Category Archives: DNA Tests

The Genetic Medicine Boondoggle

GeneticMedicine4I was beside myself when I read this:

“Over-reliance on genetic-centered approaches in predicting, diagnosing and treating disease will lead to few future scientific breakthroughs, cautioned a researcher who co-authored an article that advocates for a greater emphasis on the body’s metabolites in understanding illnesses.”

I think that’s true.  But you’d never know it to see all the genetic tests (e.g. 23andMe) and media reports on gene-based medicine, rather, “hope” for such medicine.

The quote is from the article: Metabolites’ Role In Understanding Disease Emphasized, ScienceDaily, 3 April 2014

And is based on the study: Systems Genomics Of Metabolic Phenotypes In Wild-type Drosophila Melanogaster, Genetics, March 2014

Lead author, Laura Reed, also said:

“The Human Genome Project has been sold as something that is going to revolutionize medicine — that soon we will get our genomes sequenced, and we will be able to figure out exactly what diseases we are at risk for and, maybe, the best way to treat them,” said Reed. “While it’s true there are important innovations to come from that kind of information, it is much more limited than some may have hoped.”

Lifestyle changes such as eating a healthful diet and not smoking have been found to overcome genetic predispositions.  Reed’s team looked at various diets in fruit flies. Diet had a significant effect on the 187 metabolites they measured.

“One of the important things we found is that the effects of diet are relatively small for gene expression, but much more significant for all the metabolites.”

Metabolites include things like cholesterol and blood glucose, molecules we currently measure to predict disease. Reed said there are many more metabolites we could be studying, e.g. glycine “a metabolite which serves as both an essential amino acid and a neurotransmitter, has previously been shown as a predictor of heart disease and certain cancers.”

When it comes to disease, a more fruitful line of research may be study of metabolites instead of genes, for a mutation in a gene[s] does not guarantee disease (but changes in metabolites may just):

In another aspect of the research, the scientists tracked how the frequency of genes in wild flies changed through time (over multiple generations) in response to diet. Rather than seeing changes in one particular gene or a small group of genes, the researchers saw changes across the entire genome.

We can’t expect to find a gene or just a few genes that explain any phenotype, including disease,” Reed said. Disease is a holistic problem, she said, and it’s unlikely that additional “miracle drugs” await discovery.

It’s going to be a holistic solution,” Reed said.

Reed said she realizes the paper may not be warmly embraced by all her fellow geneticists.

“The overall point of the paper is not a very popular idea,” Reed admitted, “because it basically means things are much more complicated than we want them to be. But, that’s reality.

“This does not mean that we can’t incrementally improve things by understanding the genes that are involved, but, perhaps, a more expedient approach would be analyzing higher level traits, like metabolites, that might summarize what’s occurring in the genome in ways more useful for diagnostic or treatment purposes.”

CampbellWholeDoes this “holistic” point of view remind you of anything? It is the essential message in Campbell’s book, Whole: Rethinking the Science of Nutrition. From the book’s description:

What happens when you eat an apple? The answer is vastly more complex than you imagine.

Every apple contains thousands of antioxidants whose names, beyond a few like vitamin C, are unfamiliar to us, and each of these powerful chemicals has the potential to play an important role in supporting our health. They impact thousands upon thousands of metabolic reactions inside the human body. But calculating the specific influence of each of these chemicals isn’t nearly sufficient to explain the effect of the apple as a whole. Because almost every chemical can affect every other chemical, there is an almost infinite number of possible biological consequences.

And that’s just from an apple.

Nutritional science, long stuck in a reductionist mindset, is at the cusp of a revolution. The traditional “gold standard” of nutrition research has been to study one chemical at a time in an attempt to determine its particular impact on the human body. These sorts of studies are helpful to food companies trying to prove there is a chemical in milk or pre-packaged dinners that is “good” for us, but they provide little insight into the complexity of what actually happens in our bodies or how those chemicals contribute to our health.

Campbell explains his ideas further in his blog post: Making Ourselves Whole.

You can’t take something out of context and try to understand how it operates within a complex system. You have to observe it within its system. It’s difficult, because the thing you are observing will behave in response to the machinations of the system within which it resides.  So what.  That’s the challenge.

There’s an irony here in that you almost have to study in a reductionist way before you can come to appreciate the complexity and interconnectedness of things.

Regarding genetic medicine specifically, Campbell is no fan. He calls it “the ultimate reductionist fantasy.” From his book, “Whole”:

“Genetic medicine is the ultimate reductionist fantasy. It sidesteps the messy big-picture factors that influence health and the development of disease, and focuses on millions and millions of tiny, deterministic elements with no room for fuzziness or randomness. It lets scientists point to a bit of DNA and say, “There, that’s why you got pancreatic cancer!” And despite all the evidence calling in to question a direct link between genes and cancer (and most other chronic diseases), geneticists are now pointing to bits of DNA and asserting, “There, that’s why you’re probably going to get pancreatic cancer within the next forty years.”

The “messy big-picture factors that influence health” include the same “metabolites” that Reed refers to above.

People are taking extreme actions based on the results of genetic tests, e.g prophylactic mastectomies. Is it warranted? Whether it is or not, genetic medicine and it’s outcroppings (tests, drugs, surgeries) are extremely lucrative for the businesses involved.

I really like Campbell’s expansive take on wholism. It invites you to consider how things like climate change and income inequality impact on health and the human condition:

“We must be willing to embrace wholism beyond the realm of nutrition. The body is a complex system. Bodies gathered together in societies are even more complex. And human life, interwoven with all of nature on this planet, is complex beyond our imagining.”

The Risks Of Direct-To-Consumer Gene Tests

23andMe2There’s an opinion piece in the New England Journal of Medicine (NEJM) that discusses these new direct-to-consumer gene tests, of which 23andMe is one:

23andMe and the FDA, NEJM, 13 March 2014

I really agree with this:

“Before genomic tests have been validated, however, genomic information can be misleading — or just plain wrong — and could cause more harm than good in health care settings. In most cases, family history is likely to be at least as informative about an individual’s health risks as SNP-based testing like that used by 23andMe. In this regard, the FDA’s warning letter to 23andMe for its nonvalidated PGS, which resulted in 23andMe’s ceasing to sell its product, is not currently depriving people of useful information; the agency is merely requiring that companies that want to sell their health-related medical devices to the public demonstrate to the FDA that they are safe and effective — in this case, that the tests do what the company claims they do. That is traditional consumer protection and what the public expects from the FDA.

The heart of this debate is not the cost of the sequencing (or SNP testing), but rather whether the information produced can be used in ways that improve our health.”

As I’ve said before, 23andMe was wrong to provide a direct-to-consumer gene test that was not validated. What if it said someone’s risk for breast or colon cancer was 90%?  But, how many people’s genes were (with informed consent) in the database for comparison? Does the risk change if you use a different database? What other factors (race, ethnicity, places lived, smoking, pollution, diet, radiation, other genes, epigenes, etc.) may have been acting together with those genes to precipitate and grow that cancer? What if, after validation, the increased risk was only 15%, but the person already choose to expose themselves to tests involving radiation?  To surgery? Already chose to enlist the help of mental health professionals in dealing with the anguish? Or not? Already took a financial hit in paying for these and other services?

This is not information that is being sold. It isn’t information until it is validated.

DNA Tests Return Varying Results On Disease Risks

Kira Peikoff, 28, had her DNA tested by three direct-to-consumer companies; the results didn’t agree.

Graduate student Kira Peikoff sent her DNA specimen to three laboratories. She received different results:

I Had My DNA Picture Taken, With Varying Results, New York Times, 30 December 2013

“23andMe said my most elevated risks — about double the average — were for psoriasis and rheumatoid arthritis, with my lifetime odds of getting the diseases at 20.2 percent and 8.2 percent. But according to Genetic Testing Laboratories, my lowest risks were for — you guessed it — psoriasis (2 percent) and rheumatoid arthritis (2.6 percent).”

These tests don’t inform with actionable risks.  They don’t take into account lifestyle, environment, or any other variable that affects disease risk. Only genes, and then, only parts of genes. As Peikoff describes, they only examine a few segments of DNA, they don’t analyze your whole genome.

Here’s Dr. Robert Klitzman, a bioethicist and professor of clinical psychiatry at Columbia.

“Imagine if you took a book and you only looked at the first letter of every other page, … You’re missing 99.9 percent of the letters that make the genome. The information is going to be limited.”

Also, labs look at different DNA segments, compare those segments to different databases, and interpret them differently … even when they’re investigating a risk for the same disease.

If these companies return inaccurate risks, it can lead to harm. In…

Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls, Cancer Epidemiology, Biomarkers and Prevention

… Shields used the case of PCB exposure as an example of how to relate population data with individual risk, cancer risk in this case. He said that misinterpretations…

“… can lead to false conclusions about what caused a cancer in a specific patient, undue anxiety about future cancer risk, inappropriate cancer screening, and attendant increased morbidity due to increased uses of the medical system and complication rates from medical procedures. The communication of research findings by scientists must be presented with caution, resisting the temptation to extrapolate, inappropriately, research data to the general population.”

These tests are not standardized, they’re not validated, and they’re not actionable.  The FDA sent a warning letter to one of the companies, 23andMe, telling them to stop marketing the test for health-related conditions until they provide evidence of the test’s validity.

I don’t know how these tests are being sold as providing accurate and useful health information.  Maybe they aren’t.  Maybe they are just an expensive party game.  Dr. Caplan, director of medical ethics at New York University said:

The tests “may be interesting as a kind of entertainment, but do not take them seriously yet in driving your health care or your lifestyle. … He added: “If you want to spend money wisely to protect your health and you have a few hundred dollars, buy a scale, stand on it, and act accordingly.”

23andMe Stops Selling Health Reports Based On Gene Test

This is what you now see when you visit 23andMe’s site:


23andMe sells (rather, used to sell until the FDA told them to stop) a $99 test kit that tells you your risk for over a hundred diseases by having you mail back your saliva and comparing its DNA with other people’s DNA.

The test was never validated for that use, so the FDA, after years of working with 23andMe, told them they “must immediately discontinue marketing the PGS [personal genome service] until such time as it receives FDA marketing authorization.”

I have read comments from people defending 23andMe, saying the test is valid, implying that the health risks it returns are accurate, generalizable to diverse populations, and actionable. The FDA says otherwise, that the test has not been validated (“we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses”.)

Is 23andMe selling an insufficiently tested, unvalidated product to an unsuspecting public? Yes, they are. Or, they were.

A medical device should be sufficiently validated for its use in assessing risk before it is used as justification for any additional test, any surgery or other intervention, any further expense – to prevent doing more harm1 than good. Health risks associated with a DNA analysis should be communicated by a team of healthcare professionals.

Speaking of harm … See that “I Understand” button at the bottom of their splash screen? Is that here to protect the consumer?

________1 Why 23andMe Has The FDA Worried: It Wrongly Told Me I Might Die Young