Slobodan Cekic writes in response to How Much Data is a Human Genome:

Now, please do take a look at your fingertips. You ll see the fine lines of your fingerprint pattern. It is unique, and can be used to identify a human; so fine and even much finer structures are defined in your organism.
Now, how high would be only 3D positional information content needed to describe a human?

You would need to position single cells, define the inner structure of particular cell types, describe the form of single nerve cells (dendrites)…etc

Now how many cells are there in the human organism?

Without any calculation, we can see the information quantity to describe a human in uncounted Terabytes. Human chromosomes contain , as calculated here, 740 MB.

So, why for the God’s sake do we believe that the whole of our hereditary information resides in the genes?

740MB is the size of a reference human haploid nucleotide base string, not the data necessary to describe a mature human.

We believe that most of our hereditary information resides in genes because it does. However, a genome, as you say, cannot possibly fully describe a mature human. A genome is more like a brief mathematical equation used to produce beautifully complex fractal design when fed with ambient noise and interpreted as colors and coordinates on a screen.

Arguably, as other commentators have noted, this isn’t enough to describe a genome. Cytosine can be methylated —like a fifth base. Sometimes, a sequencing machine is unable to assert a base, and an extra bit would necessary to report these “no calls.”

But in reality, humans don’t have a “reference genome.” Almost every cell has its own pair of genomes, and these tend to diverge as they accumulate mutations and errors. To be pedantic, to record your Real and Complete Human Genome, one would have to sequence every strand of DNA in your body instantaneously.

Yet, these trillions of strings of millions of bases can be understood as that 740MB reference human genome like a field full of flowers can be understood as a photo of daisy.

With the “all-natural new-age herbal remedy” niche has already well-commercialized, what territory shall the ambitious huckster stake? Fortunately, the brash misapplication of science spews an unending stream of hopefully salable magic.

Now, two new online dating services promise to find your “scientific match” by testing your DNA.

[note: manually enter links; I will not promote dubious sites with html links which are rewarded by search engines and referral traffic]

The least dishonest (and most expensive) is Scientific Match [scientificmatch.com]. For a mere $1,995.95 and cells scraped out of your cheek, you too can be “physically chemically” matched to your magic sweetheart… that is, if you’re not a felon. Scientific Match is quite adamant about this in their terms and conditions. By comparison, a 23andMe genomic test is $1000, a test which is by all indications is a vastly more comprehensive and scientifically-reputable test. (Scientific Match does not explicitly state for which genes they test and how they interpret results.)

So what exactly does Scientific Match test? From http://www.scientificmatch.com/html/about_physical_chemistry_defined.php :

Physical chemistry is based on the immune system. When we analyze your DNA, we look exclusively at your immune system genes. So, quite literally, when we say that two people have “chemistry”, we’re saying that their immune system genes are perfectly matched with each other.

By perfectly matched, we mean different. After we analyze your DNA, we match you with other people who have different immune system genes from yourself.

So, encouraged by one weak study about girls smelling sweaty tshirts, they test a few random genes associated with the major histocompatibility complex, match people different test results, and then throw all that crap out and match people willing to pay $2000 for a dating service “based on science.”

Just to be clear, we don’t know of any scientific evidence suggesting that our technology will predict who you’ll fall in love with or even be emotionally attracted to. But the experts clearly see incredible potential in the power of chemical attraction.

…

As long as you’re matched with the right person, and you’ve got chemistry, then it doesn’t matter if it’s via your sense of smell or some (possibly other) chemical sensing system. The fact is, chemistry–and its effects–is real. The specific communication process, though, has yet to be definitively proven

Oh right! Just redefine “chemistry” to mean “anything” and “then it doesn’t matter!” Yet, what has been proven is that if you’re willing to spend $2000 on a dating service, you’re probably willing (and desperate enough) to believe that it works. Therefore, it probably will.

The Scientific Match’s competitor is the shabbier and cheaper Gene Partner [genepartner.com]. Gene Partner is like Scientific Match except that it costs a mere $200, its website sucks, and it’s “in collaboration” with the “Swiss Institute for Behavioral Genetics”. Hilariously, from the “Swiss Institute’s” website [sibeg.org]:

SIBeG is affiliated to GenePartner GmbH (Switzerland) which reserves the right to patent any profitable findings prior to publication.

Surprisingly, SIBeG has yet to publish any research. Hm…

The science may be bunk, but do these services work? Popular online dating review forums make no mention of these services. My suspicion is that because the expenses of running a website and outsourcing simple genetic tests to labs are negligible, and thanks to the generous media blitz by the gullible prole American media, both sites will continue to scratch out a small profit on the internet until their founders get bored. Thus, gullible singles will continued to be matched with about the same rate of success as sites with comparable service fees and web interfaces for the next ten years or less. Hooray for the miracles of genomic science.

Note: the New York Times also mentions the “sweaty tshirt and dating” study. Ok, I admit, it’s a facinating subject, but sorry, the science doesn’t exist yet.

Did anyone actually read GINA (Genetic Information Nondiscrimination Act) before lauding it for protecting the public or condemning it as over-regulation?

From GINA at The Library of Congress:

Prohibits a group health plan from requesting or requiring an individual or family member of an individual from undergoing a genetic test. Provides that such prohibition does not: (1) limit the authority of a health care professional to request an individual to undergo a genetic test; or (2) preclude a group health plan from obtaining or using the results of a genetic test in making a determination regarding payment. Requires the plan to request only the minimum amount of information necessary to accomplish the intended purpose.

So, according to this:

1. Health plans can require the results of a genetic test to make a decision regarding payment.
2. Assuming having one’s genome available to make medical decisions makes health care more effective and efficient, premiums cannot be adjusted to account for the savings.

Um, isn’t this is the worst for both effective health care and patient fairness? Doesn’t this mean that health plans can simply demand any genetic test when deciding payment (and hold that decision hostage to get that test… and what if a decision is urgent)? Doesn’t this mean that health care will be institutionally less effective because rather than instituting a single, preventive genomic test to be consulted to make better medical decisions for one’s entire life(which GINA makes illegal), instead, patients will only get ad-hoc and myopic genomic tests as demanded by health plans for payment decisions? Won’t this make health care less effective while creating a new market for inefficient, interventionist specialty genomic tests?

So, what happens when a project like the Coriell Personal Medicine Collaborative shows that using genomic personalized health care makes health care better and cheaper?

I’m embarrassed that I relied on the hype surrounding GINA and didn’t read the law to form my own opinions.

Further, if I’m right about this (I want to consult a lawyer),  I’d be deeply embarrassed for the journalists and industry representatives who should have noted this rather than publishing fluffy, feel-good fed PR. Hypothetically. I’m going to get a legal opinion before I start stomping around, naming names, and posting links!

First, thanks for the great comments about my Coriell PMC post yesterday.

“To use the Coriell service you have to actually walk in the door. If you’re not in the neighbourhood then it may be easier and cheaper to use 23andMe.”

Right, but that’s because Coriell have no incentive to rush to seize a market. Coriell could mail their saliva oragene collection kits and probably, eventually will. Remember, Coriell is an international biobank. It’s their business to send and receive biological samples by mail.They don’t because requiring participants to physically visit their office carefully limits the scale of their program. Coriell will probably be forced to send kits by mail to achieve their goal of 100,000 participants.

Further, for the $2500 cost of a Navigenics test, a better, free, declaratively medical test from Coriell is worth the daytrip and flight for the majority of people. The same is true for a $1000 23andMe or deCODEme test. Come on, this isn’t some fire sale at some outlet store in Kansas, this is an expensive medical test.

“Coriell will not give you access to your raw data, only their interpretation of items that they consider ‘medically actionable.’”

So? I don’t get back the raw data of any other medical tests I take. If you just want a SNP sample of your genome because it’s cool, go buy a 23andMe or deCODEme test. That’s like getting an x-ray because you “want to see what your bones look like.” OK, some people may want to do this… and hey, I bought a 23andMe test for this reason… but most people aren’t choosing their x-ray test provider based on whether they get to keep their x-rays.

“The author is naive if he thinks that this initiative is going to wipe out all the for-profit ventures in this arena.”

No, of course DTC genomic companies aren’t going to be immediately wiped out. People will continue to buy DTC genomic tests, and most of the fly-by-night competitors have already been swept away by regulatory scares.

The problem is that DTC genomic companies aren’t profitable. They are investment-funded companies. (deCODE is a public company, but it too has never been profitable and operates by spending investment.) To raise additional capital to continue operation, these companies must convince investors that they will earn a return on their investment. However, given the Coriell PMC, investors must be convinced despite that

• The current market price of a genomic test has dropped from $1000 to $0 for the first 100,000 customers.
• The government has proved that will fund competing efforts to offer the same services and perform the same research. These efforts will use superior, better established institutional resources and have no obligation to return capital.
• (BIGGEST) The existing medical research establishment has proved that it will conduct its own genomic services and research rather than work with venture-funded startups like Navigenics.

Especially for Navigenics, the idea is that these tests will eventually be medical information to be used by doctors and purchased by pharama companies. That is the investment. Unfortunately, the Coriell PMC is a political statement that clearly states: “No, we don’t want or need your company. We will provide these ourselves, we will undermine the market for your genomic data by conducting the same research better than you can, and we’re not going to help you.” This is FAR worse than the former two points because it extends to hypothetical genomic products like sequencing, not just SNP set tests. Otherwise, one could make a credible argument that the Coriell PMC will prime the genomic testing market with government money, and once the project concludes, a company like Navigenics would be ideally suited to serve that market (assuming it was well-enough funded to weather the government-sponsored “free trial.”)

“Actually, GINA says that insurers/employers cannot request or require that you take a genetic test. So discrimination based on *not* having a test is still illegal.”

This merits its own post (coming)…

Josh: I never would have thought that an autoimmune disease could be triggered by a mutation such as this. I suppose many things in biology and medicine are unexpected and don’t work as you would initially expect. Take, for example, the view of how the heart worked before William Harvey published On the Motion of the Heart and Blood in Animals; Galen’s works stated that blood was a nutritive substance that did not flow in a circuit through the body, and that the purpose of the lungs was to cool the blood. Like Harvey’s discovery, I think unexpected causes such as this will be taken much more seriously in the future and lead to a re-writing of text books. It’s unfortunately a common trend for unexpected results or data to be discarded since it doesn’t fit the accepted theory or view.

A security system wired within every cell to detect the presence of rogue viral DNA can sometimes go awry, triggering an autoimmune response to single-stranded bits of the cell’s own DNA, according to a report in the August 22nd issue of the journal Cell, a Cell Press publication. The source of that single-stranded DNA is so-called endogenous retroelements—genetic elements accounting for a substantial portion of the genome that can move to new locations using a “copy and paste” mechanism, according to the researchers.

The new findings help to explain the cause of a rare autoimmune disorder known as Aicardi-Goutieres Syndrome in which infants appear to suffer from an acute viral infection, despite the fact that no virus had ever been found.

“We and others had demonstrated the existence of a DNA detection pathway within cells, but we are still early in our understanding,” said Daniel Stetson of the Howard Hughes Medical Institute and the University of Washington, Seattle. “Our findings offer an important piece of evidence that this pathway is not only very relevant, but it can be the cause of severe autoimmune disease.”

Detection of foreign nucleic acids is an ancient form of host defense, the researchers explained. In vertebrates, nucleic acid detection activates a program of antiviral defense designed to neutralize the spread of infection. This antiviral program is coordinated by type I interferons (IFNs), which direct a multifaceted response to restrict viral replication within infected cells, alert neighboring cells to the presence of infection, and expand white blood cells to provide long-term and specific protection against the virus.

The defense mechanism includes two systems: one consisting of “Toll-like receptors” on specialized, sentinel immune cells that monitor for infection and another that detects viral nucleic acids within the infected cell itself. That internal system includes one arm for detecting RNA and another for detecting DNA.

The biological relevance of those internal DNA sensors remained somewhat mysterious, according to Stetson, because the “nuts and bolts” of the system hadn’t been worked out.

In a screen for proteins relevant to this pathway they call the interferon-stimulatory DNA (ISD) response, the researchers now identify an enzyme known as 3′ repair exonuclease, aka Trex1. In studies of mice, the researchers showed that single-stranded DNA fragments derived from endogenous retroelements accumulate in Trex1-deficient hearts. Those fragments are produced through a process known as reverse transcription in which specialized enzymes copy RNA back into single-stranded DNA. Trex1 usually breaks down reverse-transcribed DNA of those endogenous retroelements, keeping the ISD response in check.

Mutations in the human Trex1 gene were already known to cause Aicardi-Goutieres Syndrome, although the mechanism remained uncertain. The new findings suggest that the syndrome is triggered by an accumulation of reverse-transcribed DNA. “In a sense, it’s an enemy from within,” Stetson said.

A similar mechanism may underlie other immune disorders as well, he added. In fact, other mutations in Trex1 have been linked to an autoimmune disorder called chilblain lupus and are found more frequently in people with systemic lupus erythematosus than in healthy individuals.

The findings also suggest an unanticipated contribution of endogenous retroelements to autoimmunity.

“Just as commensal bacteria outnumber our own cells by four or five orders of magnitude, endogenous retroelements outnumber our genes by at least 100-fold,” the researchers concluded. “Both have the potential to be detected by the immune system and cause autoimmune disease. Therefore, specific mechanisms evolved to prevent this, and Trex1 represents the first example of a mechanism to prevent autoimmunity caused by endogenous retroelements.”

Source: Cell Press

Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity. Daniel B. Stetson, Joan S. Ko, Thierry Heidmann, and Ruslan Medzhitov. Cell. August 22, 2008: 134 (4)

Yesterday, I donated my personal genome at the Coriell Institute for Medical Research to participate in the Coriell Personalized Medicine Collaborative. I also got lost in the Camden ghetto and learned to hate New Jersey. In all, it was a mixed day for magnanimity.

What is the Coriell Personalized Medicine Collaborative? (PMC)

So, what if a government institution, figuring they’ve already spent $3 billion dollars on the Human Genome Project, shrugged, and threw down a few spare million to learn how this information is actually relevant to medicine? What if this study had the institutional support of the medical establishment, the scientific establishment, and American government and thus was unlikely to try something illegal like operate a non-CLIA laboratory or suggest profit-sharing to doctors to sell tests?

And what if it was free?

Thus: the Coriell Personalized Medicine Collaborative.

The Coriell genomic test itself is like direct-to-consumer tests Navigenics, 23andMe, deCODEme… but better. Functionally, the tests use the same technology: Oragene saliva kits, Affymetrix SNP chip machines, and a web portal for reports. Both strive to test for all meaningful genomic variations that aren’t already patented, are identifiable by a single nucleotide change, and don’t risk the crushing liability and ethical problems of reporting untreatable, terminal genetic diseases like Huntington’s. But Coriell’s genomic test so much better because:

• It’s free. Navigenics costs $2500 plus subscription, 23andMe and deCODEme both cost $1000.
  So: More people can and will participate and benefit. I believe Coriell has already recruited more participants than all other direct-to-consumer competitors combined.
  So: The resulting medical research will be better because the sample size is bigger.
• It’s newer, so it includes more, newer, better reviewed research.
  So: Test results will be qualitatively and quantitatively better.
• It’s medical information and is presented as such.
  So: Medical and pharmagenomic tests like “Warfarin metabolism” can be offered. (Useful if you ever need to take blood-thinning drugs.)
  So: Doctors can apply test results to practice better medicine. (How can a doctor credibly use “explicitly non-medical” information in medicine? Even if non-medical test results were available, the doctor would be obligated to repeat the test.)
• It’s offered by a well-established medical research institution. (founded: 1953)
  So: Institutional support and funding exists.
  So: The Coriell institution can be trusted to last… unlike unprofitable, venture-funded companies less than ten years old.
  So: All people, including patients, doctors, and scientists will be more willing to invest time and money in the program.
  So: The medical establishment will be more comfortable applying the test results in medical practice.
  So: The scientific establishment will be more comfortable trusting the medical research produced by the program.
  So: Patients, medicine, and science will better benefit from their test results.

From the Coriell website:

The Coriell Personalized Medicine Collaborative is a pioneering research study that seeks to explore the utility of using genome information in clinical decision-making. The goal is to better understand the impact of genome-informed medicine and to guide its ethical, legal and responsible implementation. This research study is a forward-thinking, collaborative effort involving volunteer study participants, physicians, scientists, ethicists, genetic counselors and information technology experts. The study seeks to enroll 10,000 participants by the end of 2009, with an ultimate goal of 100,000 individuals.

With a budget of “the government,” no accountability to profit, a goal of “research,” scientific and medical institutional support, and the low, low price of free…

…screw it. I was going to say something banally optimistic like “I’m confident Coriell will continue to succeed in their endeavor to integrate genomic science into medicine.” But, really, how can Coriell fail? Not profit? They’re non-profit and funded by the government. Not get enough volunteers for their free, riskless, non-invasive saliva test worth over $2500 in sexiest, newest medical field? The government will pay to hand some nurses orgenes and waivers to distribute at a few hospitals and universities. Not able produce any successful research? Impossible: the successful research will then be “we were unable to produce any successful research.”

Basically, the only way Coriell can screw this up is if they embarrass themselves mishandling samples. This is unlikely considering they operate an international biobank of human cell lines. I met the lab director for the Coriell PMC. Where DTC companies were busted by the government for operating without certification, this guy rattled off CLIA specifications like they were trivial. Considering the hundreds-of-thousands living cell cultures preserved in liquid-nitrogen-cooled vats downstairs, to him, for a few SNP chip machines and some dead somatic cells in spit, they were.

The good news for genomic testing DTC competitors 23andMe, Navigenics, and deCODEme is that they were the trailblazers and that Coriell is following their lead. The bad news is that another word for “trailblazer” is “cannonfodder.” Sure, you might get a statue, but you’re going to be dead. (It’s typically bad for business when an established, well-funded, experienced competitor releases a better version of your product for free.) So what will these statues look like?

• 23andMe: 23andMe is the biggest winner because it has already accomplished everything it was founded to do: launch the biologist wife of a nerdy silicon valley billionaire into high society while ostensibly achieving something important. Technically, deCODEme launched before 23andMe, and technically, a .5MM SNP chip isn’t a genome, but 23andMe, particularly, Anne Wojcicki, will be remembered for being the first to realize the $1000 genome. (If this is confusing, what’s called “philanthropist” is called “web 2.0 startup founder” in Mountain View, CA.)
• deCODEme: deCODE clearly expected to profit from deCODEme eventually, but how does one expect to compete in a market with immortal competitors like Coriell? deCODE will continue to sell its genomic tests, but deCODEme has been notably quiet lately and will likely continue to get quieter… Fortunately, deCODE didn’t invest much into deCODEme since they already have a lab and websites are comparably cheap.
• Navigenics: To Navigenics, the “serious medical brand” of DTC genomics, Coriell’s PMC isn’t so much “bad news” as it is a big “F-You” shouted self-consciously at effigy of Craig Venture in a Navigenics t-shirt.  It wasn’t enough to demolish Navigenics’ business model; Coriell had to completely discredit any hope of Navigenics ever being considered as a credible medical tool by any medical establishment. Fortunately, “Navigenics does not provide medical advice, diagnosis or treatment,” so that’s not a problem for Navigenics… right?

While I know that Coriell will be successful, the degree of that success is uncertain. Coriell is a non-profit science company trying to reach the mass public, so its greatest weakness will be marketing. For example, a Google search reveals 471 hits for “Coriell Personalized Medicine Collaborative” versus 365,000 for 23andMe.

Coriell will also need some help with their web software portal. (for example: coriell.org is temporarily offline). But as a smart 15 year old can run a basic web server, Silicon Valley has already built several good genomic web UIs for “inspiration” (hint: Print Screen + View Page Source + Django | Ruby on Rails == ++Inspiration), this is an feasibly addressable issue.

So what does the Coriell PMC mean for the future of genomic medicine?

First, the market for expensive SNP chip tests for unpatented mutations is dead. Genomic testing companies will still exist, but they’ll be more like products offered by commodity medical test providers than sexy consumer brands. I must repeat: any customer of DTC genomic testing can get a better test for free from Coriell. There is no reason for anyone to ever again buy any DTC genomic test other than to conspicuously spend money (up to 100,000 participants, but that is enough to kill today’s $1000 SNP test market.)

A market for expensive patented genomic tests like BRCA will continue to exist because it’s illegal for organizations like Coriell to provide them for free (even though they could easily do so). However, the good news for consumers is that these patents will become increasingly unenforceable as full-genome sequencing replaces SNP chip technology. At first, testing companies will refuse to provide official interpretations of legally conflicted results, leaving them as “exercises for the reader.” But as patents are public and “trade secret” medical science is quackery, eventually, BRCA-type patents will seem ridiculous and fade away. Maybe not in five years, but certainly in a few decades.

Ultimately, if the government is willing to pay to bring SNP chip genome testing to the masses, then it will be willing to pay to bring genome sequencing testing to the masses when it’s cheap enough. It will be. Eventually, a genome sequence will be performed with as much institutional banality as childhood vaccines. Your genome will go into some medical record where it will be used to aid every medical decision. This will normal and unnoticed except the occasional slow news day when MSN Health reports some prole alarmist dreck like “Is Your Genome Really Private?” or “Top Ten Mutations That Affect Your Health.”

Every variable: cost, medical application, availability, liability, institutional capacity… inexorably points to this the “genome banality scenario” except one: some pseudo-religious aversion to sharing one’s genome. However, the pressures to solve mounting health care costs, provide better care, and to avoid liability will be too great. GINA may protect Americans from discrimination based on what one’s genome says, but it does NOT protect discrimination based on not having a one’s genome on record.

EDIT: GINA statement may wrong, I’m looking into this..

Josh: We must remember that not all inherited diseases are genetic in origin. Not only does the “genetic code”, the sequence of A, G, C, and T, matter but so do other modifications to that code. Examples are DNA methylation and histone modification.

A new study in the September issue of the Journal of Lipid Research suggests an unusual form of inheritance may have a role in the rising rate of diabetes, especially in children and young adults, in the United States.

DNA is the primary mechanism of inheritance; kids get half their genes from mom and half from dad. However, scientists are just starting to understand additional kinds of inheritance like metabolic programming, which occurs when an insult during a critical period of development, either in the womb or soon after birth, triggers permanent changes in metabolism.

In this study, the researchers looked at the effects of a diet high in saturated fat on mice and their offspring. As expected, they found that a high-fat diet induced type 2 diabetes in the adult mice and that this effect was reversed by stopping the diet.

However, if female mice continued a high-fat diet during pregnancy and/or suckling, their offspring also had a greater frequency of diabetes development, even though the offspring were given a moderate-fat diet. These mice were then mated with healthy mice, and the next generation offspring (grandchildren of the original high-fat fed generation) could develop diabetes as well.

In effect, exposing a fetal mouse to high levels of saturated fats can cause it and its offspring to acquire diabetes, even if the mouse goes off the high-fat diet and its young are never directly exposed.

The study used mice so it’s not time to warn women to eat differently during pregnancy and breastfeeding but earlier research has shown that this kind of inheritance is at work in humans. For example, there is an increased risk of hypertension and cardiovascular disease in children born of malnourished mothers.

Source: American Society for Biochemistry and Molecular Biology

“Effects of High Fat Diet Exposure During Fetal Life on Type 2 Diabetes Development in the Progeny”. Donatella Gniuli, Alessandra Calcagno, Maria Emiliana Caristo, Alessandra Mancuso, Veronica Macchi, Geltrude Mingrone, and Roberto Vettor. Journal of Lipid Research, Vol. 49, 1936-1945, September 2008