanted it. But the researcher's employer, Miami Children's Hospital Research Institute, patented the gene and refused to allow any health care provider to offer the test without paying a royalty. The parents did not believe genes should be patented and so did not put their names on the patent. Consequently, they had no control over the outcome.

The case is described in more detail by a Science news article from 2000.

Thirteen years ago, the father of two children suffering from Canavan disease--a fatal illness whose symptoms begin appearing 3 months after birth--approached a scientist named Reuben Matalon and persuaded him to begin developing molecular probes to trace the disease to its source. They also set up a registry of families and helped recruit tissue donors. The disease, which affects 1 in 6400 Ashkenazi Jewish children, is caused by a mutation on chromosome 17 that leads to a deficiency of the enzyme aspartoacylase, gradually destroying the central nervous system. With the families' support, Matalon found a Canavan gene in 1993 and developed a genetic test. Matalon's employer at the time, Miami Children's Hospital (MCH), obtained a patent on the gene in 1997, and the next year began licensing a test that could identify lethal Canavan mutations.
...
The plaintiffs object to the $12.50 royalty fee MCH is charging. In addition, according to the complaint, they claim that MCH has tried to restrict access and promote a lead test center by setting a limit on the number of tests that can be performed by each licensee. The Canavan Foundation was forced to stop offering free genetic screening, according to the complaint, after being advised that it would have to pay royalties and comply with other licensing terms.

A recurring problem keeps coming up in examples like Canavan disease: a motivated risk group -- in this case, parents of Canavan children -- wants a good test, so that they can assess risks more accurately and possibly direct resources toward a cure. To this end, they are willing to undertake a lot of volunteer effort so that researchers will be able and willing to help them. But that volunteer effort is seldom repaid, and sometimes exploited, at least from their point of view.

In some cases, the volunteer effort is repaid by higher royalty payments for the volunteer group, as for BRCA2 testing in Ashkenazim.

Crichton and others have a good argument in this sense: gene testing patents really are not very much like most other kinds of patents. They are more like mining claims -- nobody "made" the gold, either, but it takes some development of the resource to be able to extract it. But here, "extracting" the information means making somebody pay for their own biological information.

Still, this isn't in principle any different than making people pay for a cholesterol test, or a blood typing test, or a blood chemistry panel. That's biological information, too. Nobody "made" it either. But people did invent the means of assaying the information from the biological sample.

The problem with gene testing is the high prices that people are willing to pay (often, on advice from their doctors) for information that is rarely valuable. Even within a risk group, most results will be negatives (with a few false positives thrown in for panic-inducing uncertainty). Sure, it may well be worth $500 or more to a patient's peace of mind to know she doesn't carry a risk-increasing mutation. But the incremental cost of SNP assays on a gene chip is now so low as to make most gene tests look ludicrously expensive. Paying $500 or more for a genetic test is like buying a Lamborghini instead of a Toyota -- without the extra horsepower.

Patents are dangerous from an important perspective: an overly-broad patent on a testing procedure prevents the development of cheaper alternatives. And given the clear precedent for patents that cover small risk populations, there will be many cases for which most almost anyone can obtain a cheap test except for people who most need it.

That is unquestionably a problem -- and moreso for simple Mendelian traits, for which only a single gene test will really be effective. To the extent that such a gene is covered by patents that restrict testing, they really can impose a cost on research and health.

The poor performance of many gene tests in predicting disease outcomes is the focus of an article today by Denise Caruso. There has been a proliferation of "tests" for risk factors, that really encompass only a small proportion of the genetic variation underlying disease traits:

Yet most of those hard-wired gene-disease links -- as many as 95 percent of them, according to one British study published in 2003 -- dont hold up to closer scrutiny. Instead, follow-up studies find that if there is any measurable genetic link to these common diseases, it results from the more complex interactions of many genes with one another, as well as with the environment.

Here, a major problem is that genetic tests have no approval process:

Commercial laboratories do not have to negotiate any formal approval process before offering a new genetic test, "and government requirements to ensure that genetic testing laboratories are getting the right answers to patients are minimal," according to an issue brief by the Genetics and Public Policy Center at Johns Hopkins University last September.
What's more, the center added, there is no government requirement that a test must "actually relate to a particular disease or risk of disease" in order to be sold.

This puts genetic testing roughly at the same level as herbal supplements.

I was talking to a group of genetics graduate students last fall, and frightened to realize that there is no requirement that they take courses in evolutionary biology or know anything about it.

Why is this relevant? Because the people developing these genetic "tests" for disease risk factors didn't have to learn anything about normal human variability in the course of their training. There are certainly exceptions, but in my experience the procedures that lead to disease-allele associations are based on samples of people designed to exclude most aspects of real-world variability. This includes simple questions, like "Why should this apparently bad allele be there at a high frequency?"

Since the answers to such questions usually involve selection or population history, the results from one sample often don't apply to other samples -- for instance, because they are influenced by "genetic background", meaning the presence or absence of alleles at other loci.

Under H.H.S. guidelines, called Clinical Laboratory Improvement Amendments, tests developed by individual labs do not require regulatory review. What's more, the guidelines require only technical proficiency; they do not require labs to prove their tests are clinically valid, said Dr. Daniel G. Schultz, director of the F.D.A.'s Center for Devices and Radiological Health.
He said in-vitro diagnostic multivariate index assays "are based on algorithms that don't permit even a well-trained physician to really understand whether or not the results are accurate and meaningful or not."

"If that technology purports to tell an individual whether or not the type of ovarian or breast or colon cancer is or isn't likely to recur, and would or wouldnt require additional therapy -- well, we think there needs to be somebody looking at the testing that was done to create those algorithms," Dr. Schultz said. "No one else is doing that, and if we don't do it, no one else is going to."</blockquote>

The problem is that there are a very small number of people who can design the algorithms, and all the algorithms involve assumptions, and only the people who design the algorithms are in a position to know what the assumptions are. The only way to find out if the assumptions are right or wrong is to see whether the algorithms predict outcomes successfully for new samples of patients.

A company with a prospective test has two options. They can conduct extensive trials, offering the test for free to affected populations, to see how well it predicts outcomes on new samples. Of course, better technology in 2 or 3 years will probably offer tests with finer resolution, depreciating much of the commercial value of the test during this initial trial phase.

Or, the company can introduce the test at a price, advertise it as an advisory procedure based on the initial sample to which the algorithm had been applied, and use the proceeds to fund the next round of test development.

It seems obvious that without some kind of government intervention, a company would be insane to conduct free trials. Heck, if the company didn't cash in right away, their shareholders might sue!

I view this ultimately as a symptom of the systematic problems with the health system. The value of testing is generally overrated, and people are willing to pay enormous surcharges to get test results of questionable value. Doctors request unnecessary tests because very occasionally they prevent an incorrect diagnosis, or lead to a better treatment course. But usually, they are just fluff padding the bill. People focus heavily on positive outcomes, which enable some kind of informed response. They tend to ignore a high rate of negative outcomes, regardless of the cost of testing, because negative results cause visible relief.

Gene tests are novel, but they present the same problems as unnecessary MRI tests or blood panels. Even cholesterol tests are vastly overused. Ultimately, the problem is that people don't understand risks, and do a poor job of assigning value to information.

The problem is worse when the "information" comes in the form of "high-tech" results, but is by no means limited to those contexts -- I'd say, poor risk assessment is a human universal.

Is there a bottom line?

As I'm finishing this up, I'm noticing that I've been describing several problems without presenting a consistent point of view. I mean, are gene patents bad or not? Should the FDA regulate gene tests or not?

Personally, what I'm noticing is that every time I read somebody who has taken a consistent point of view on gene patents, like Crichton's op-ed, they usually selectively leave out details. For instance, how much does it cost to develop a gene test? Why are the volunteer efforts to build up samples of affected populations so valuable? How will the relative values of these efforts change with changes in gene assay technology? How much government (e.g., NIH) investment has contributed to research versus private (e.g. Gates Foundation) funding? Are the patents owned by pharmaceutical corporations (rarely) or universities (commonly)?

In effect, the answers to these questions are different for every different disease phenotype -- because some affect a narrow historically-defined population and others affect global or continental groups, some traits are Mendelian and others much more complex, some are more affected by genetic background and others less so, some are invariably fatal and others rarely so, etc.

To date, the defendants in most of the best-known gene or cell-line patent cases have been research institutions or universities (Miami Children's Hospital for the Canavan test, the University of California for the Mo-Cell case, the NIH for the Hagahai T-cell case). So I'm hard-pressed to describe the problem as "evil corporations" and the profit motive. Maybe the problem is really infrastructural, maybe "evil corporations" are more likely to settle cases quietly, maybe patient groups are less likely to approach and cooperate with corporations, therefore making them less likely to feel betrayed by royalty licensing.

In any event, the problem is not simple, and I am skeptical of any dogmatic conclusions. Suppose somebody tomorrow developed a whole-genome scan that could practically assess risks for obesity, cardiovascular disease, and diabetes in one test. Should that test be patentable? Since the effectiveness of the test would essentially result from the particular combination of markers it uses, patenting such a test is equivalent to patenting a combination of gene markers. They're "natural" information. Should they be patentable? Should the government require that the developer conduct random trials to determine the test's real predictive value, or should it be made immediately available to anyone who wants it?

Such a test looks like more of an "invention" than a single-gene assay for a Mendelian disorder, but only 10 years ago single-gene assays themselves seemed pretty inventive. Both are essentially data-mining exercises, given the right samples. But then, the tungsten filament seems like an obvious application of data mining on physical systems, in retrospect...

References:

Marshall E. 2000. Families sue hospital, scientist for control of Canavan gene. Science 290:1062. doi:10.1126/science.290.5494.1062