Massive genetic sharing effort shows power but also shows how little we know

Your genes are not your fate. 

Nonetheless, genes can tell us a lot about our risk for disease, and sometimes they can tell us how to lead healthier lives.

The landscape of the human genome is vast and mostly unexplored. There is far, far more that we don’t know than we do know. This is why it’s so important that as we test people for genetic mutations, we share information as much as possible. Genes have different effects on different people, and a mutation that is harmful in one group might be harmless in another. If we’re ever to fill in all the gaps in our knowledge, we have to pool our resources by sharing data.

This is the goal of ClinGen, a new project described in this week’s New England Journal of Medicine. ClinGen relies on a public database called ClinVar, where researchers, clinical labs, clinicians, and patients can deposit information about genetic variants and their effect on disease. 

What makes this effort so complex is that many disease-causing mutations are quite rare. If two patients share the same disease and the same genetic mutation, and if we’ve never seen that mutation before, can we claim that the mutation cause the disease? Not really: we might have to wait until we’ve seen many more patients before we can have any confidence in the cause-and-effect relationship. This is why sharing data is so important: more data means more power to discriminate between real effects and coincidences.

ClinGen has already shown us that our knowledge has flaws: perhaps 17% of the disease associations that clinicians have reported might be incorrect. More precisely, the NEJM paper reports that out of more than 118,000 mutations that have a clinical affect, almost 13,000 were reported by more than one lab. Of those, 17% were interpreted inconsistently, with some labs calling mutations "pathogenic" while other labs calling them benign.

I disagree with the headline of an AP report headlined “flaws in gene testing,” which reported that 

“The first report from a big public-private project to improve genetic testing reveals it is not as rock solid as many people believe.”

This is a straw man argument: experts in the field don't think genetic testing is “rock solid”, and the 17% rate of disagreement in disease-mutation association is not that surprising. What's more, these conflicts don’t always represent flaws, but rather holes in our knowledge that we just haven’t filled yet. 

Disagreements over the effects of a genetic mutation represent opportunities to clarify and improve our genetic knowledge base. And as the ClinGen authors emphasize, it’s only by sharing our findings that we can discover and correct these flaws. This is why clinicians, scientists, and labs need to adopt a culture of sharing results, as the ClinGen project has emphasized (see their “Wall of Fame” of labs and institutions that have shared data).

All of us have mutations in our DNA; geneticists estimate that each of us carries perhaps 30 new mutations that even our own parents don’t share. The vast majority of these, fortunately, are harmless. Even mutations that do affect our health usually only have a small influence, changing our risk for disease but not actually causing it.

I'd be remiss if I didn't point out that sometimes, your genes are your fate. If you have certain mutations in the CFTR gene, you will have cystic fibrosis, and some mutations in the HTT gene will inevitably cause Huntington’s disease. 

As geneticist Luke Jostins cogently wrote, identical twins usually don’t die from the same thing. So even though genes may influence our fate, we still have control over it. Knowing your genetic risks can be valuable, but we have a lot more to learn about how our genes influence our health.

Can a cosmetic lotion turn back time? Not yet.

A few years ago, L’Oréal introduced two new product lines that used “gene science” to "crack the code" and make your skin young again. The new products were supposed to boost the production of “youth proteins” in your skin, making it look years younger. According to L’Oreal’s ad campaign, the benefits were clinically proven.

Except they weren’t. Last week, the FTC announced that L’Oréal had settled charges that the advertising for these products, Youth Code™ and Lancôme Génifique, was deceptive and misleading.

In a statement, L’Oréal responded that these claims "have not been used for some time now" and "the safety, quality, and effectiveness of the company's products were never in question."

What did L’Oréal claim? Here are some quotes from an ad for Lancôme Génifique:

"At the very origin of your skin's youth: your genes. Genes produce specific proteins. With age, their presence diminishes. Now, boost genes' activity and stimulate the production of youth proteins."

This sounds pretty amazing - and expensive, as much as $132 per bottle for Lancôme Génifique. L’Oréal Youth Code™ makes similar claims: on of its ads asks "Imagine: what if you could grow young?" and then goes on to promise "Even though you can't grow young, we now have the knowledge to help you begin cracking the code to younger acting skin."

The FTC apparently disagrees with L’Oréal's statement that the effectiveness of these cosmetics was not in question. Here is just one claim from a L’Oréal's ad that was highlighted by the FTC:

Génifique Youth Activating Concentrate is clinically proven to produce perfectly luminous skin in 85% of women, astonishingly even skin in 82% of women, and cushiony soft skin in 91% of women, in seven days.

This claim appears in a very scientific-looking bar graph in ad for Lancôme Génifique. It must be science - it's a graph! Alas for L’Oréal, the FTC states that science doesn't support this claims and that it is "false and misleading."

When I asked what studies supported the claim that these products could activate genes, a L’Oréal spokesman pointed me to two published studies, here and here. These are indeed peer-reviewed studies in high-quality journals. However, they don't support the claims made for these skincare products. Instead, they examine which genes are activated when the outer layer of skin is stressed by tape stripping, UV radiation, and washing with detergent. Neither study provides any evidence for a lotion that could activate the same genes, nor do they show that activating those genes could restore skin to its youthful state.

Can skin cream possibly make your skin young again? Well, it's plausible. A baby's skin does behave differently from an adult's skin, and much of that difference may be due to genes being turned on or off. But today, even if we knew the identity of these "youth proteins", we don't have the technology to turn them on.

To their credit, L’Oréal does invest significantly in research, so maybe they will find a youth-restoring cream one day. But not yet.

It's easy to find dramatic claims for products that restore youthful skin. Procter and Gamble's Olay® has many webpages devoted to anti-aging products, and you can be pretty certain that none of them will make you young again either. Like L’Oréal, P&G makes claims about genes:

"That discovery [the human genome] led P&G Beauty Scientists to explore how skin-related genes respond to aging and environmental stress at the molecular level."

As a geneticist myself, I can't help liking the idea that we might somehow convince skin cells to turn on a set of genes to restore their youthful state. Perhaps one of these companies will someday develop a lotion to do this - I hope they will. But they haven't done it yet. So for now, save your money: expensive skin creams are no better than inexpensive ones.

1098 reasons why women are genetically superior to men

Calico cats prefer Mother's Day

Everyone knows that women have two X chromosomes, while men have just one.  Instead of a second X, men have a Y chromosome. The X chromosome is far larger than Y, with 1098 genes  versus just 27 genes that are unique to the Y chromosome.

Well, one might argue, men have all the X chromosome genes too, so what's the advantage to having an extra copy?  It seems that we only need one copy of each of these 1098 X genes.

As it turns out, female mammals (not just humans) have a unique advantage over males: they get to choose, for each copy of those 1098 genes, which ones to use.  And they can pick and choose different ones along the X chromosome, sometimes using the gene (called an allele) from their own mother, other times using the allele from their father.  The other copy is turned off, through a remarkable process called X inactivation.

The female advantage is more than just the choice of which X chromosome to use.  An amazing feature of genetics is that females can use different genes in different cells.  The calico cat shown here is a beautiful illustration of this: early in development, some of the pigment cells in this cat chose the orange fur gene, while other cells chose the black fur gene.  As these cells divided, they created patches of black and orange fur.  As far as anyone can tell, these choices are random, which is why every calico cat has a different pattern of black and orange fur.

It's also why every calico cat is female.

So there you have it: women have over 1000 genes that offer a choice, while men are stuck with a single X chromosome.  Quite an advantage.  (Of course, we men can argue that those 27 Y chromosome genes must be pretty special too.)

Oh, and there's one more advantage women have over men: only women can be moms.  Happy Mother's Day!

Federal judges decide that private companies own your DNA

Many scientists cheered last year when a federal judge ruled that human genes couldn't be patented. The case involved Myriad Genetics, which holds the patent rights on two genes, BRCA1 and BRCA2, that are associated with increased risks for breast and ovarian cancer. Thanks to these patents, you can't look these genes in your own body without paying a fee to Myriad. Sounds ridiculous, right? Well, that was the state of gene patents until last May, when judge Robert Sweet ruled that the Myriad's patents were invalid.

But now the courts have reversed themselves again. In a 105-page decision, two federal judges decided that the whole matter comes down to the meaning of the word "isolated." I kid you not.

Judge Sweet's ruling last year was based on the obvious scientific fact that genes are a product of nature, not an invention, and therefore they could not be patented. Patent lawyers were very upset over Sweet's ruling. Why was this controversial? Well, because the U.S. Patent and Trade Office has been granting gene patents for decades. Basically, once the USPTO decided to allow one gene patent, they never looked back, and they've now given out patents for over 4,000 human genes.

But this past week, an appeals court reversed last year's ruling and said yes, Myriad Genetics does indeed own the rights to the BRCA genes. The decision by Judge Alan Lourie reveals an astounding lack of understanding of DNA, genes, and genomes. I guess I shouldn't be surprised, but I had been hopeful that after the earlier ruling throwing out these patents, science and logic would prevail. I guess I should never underestimate the scientific ignorance of judges, though I should add that one of the three judges voted against his colleagues.

What was their contorted reasoning? They decided that "isolated DNA" is not the same as the natural DNA in your body, and that this distinction allows companies to patent it. (The word "isolated" occurs 219 times in the decision.) The judges wrote:

"According to Myriad, isolated DNA does not exist in nature, and isolated DNAs, unlike native DNAs, can be used as primers and probes for diagnosing cancer."

The mind boggles. Following this nugget, Judges Lourie and Moore give us a little mini-lesson in molecular biology:

"Native DNA exists in the body as one of forty-six large, contiguous DNA molecules…. Isolated DNA, in contrast, is a free-standing portion of a native DNA molecule, frequently a single gene…. Accordingly, BRCA1 and BRCA2 in their isolated state are not the same molecules as DNA as it exists in the body."

This is scientific nonsense, but the court bought it. (Over at TechDirt.com, Mike Masnick made the colorful analogy that this is like "arguing that because a severed finger is not attached to a hand, the finger is not naturally occurring, and, thus, is patentable.") Wrote the judges:

"we conclude that the challenged claims are drawn to patentable subject matter because the claims cover molecules that are markedly different—have a distinctive chemical identity and nature—from molecules that exist in nature."

Among other problems, Judges Lourie and Moore don't understand a basic fact of genetics: that genes are "isolated" by our body's own genetic machinery when they are copied into RNA and then translated into proteins. Or perhaps they do understand, but they don't care because they just want an excuse to keep gene patents around. This is what can happen when lawyers (judges) make scientific decisions: they go on for pages and pages about the semantics of a word ("isolated"), and produce a result that is scientifically meaningless.

Judge Bryson makes much more sense in his dissent, writing:

"the question in this case is whether an individual can obtain patent rights to a human gene. From a common-sense point of view, most observers would answer, `Of course not. Patents are for inventions. A human gene is not an invention.' The essence of Myriad’s argument in this case is to say that it has not patented a human gene, but something quite different—an isolated human gene."

So that's two judges (Sweet and Bryson) against human gene patents, and two in favor. This case isn't over yet; last week's ruling by the 3-judge panel will likely be appealed to the full appeals court next. It's hard to predict what they will say. Meanwhile, Myriad charges $4000 to run tests on BRCA1 and BRCA2, as I wrote last year. This means that if a woman wants to test her own DNA for any mutations in the BRCA genes - including mutations that weren't even known when Myriad got the patent - she must pay Myriad merely to look at her own genes.


I'm not a lawyer, but I already see one way around Myriad's patents in this flawed decision. The judge's (and Myriad's) reliance on "isolated BRCA genes" refers to the process of isolating and copying the genes using a laboratory method called RT-PCR, and then sequencing just the isolated bits. Today, though, we can sequence a person's entire genome, without "isolating" any particular genes, for under $5000, and then we can test for mutations in the BRCA genes without ever "isolating" them. In fact, a colleague and I published a paper just last year describing how to do this, and we released a free software package that allows anyone to test their BRCA genes at home on a desktop computer. Genomics Law Report has a detailed legal analysis of what our software means for the Myriad case.

Scientifically, it shouldn't matter how the judges define "isolated" DNA. And as two federal judges have now ruled, genes are not inventions, full stop. What's more, gene patents slow down science by throwing legal barriers in the path of anyone who wants to work on those genes. Finally, I'm amazed at the hubris of companies like Myriad - or anyone else - who claim they "own" a gene. Let's hope the full appeals court will reverse the tortured reasoning of Judges Lourie and Moore, and get the patent lawyers out of the laboratory.

U.S. comes down against gene patents

In a surprising move, the U.S. Justice Department filed a brief last Friday that declared, for the first time, that the U.S. government does not support the patenting of naturally occurring human genes. This new position is contained in a document filed as part of the ongoing legal challenge to the gene patents on the human breast cancer genes, BRCA1 and BRCA2.

As background: a company called Myriad Genetics has held the patents on these two genes since the late 1990s. They sell diagnostic tests that cost nearly $4,000, and if a woman wants to test her own DNA for any mutations in the BRCA genes, they are required to pay for this very expensive test. The gene patents prevent any competitors from offering the same test without paying Myriad a license fee. Earlier this year, the ACLU challenged these patents in federal court, and the initial court ruling, which came as a surprise to many, invalidated the patents. Myriad appealed, and it seems likely this will end up in the Supreme Court before it is finally settled.

I have a scientific interest in this case, having just published a paper that directly challenges gene patents by providing free software that allows anyone to test their own DNA for mutations in the BRCA genes. Our software requires that you first have your genome sequenced, which (of course) is not feasible for most people today, but which I think will be routine in the not-too-distant future.

It seems absurd that, having your own DNA in hand (on a flash drive, perhaps), you wouldn’t be allowed to check your own genes for mutations without first paying a license fee to a company. Actually, under current law you might have to pay hundreds of license fees, because thousands of human genes have already been patented.

The same government that issued these patents has finally woken up to this absurdity. In their amicus brief, the Justice Department wrote:

“the unique chain of chemical base pairs that induces a human cell to express a BRCA protein is not a ‘human-made invention.’ Nor is the fact that particular natural mutations in that unique chain increase a woman’s chance of contracting breast or ovarian cancer. Indeed, the relationship between a naturally occurring nucleotide sequence and the molecule it expresses in a human cell – that is, the relationship between genotype and phenotype – is simply a law of nature. The chemical structure of native human genes is a product of nature, and it is no less a product of nature when that structure is ‘isolated’ from its natural environment than are cotton fibers that have been separated from cotton seeds.”

Rarely have I seen such sensible scientific reasoning from lawyers, and I must say it is very refreshing. Just in case the text quoted above is isn’t clear enough, the brief goes on to point out that “the patent laws do not, however, embrace the products and processes of nature itself.” The reason for the bit about “isolated” DNA is that Myriad’s patents cover DNA that has been “isolated” from the cell, and the Justice Department wanted to make it clear that this distinction should not somehow make the DNA patentable.

The legal implications of my own challenge to the BRCA gene patents were discussed at length at Genomics Law Report, and by Forbes blogger Robert Langreth. It will be interesting to see how this latest filing by the Justice Department changes the picture. The implications go far beyond the BRCA gene patents: if the initial court ruling and the Justice Department’s position hold up, then virtually all gene patents, on human genes and on many other species’ genes, will become invalid.

It’s about time. New genes have been the basis of many exciting discoveries, but they are not inventions. No one should have exclusive rights to a gene that occurs naturally in a human, another animal, a plant, or any other living species.

Personal genetic testing, available soon at your local pharmacy

This past week, Pathway Genomics and Walgreens announced that they would start selling Pathway’s genetic testing kits at 6000 Walgreens stores. I thought this was good news – I, for one, would like to be able to run my own genetic tests. I’d like to know what risks my genes might carry, particularly if there was something I could do to reduce those risks. But what does Pathway’s test tell you, and is it worth it?

Pathway has been selling its testing kits since September, but selling them at a large chain store like Walgreens would undoubtedly reach many more customers. After their joint press release last Tuesday, though, someone at the FDA noticed, and stepped in to ask a few tough questions. In a letter on May 10 (read it here), the FDA told Pathway that they had to get FDA approval for their diagnostic kits, or else explain why they don’t need it. Pathway claims its kit is exempt from FDA approval, but that might be a tricky argument to prove. After the FDA sent its letter, Walgreens announced that it would hold off for now on selling the kits.

Meanwhile, the real question is, what will Pathway’s test tell you about your genes? Some biomedical scientists are saying that the science of genetic testing is too new to offer directly to consumers. They argue that the results of a genetic test are difficult to interpret, and that patients shouldn’t be given this complex information without expert guidance. Stanford University’s Hank Greely, quoted in the Washington Post, said "Information is powerful, but misunderstood information can be powerfully bad." Are doctors just trying to protect their business, or are they right? I decided to take a look.

Pathway promises to tell you about your risk for up to 70 diseases and conditions, if you pay $399 for the full suite of tests. (That's the price if you order directly from Pathway, which you can do right now. The Walgreens price was supposed to be lower.)

For example, if you are a carrier of the cystic fibrosis gene (which is included in the Pathway test), and if your spouse is also a carrier, then as a couple you have a 25% chance of having a child with cystic fibrosis. The genetics of this disease are well understood, and the test for the mutation should be highly reliable. This seems like a good value to me, and I see no reason why people shouldn’t be allowed to know if they’re a carrier for cystic fibrosis; it may be important to their future plans for having children.

For other diseases, though, the Pathway test provides much more ambiguous information. Let’s look at late-onset Alzheimer’s disease, something that almost everyone worries about as they get older. The Pathway site doesn’t specify which gene they test, but there is no known “Alzheimer’s gene.” Research on Alzheimer’s has demonstrated that some genetic mutations are associated with an increased risk, but the picture is far from clear. For example, mutations in the Apolipoprotein E (APOE) gene on chromosome 19 appear to increase the risk for Alzheimer’s after age 60. According to the National Institute on Aging, the e4 (epsilon-4) variant of this gene:

“occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population. People with AD are more likely to have an APOE e4 allele than people who do not develop AD. However, many people with AD do not have an APOE e4 allele.”

Complicated, no? And this is the clearest association between a genetic mutation and Alzheimer’s — a half-dozen other genes are associated with slightly increased risk, and research is ongoing. So should anyone be allowed to test his/her genome for this mutation?

Yes, emphatically yes!

It’s my genome, and I should be able to look at it if I want to. So what if the information is complex? If someone is curious enough to pay for this test, then when they get their results back, perhaps they’ll be motivated to learn more about genetics so that they can understand their own risk. Giving people information about their own genome seems like a great way to educate the public, and to make people more aware of the power of genetic information. Of course there are risks: charlatans might offer to sell bogus treatments for all kinds of genetic conditions, for example. People might misinterpret the results. But that doesn’t mean we shouldn’t allow people to discover more about themselves.

In a very real way, genetic information is no different from other medical facts. We have easy access to our blood pressure numbers, and no one is suggesting that we shouldn’t, despite the fact that interpretation of blood pressure numbers can be complicated. (For example, should you reduce salt intake, or take statins to lower your blood pressure, or change your lifestyle in other ways?)

I hope the FDA allows Pathway to sell its DNA test at Walgreens. Personally, I think the value of the tests they’re offering today is mostly to satisfy curiosity – we don’t have treatments for most of the genetic diseases they can detect, so there's not much you can do about them. Some of the results will be useful to some people, though, and over time we’ll develop new treatments that will make more genetic tests valuable. Now that Pandora’s box is open, we can’t close it again. And we shouldn’t.