Good News from SCOTUS on Gene Patents, But Questions Remain

Today the U.S. Supreme Court issued a unanimous decision on the Myriad Patent case, having to do with the company’s ownership of BRCA-1 and BRCA-2 gene sequences. The main opinion, authored by Justice Thomas, says this:

“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.

At first glance, this is terrific news for patients world-wide. It means is that no company, university, other entity or individual can patent human genes.

Keep in mind – the case doesn’t just apply to BRCA and evaluating a person’s risk for breast and ovarian cancers. Rather, there are hundreds of human genes implicated in cancer that are potential targets for treatment, that might be evaluated, and thousands linked to other diseases. The decision continues:

“Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA. It found an important and useful gene, but groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the… <patent law>

West façade of U.S. Supreme Court Building. (Franz Jantzen)

West façade, U.S. Supreme Court (Franz Jantzen), gov’t image

What’s clear is that gene sequences, as they occur in human cells, can’t be owned just because they’re found, no matter how important they are. This circumstance should allow other researchers and firms to create cDNA from the natural sequences to develop new (competing and potentially less costly) assays and, even better – do their own work – tantamount to providing “second” and “third” opinions (etc. & n.b. IMO more is better!) research to understand how the genes lead cause disease in some people and might targeted for therapy. Great –

But the decision suggests that many lab-generated complementary DNA (cDNA) strands remain patentable, or up for grabs once created – which may be the reason some biotech stocks have rising values today. I’m neither a lawyer nor an analyst, but I do know from my experience as a researcher that it’s essentially trivial to generate cDNA from a short DNA segment, potentially with a mutation of interest. So how might the cDNA be patented, if anyone who has access to the original genetic sequence might form the cDNA by routine lab methods?

Near the end of the opinion, the justice writes:

“…but the lab technician unquestionably creates something new when cDNA is made. cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, cDNA is not a ‘product of nature’ and is patent eligible under <patent law §101>, except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA.

The document clarifies the cDNA issue just slightly:

“It is important to note what is not implicated by this decision. First, there are no method claims before this Court… the processes used by Myriad to isolate DNA were well understood by geneticists at the time of Myriad’s patents ‘were well understood, widely used, and fairly uniform insofar as any scientist engaged in the search for a gene would likely have utilized a similar approach’…

Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of <patent law §101> to such endeavors.

How I interpret this is that if a researcher generates a short cDNA segment based on a gene, that’s not patentable, but if it’s a long strand involving lots of clipped introns, that might be patentable.

Taking in all this, which is far from simple, I have a question and a wider point:

What goes unaddressed by the justices is the patentability of cDNA based on common genetic variants in cancer. Those are “naturally occurring” mutations, inasmuch as they arise in humans. But the cDNA generated from those sequences might remain patentable. There are loads of examples in this regard: Consider, for example, the genetic mutations in EGFR, and ALK, that are used in lung cancer diagnosis, treatment decisions and development of new targeted drugs. In the current issue of the New England Journal of Medicine, doctors report on SALL4, a gene that occurs in some liver cancers and might be a good, useful target for therapy in that disease.

The point is that the Supremes – and those would be lawyers – need to know about biology. Justice Scalia, sadly in my view, wrote his own opinion not because he disagreed with the others, but because he felt there was too much science in the decision. From the Scotus Blog today:

“Many readers no doubt will share the view of Justice Antonin Scalia, in a short, separate opinion refusing to join in a section “going into the fine details of molecular biology,” of which he said he had neither knowledge nor belief.  Scalia said he did understand enough …

This scares me, that one of the Justices, our most accomplished lawyers who might make decisions on cloning, and stem cells and who knows what in the future, copped out because he lacks science education – what should be required high school biology in  U.S. schools, public and private – to form an opinion that matters so much.

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New Findings on Leprosy and Armadillos

A surprise lesson arrived in my snail mailbox today: the April 28 issue of NEJM includes a fascinating research paper on a probable cause of leprosy in the southern U.S. New, detailed genetic studies show that armadillos, long-known to harbor the disease, carry the same strain as occurs in some patients; they’re a likely culprit in some cases.

Dr. Gerhard Henrik Armauer Hansen, who identified the bacteria causing leprosy

Dr. Gerhard Henrik Armauer Hansen, who identified the bacteria causing leprosy

For those who didn’t go to med school: Leprosy is a chronic, infectious disease cause by Mycobacterium leprae. In my second year we were told to refer to the illness as Hansen’s disease. We learned that some people are more susceptible to it than others, possibly due to inherited immunological differences, a point that is reiterated in the current article.

The World Health Organization reports there are under 250,000 cases worldwide every year. Here in the U.S., Hansen’s disease is quite rare, with about 150 new cases reported annually according to the study authors. The condition wasn’t evident in the Americas before Columbus’ travels, but by the mid-18th Century it was affecting some settlers near New Orleans. Today, most cases in the U.S. arise in travelers and others who’ve lived or worked abroad in regions where leprosy is endemic. About a third crop up in people who’ve never left the country, and these cases tend to cluster in the southeastern U.S.

Leprosy tends to affect the skin, and what the NEJM investigators first did was examine skin biopsy specimens from patients who live in the U.S. and hadn’t traveled. It’s been known for decades that armadillos can carry these bacteria, and so the researchers took specimens from wild armadillos in five southern states, and analyzed the M. leprae bacterial genomes. They matched. Then they looked at more patients’ samples, and also analyzed M. leprae sequences from patients in other parts of the world.

The conclusion is that wild armadillos and some leprosy patients in the southern U.S. are infected with an identical strain of the bacteria that causes leprosy. From this information, the authors infer that armadillos are a reservoir for this stigmatizing germ, and that they may be the source of some patients’ infections.

So the news is that leprosy may be a zoonosis.

A personal note –

Only once I saw a patient with Hansen’s disease, at the Bellevue dermatology clinic, when I was a fourth-year student. She was an elderly woman from China. Her face, which I can picture now, had classic leonine features. The resident caring for her,  an intern with a plan to become a dermatologist, prescribed antibiotics.

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Learning About the Cancer Genome Atlas

A tweet from a former research colleague reminded me about the Cancer Genome Atlas, which I’d been meaning to check out. This website covers a project jointly funded by two NIH institutes: the NCI and the National Human Genome Research Institute (NHGRI). The project is about documenting cancer genetics for many, many human tumors.

Cancer Genome Atlas image

Some basics –

We all have genetic sequences we’re born with: our personal genomes. If you were to get your genome sequenced by a company, like 23andMe, they’d get some DNA from any of your cells or body fluid, and sequence your “somatic” or cellular genome. They would identify variants and mutations that you carry in the DNA of all or most of the cells in your body.

Cancer cells often contain genetic mutations that are not present in the patient’s healthy cells. So an individual’s breast cancer genome, for example, might differ from her baseline, inherited genome.

The purpose of the cancer genome project is to sequence DNA present in tumors samples so that researchers can identify specific, genetically distinct cancer forms and, eventually, develop smarter drugs that take aim at those tumor-specific mutations.

The site offers some cool, public-domain pathology and genetics images through a multimedia library. Good to know –

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A New Source of Potential Error in Scientific Research

In today’s Times, Nicholas Wade reports on a potentially serious, besides costly, problem for biomedical researchers: Human DNA Contamination Seen in Genome Databases. He writes:

Nearly 20 percent of the nonhuman genomes held in computer databases are contaminated with human DNA, presumably from the researchers who prepared the samples, say scientists who chanced upon the finding while looking for a human virus…

The full report was published yesterday in PLoS One. The investigators, based at the University of Connecticut, screened for a common human sequence in 2,749 non-primate public databases – NCBI, Ensembl, JGI, and UCSC – and found 492 were contaminated with human DNA. Affected sequences included include bacterial, fish, plant and other genomes.

The implications are broad because if the findings in this report are true, scientists throughout the world have drawn inferences and conclusions and published papers based on incorrect DNA sequence information. As the PLoS authors write in their introduction:

The danger in the propagation of errors in scientific discourse has been demonstrated in cases of both scientific fraud as well as incorrectly described or referenced experiments in reviews [1], [2].

abstract double helix (Wikimedia Commons)

Sound familiar? Think of Lies, Damn Lies and Medical Science, as I considered in a December post on the Decline Effect and other problems that cast doubt on research findings we take for granted.

What happened is likely that, over the years and at many separate institutions, researchers handling cells from which DNA would be extracted, or perhaps just handling the DNA and doing sequencing and other experiments with that, contaminated the specimens with their own genetic material. This is a real headache for researchers, or should be.

Yesterday an on-line colleague and patient advocate, Trisha Torrey, (via a Twitter conversation) to the “HeLa bomb” as recounted in Rebecca Skloot’s The Immortal Life of Henrietta Lacks. In that, Skloot describes 1960s researchers who realized that the cells they’d been using for cancer research experiments were contaminated in vitro. HeLa cells tended to grow so rapidly, they’d sometimes overwhelm other cultures growing in nearby petri dishes or flasks. Once scientists realized that the cells they were using weren’t what they thought they were, and that HeLa cells weren’t all the same due to acquired mutations, their results became questionable.

My take is that researchers need to take care, and not make assumptions, such as “the cells I have received for analysis from a colleague’s lab are the cells they are said to be on the label.” Vials get mislabeled, sometimes. Cultures get contaminated by bacteria and fast-growing cell lines. And now it’s evident that at least some published genomes are incorrect.

But also – and more generally, we should constantly be questioning and checking and reviewing our methods and reagents, and whatever forms evidence, especially when results are surprising (think Madoff) and/or have implications for patient care and therapy, because errors do really happen in all realms of medical and scientific research.

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Perspective on Screening for Sickle Cell Trait in Student Athletes

Today I watched a video, The Student-Athlete with the Sickle Cell Trait, sponsored by the National Collegiate Athletic Association (NCAA) on its website. The 12-minute presentation provides some helpful background on what it means to have sickle cell trait and how awareness of that condition might influence a student’s (or coach’s?) behavior during rigorous conditioning and competitive sports.

“The more medical information we know about our student athletes, the better equipped we are to help keep them safe,” says Mark Richt, Head Coach at the University of Georgia, at around 3 minutes into the clip.

A new NCAA policy mandates screening all Division I college sports participants for sickle cell trait. Not coincidentally, the Sept 9 issue of the New England Journal of Medicine opens with a noteworthy perspective* on this topic. The screening recommendation, effective at the start of this academic year (i.e. now) directly affects more than a few young adults in the U.S.: among nearly 170,000 athletes who’ll be tested this year, it’s expected that several hundred “carriers” will be identified.

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On Sergey’s Search (for a Cure for Parkinson’s Disease)

This week I brushed up on Parkinson’s disease. What drew me into this mini-review is an informative article, “Sergey’s Search,” that appeared in the July (print) issue of Wired and is now available on-line. The feature, by Thomas Goetz, offers insight on what it’s like to know that you’ve got a genetic disposition to Parkinson’s, details on some enzymes implicated in the illness and, further, considers what might be done to help future patients.

I recommend this article to any of my readers who are interested in genetics, Parkinson’s and/or what some even consider as a new era for health-related research.

There’s a lot to take in –

The Wired story starts with Google co-founder Sergey Brin. A Moscow native and, more recently, a California swimmer, Brin’s got his reasons for concern. He’s got a strong family history, for one thing: the illness has affected both his mother and aunt. It turns out Brin has a genetic disposition to develop the condition because he shares the disease-associated G2019S mutation with his mom. As Goetz explains, this alteration in the DNA segment of the gene encoding LRRK2, a leucine-rich repeat kinase, involves a single-nucleotide switch of an adenine for a guanine.

(I’ll add this, just in case you’re interested: the gene encoding LRRK2, or dardarin, resides at human 12q12 – that’s the long arm of chromosome 12. The G2019S nomenclature indicates that the mutation results in a change at the 2019th amino acid position along the protein’s encoded structure, so that a glycine, normally present, is replaced by a serine molecule at that spot. A fascinating tidbit, news to me today, is that when the gene was first cloned in 2004 the researchers, who’d studied several affected families of Basque origin, called it dardarin, derived from the Basque word dardara, meaning tremor.)

The G2019S mutation is relatively common among Ashkenazi Jews. Still, not all of those who carry the mutation develop the disease, and not all who have the disease have this particular mutation. Other genetic variants have been identified, and it’s not clear exactly how these wreak havoc with LRRK2’s function. Enzymes like LRRK2, a kinase, usually transfer ATP molecules from one protein to another. The presumption is that in Parkinson’s, abnormalities in this enzyme’s function – whether they’re caused by this particular mutation or another – somehow lead to loss of dopamine-producing cells in the brain.

Back to Sergey’s story –

“Brin didn’t panic,” Goetz reports (a point I’d emphasize too). Rather, he was reassured by his mother’s experience and high level of functioning with the disease. She still goes skiing (among other things one’s mother might do), he reasons.

What Brin is doing, along the lines of Goetz’s Decision Tree approach, is cutting his risk as best he can. He exercises regularly, doesn’t smoke, and funds research.

Like other rock star informaticists before him (think of Netscape founder James H. Clarke, who launched Healtheon and Steve Case, who started Revolution Health – these are my examples), Brin is struck by the slow pace of medical investigation:

“Generally the pace of medical research is glacial compared to what I’m used to in the Internet,” Brin says. “We could be looking lots of places and collecting lots of information. And if we see a pattern, that could lead somewhere.”

If only medical research could be more like Google…

Some clinical background:

Parkinson’s, a progressive and often debilitating neurological condition, affects a half million or so people in the U.S. As a practicing as a physician, I cared for many patients who had this illness. Although I would see them for other reasons, it was hard not to notice, and know, the characteristic tremor, rigidity and shuffling walk of those affected. The onset of symptoms is usually insidious, slow and unnerving.

As Goetz indicates, most of what doctors understand about Parkinson’s comes from observing patients in the clinic. Illness emerges, it’s thought, as the number of dopamine-producing cells in the brain diminishes. Dopamine is a neurotransmitter, a molecule that transmits messages between cells or groups of cells within the nervous system. Since around 1967, when the drug Levodopa was first marketed, doctors have prescribed this and other pills for people who have Parkinson’s. While these meds can ameliorate symptoms, these don’t reverse the unstoppable deterioration of body and, ultimately, the mind.

One problem with Parkinson’s research and treatment is that once the disease becomes evident, it’s hard – probably too late – to reverse the loss of dopamine-producing cells. Most people don’t develop symptoms until dopamine production is around 20 percent of normal levels. Now, with the advent of genetic markers and potential to “catch” this disease early on, there’s an opportunity for early intervention.

One promising area for Parkinson’s research:

LRRK2 is a kinase, a kind of enzyme that’s over-active in some cancers. Already, pharmaceutical companies have developed specific kinase inhibitors; a dozen or so are already FDA-approved for treatment of particular cancers, and many more are in the pipeline.

What excites me, in all of this, is the possibility that these drugs might be effective in patients with Parkinson’s disease. And because the same enzyme – LRRK2, or dardarin – is implicated in cases without the particular G2019S mutation, it may be that these drugs would work even in cases that lack this particular genetic feature. (There are examples in oncology, in terms of tumor genetics and responsiveness to targeted drugs, that would support this contention, but that’s just theory for now.) The bottom line, as I see it, is that these new drugs should be carefully tested in clinical trials.

Sergey’s view:

One of the key ideas in Goetz’s piece has to do what he considers and may well be a revolutionary approach to medical research.

…Brin is after a different kind of science altogether. Most Parkinson’s research, like much of medical research, relies on the classic scientific method: hypothesis, analysis, peer review, publication. Brin proposes a different approach, one driven by computational muscle and staggeringly large data sets. It’s a method that draws on his algorithmic sensibility—and Google’s storied faith in computing power…

In what may indeed be a “fourth paradigm” of science, as attributed to the late computer scientist Jim Gray, there’s an inevitable evolution away from hypothesis and toward patterns.

As I understand it, Brin seeks to invert the traditional scientific method by applying Google-size data-mining power to massive and very imperfect data sets in health. Already, he and his colleagues have accomplished this by Google’s Flu Trends, which several years ago beat the CDC to an epidemic’s discovery by two weeks.

You should read this article for yourself, as I’m afraid I can’t adequately describe the potential powers of computational health and science analyses that might be applied to well, pretty much everything in medicine. This goes well beyond a new approach to finding a cure for Parkinson’s disease.

This story, largely based in genomics and computational advances, reflects the power of the human mind, how the gifted son of two mathematicians who fell into a particular medical situation, can use his brains, intellectual and financial resources, and creativity, to at least try to make a difference.

I hope he’s successful!

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DNA Comes Home, or Maybe Not

Earlier this month employees at most of 7500 Walgreens pharmacies geared up to stock a new item on their shelves: a saliva sampler for personal genetic testing. On May 11, officials at Pathway Genomics, a San Diego-based biotech firm, announced they’d sell over-the-counter spit kits for around $25 through an arrangement with the retailer. A curious consumer could follow the simple package instructions and send their stuff in a plastic tube, provided in a handy box with pre-paid postage, for DNA analysis.

DNA helix structure (Wikimedia Commons)

Once the sample’s in the lab, the cost of genomics testing depends on what, and how much, you want to know. Pathway offers a variety of options. A pre-pregnancy planning report would check to see if you carry mutations for each of 37 inherited diseases – conditions as varied as beta thalassemia, cystic fibrosis and familial Mediterranean fever – for $179. A profile of tests for genes involved in metabolizing specific drugs, such as Plavix and Coumadin, goes for $79. A vaguer, health conditions panel suggests a propensity to develop particular diseases including Type II diabetes and melanoma. This series runs $179 if purchased separately, but might be had for less through a discounted package rate. A genetics ancestry evaluation lists for $249.

Within two days, after some controversy and a receipt of a letter from the FDA Office of In Vitro Diagnostic Device Evaluation and Safety addressed to James Plante, Founder and CEO of Pathway (dated May 10), Walgreens nixed the plan. Now, Congress wants to know more about direct-to-consumer personal genomics testing. On May 19, the House Committee on Energy and Commerce sent letters to Plante and the CEOs of two major competitors – Navigenics and 23andMe. House Committee Chairman Henry Waxman and colleagues have some questions about how samples are processed and the accuracy of the results:

“The Committee is requesting information from the companies on several aspects of the tests:  How the companies analyze test results to determine consumers’ risk for any conditions, diseases, drug responses, and adverse reactions; the ability of the companies’ genetic testing products to accurately identify any genetic risks; and the companies’ policies for the collection, storage, and processing of individual genetic samples collected from consumers.

The Federal Trade Commission has cautioned consumers about genetic testing kits since 2006.  Still, personal genomics tests are readily through available on-line sales. You can get the 23andMe “DNA Test for Health and Ancestry Information” from the manufacturer or at Amazon.com for $499. Navigenics takes a distinct approach by marketing its genetic tests strictly as a laboratory service for medical practitioners and so, thus far, avoids some rules regarding in vitro diagnostic tools.

New York State, my home, is one region where Walgreens wouldn’t have sold the kits in stores. That’s because of stricter state laws regarding genetic testing.

Dan Vorhaus, writing for the Genomics Law Blog, provides a considered analysis:

At present, whether a genetic test is subject to FDA regulation largely depends on how it is developed and marketed. The literature, as well as current FDA regulatory policy, divides genetic tests into two primary categories:

(i) in vitro diagnostic test kits (also sometimes referred to as IVD kits or, simply, as genetic test kits), which may be sold by their manufacturers directly to consumers, testing laboratories, clinicians or other approved recipients, depending on the device; and

(ii) laboratory developed tests (or LDTs, also sometimes referred to as “home brew” assays), which are not sold directly to the general public or to physicians; rather, a testing service (as opposed to the actual test itself) is marketed, and samples (e.g., of saliva) are collected and submitted to the laboratory for evaluation.

The FDA regulates IVD kits as medical devices…

Up until now personal genomics testing companies have had few constraints, and little profit. What’s clear from the recent news is that we’ll be hearing more about these kits – their manufacture, distribution, accuracy and interpreting results. And that doctors, for our part, have some serious studying to do. Whether the test results go directly to patients, or not, they’re sure to raise many legitimate questions. We’ll need some solid answers about the testing process in itself, besides meaningful responses about what’s found in our DNA.

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