Another Steven (this time its Pinker) Comments on Genomics!

No I don't spell my name with a ph, but that is just one of a few differences I have with Dr. Stephen Pinker(Erratum, turns out he spells it with a V, just like me. My Mistake) , one of the PGP 10. His article that I read on Saturday online is now being read by millions in print.

Steven and I both are participating in Genomic Research. I haven't told many people, but I am a participant in the Coriell Personalized Medicine Collaborative. So I read his article with curiosity. Not only because he is a developmental psychologist, but also because he (like me) thinks that most behavior is inherited.

So I wondered how his response to having his Exome released would further "shape him".....and thus when my results come in how will they "shape me".

"All this sets the stage for what we can expect from personal genomics. Our genes are a big part of what we are. But even knowing the totality of genetic predictors, there will be many things about ourselves that no genome scan — and for that matter, no demographic checklist — will ever reveal. With these bookends in mind, I rolled up my sleeve, drooled into a couple of vials and awaited the results of three analyses of my DNA."

He preceded these comments by stating in essence that Genes aren't everything, but they are a whole lot....

Then he explains the probabilistic view...

"Only a portion of my exome has been sequenced by the P.G.P. so far, none of it terribly interesting. But I did face a decision that will confront every genome consumer. Most genes linked to disease nudge the odds of developing the illness up or down a bit, and when the odds are increased, there is a recommended course of action, like more frequent testing or a preventive drug or a lifestyle change. But a few genes are perfect storms of bad news: high odds of developing a horrible condition that you can do nothing about."

I imagine mine will hopefully be the same. I have family history of BRCA mutation but that won't be seen on my CPMC scan......

But then he reveals the name of a company which makes me a little suspect of those ties...

Counsyl.....a company to perform universal carrier screening.......interesting.....of 100 conditions!!!

What are they? From the site......

Counsyl has developed the Universal Carrier Screen: a simple, non-invasive, saliva-based test for more than 100 serious genetic diseases. The screen will soon be offered through our website and at some of the most prestigious medical centers in the country.

So I have to say.....can you imagine the issues with counseling 100 conditions? (more on this tomorrow)

And why does Pinker mention this? He understands carrier screening as he was screened for Ashkenazi Jewish Diseases which now approximately targets 16 diseases in some screens and 11 in others. But 100 diseases?????? The real question is now that we have PGD for alot of conditions.....what is the can of worms opened up.

As for me, I am a little suspect of the fact that he promotes this DTC carrier screening company in this article......It makes my promo meter go up. Now, listen, I understand that people promo things. But you should quantify it and let people know your association with it. In this article he neither says that he is or isn't affiliated with them.....I sure would like to know. He mentions 23andMe at least 4 times, yet Navigenics or DeCode are not mentioned at all....and what about DNADynasty? Hardly fair representation.....I wonder why?????

Even with this, he is certainly right about one thing

Assessing risks from genomic data is not like using a pregnancy-test kit with its bright blue line. It’s more like writing a term paper on a topic with a huge and chaotic research literature. You are whipsawed by contradictory studies with different sample sizes, ages, sexes, ethnicities, selection criteria and levels of statistical significance.

And then he says one thing that has me thinking.

The psychologists Lars Penke, Jaap Denissen and Geoffrey Miller argue that personality differences arise from this process of balancing selection. Selfish people prosper in a world of nice guys, until they become so common that they start to swindle one another, whereupon nice guys who cooperate get the upper hand, until there are enough of them for the swindlers to exploit, and so on. The same balancing act can favor rebels in a world of conformists and vice-versa, or doves in a world of hawks.

The Sherpa Says: This has me thinking whether the genomics world is full of nice guys.....or swindlers......I think it is full of the latter......Which means, it is now time for the nice guys to get together and win!

Ouch!! CNV with lackluster results....

All it takes is 2 seconds to step on some of my readership's toes and I feel it. Yesterday I posted on a 5% error rate for Whole Genome sequencing, I argued that even at 30x coverage it would not be ready for clinical diagnosis. I had CEOs of sequencing companies emailing me and VPs calling me. I even had pound for pound one of the best bloggers in the space say he was embarrassed for me.....Ouch!

Why do I get pushback from people, when all I am doing is throwing some cold water on the party???

Get ready, because I am about to throw some more.....Remember yesterday when I said SNPs were one of 7 or 8 factors that will differentiate each of us??? Well, CNVs are another of those 7 or 8, 2 more include histone modification and methylation, telomerase activity and size would be another factor, the rest I am saving for my own....for now. I first heard about CNV is 2006 when Mike Murray at Harvard keyed me into these guys, since then I have been following the literature and hoping we could get some results....well, we have but......

Here's the cold water, CNVs are not everything either, despite what some very learned people say.....just like genetic and genomic testing is only PART of the armamentarium for a personalized medicine specialist, CNVs are only part of the story.

True, we may find some very high Odds Ratios and some very specific diagnostics in the CNV space.....unfortunately, the American Journal of Human Genetics lays an egg with a chinese study of osteoporosis CNVs that lead to an Odds Ratio of 1.7 for osteoporotic hip fracture. I was hoping some of these CNV stories would be much more exciting than SNPs....My guess is that alot of the SNPs that we found previously with GWAS may actually just be markers for CNVs....and if that is the case, can we expect that much more from CNV than SNP?

I know some who would say yes, and I look forward to their comments. I think we may see this as the key in some areas, where amount of transcript plays a huge role, like metabolism of compounds or perhaps in cell signalling and migration events, but what about diseases that don't need that so much, structural protein diseases, ciliopathies, etc......

Most importantly, what about the diseases that sneak up on us over time like diabetes or atherosclerosis? I don't think that these will be the answer here. I have a very strong feeling that my equation Genome + Environment = Phenome + Metabolome will still hold true....

The one thing I am certain of is how to make things clinically applicable and right now, CNVs, SNPs, or Whole Genome Scans....there are only a very few limited cases where we can use this stuff......Until the sequencing companies are willing to take the liability for how their product are used, there are going to be problems trying to sell it as medicine without medical professionals......

So sorry to GC, PM, CV, JR, DM and who ever else decided to email me or call me expressing their problems with my cold shower: shake it off, look for solutions and get back to climbing the mountain.

The Sherpa Says: I just want to keep the marketers from overhyping.....Because if we don't, they will "create" our science.....Through slick words and number play published in the New York Times or Wall Street Journal.

Of Slelling and Men

Way back in 2004 I was bouncing off the ideas of Helix Health of Connecticut. My ex-partner and I even spoke of how great it would be to have datasets with genomes, biomarkers, physical exam and medical history data. We posited how great it would be to sell these datasets to pharma.....We even thought about creating a CRO to carry out the genetic integration of pharma testing creating PGx specialized research.

I only mention this because I got a little blasted for tying 23andME with Tuskegee. Well, not really blasting, just a blog post from a really great new blog called Genetic Future.

First, we said "Is this a viable business model?" The answer, a resounding yes
Second we said "Will patients be ok with us giving their data to Pharma companies?" The answer, maybe...but only if they received something back.
Thirdly we said "Is it ethical to sell your patients' data?" We had seen it done. So we went to some notable ethicists....

What occurred during that time? CRO scandals, researcher kickbacks, fradulent studies, all things poised to make physicians look less than hippocratic.

That's when we abandoned the idea of physicians selling this data without EXPLICIT permission of patients. We did not want to revolutionize medicine AND look like profiteers. If we were not to tell our patients EXPLICITLY, we would just be pulling a scam. I couldn't exactly find the words but then...

The term Slel then came across my radar. It was brought up again by Jason Bobe

Slel: To take DNA from someone against his will, to create avatars of him, or perhaps children.

Well Avatars may not being created and it may not be unwillingly, but a profit could be made. I say could, only because it is not being made yet. Data acquisition is going to be required first.

Why do I react so vehemently against this? Because I sit on the Yale New Haven Health/Greenwich Hospital IRB. The US is a little different than those boys across the pond!

What do ethicists feel? Here is a great take.

7 requirements that systematically elucidate a coherent framework for evaluating the ethics of clinical research studies:

(1) value—enhancements of health or knowledge must be derived from the research;
(2) scientific validity—the research must be methodologically rigorous;
(3) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects;
(4) favorable risk-benefit ratio—within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks;
(5) independent review—unaffiliated individuals must review the research and approve, amend, or terminate it;
(6) informed consent—individuals should be informed about the research and provide their voluntary consent;
(7) respect for enrolled subjects—subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored.

So I ask 23andME, deCODE, Knome...Who OWNS the saliva and DNA contained therein?

Getting the Band Back Together...

The Sherpa is back....and with a vengeance. First, thank you to all who wished myself and my family well. We are doing fine. The family had a member get struck with cancer. It never ceases to amaze me how this horrible disease can bring families to their knees. I look forward to the day which we can detect these malignancies prior to their metastases. Even better, before they ever start.

I just spent the afternoon with Genome-Boy Misha Angrist. With Bertalan Mesko coming on Monday I feel like the Blues Brothers. Misha and I had a fun filled lunch and interview. I can't be sure who was interviewing whom, but I am certain both of us walked away more informed. I honestly admire those 10 PGP'ers. Imagine not knowing that these corporate genomics companies would be making such a huge imprint on the face and change the genomic debate. Their decisions to enlist took true courage. That being said, I loved it when I heard Misha say, just because we can sequence doesn't me we should......or shouldn't do it. He said "We just need to lower our expectations of what 600k or a million SNPs can tell us."

I agree. Which brings me to my next point. For those who read the Nature Genetics Editorial entitled positively disruptive...let me issue a huge wake up call. I am currently drafting a submission outlining the huge leaps of faith this article takes. Before I leak that info, I just want to say how can we expect physicians who went to high school before the central dogma to apply genomics? Even worse, how can we blame them for being so dismissive, when they don't appreciate what personal genomics may SOMEDAY bring?

How can we blame physicians when they don't even speak the language of genomics. I don't think I need to get into how few physicians ever received any training by a geneticist. They can learn, for sure. But it will take them about 1-2 years of consistent study. Somehow I doubt they will shut their practice doors to go back to school. Here's what gets me about this editorial...


It is not beyond most physicians' skills to explain the quantitative risks conferred by— and the research underlying—the health predictors they currently use: BMI, cholesterol, blood pressure, age and sex.


Malarky- It has been well studied that most physicians cannot even explain terms such as number needed to treat. Their innumeracy has been demonstrated time and time again in the literature. Their study is ongoing and the answer is, quantitative risk is extremely difficult to explain. This assumes that most patients are prepared and health literate.....WAKE UP PEOPLE!!! How will an internet based report ever size up whether the patient is health literate? There exists such tools, but their administration requires face to face care. But even then this type of evaluation is difficult.

Over 40% of adults in the US are either barely health literate or are frankly health illiterate. So how can we expect them to understand genomic data even written in the 6th grade level?


The individual gains a personal stake in the ongoing research effort and a huge incentive to find out more. A personal stake in finding out something that was not previously known is the key to getting students into research and may well be a powerful tool to educate and interest members of the public in the details of their own health and functioning.

Really? I just saw 13 diabetics yesterday. Not a single one feels that "Personal Stake" and they are afflicted with disease. What will make genomic information in an asymptomatic patient so special? I would love to see some STRONG data on this one. Remember, patients have to be health literate to understand the implications of their disease or pre-disease.

The pressure of information also creates a need for genetic counselors, but if uptake and use of individual genomics spreads as fast or widely as it seems likely to do, the counseling curriculum will undergo a rapid shift of emphasis away from rare mendelian diseases to both rare and common genetic determinants of common diseases and will acquire a new set of courses to deal with evaluating environmental risks.


Hmm <3000,>300 million US citizens, >120 million who are health illiterate. The majority who went to high school before the 80's or even the 90's When was the last time academia moved at the rate of anything other than Glacial Speed?


In the meantime, individual genomics will have informed thousands participating in one of the most exciting areas of biomedical research, and it may recruit participants in prospective studies that they will have funded partially from their own pockets.

Likely unwittingly.......Hat Tip 23andME

That being said, they are co-investigators, not patients, and the experiment will be conducted on their own terms!

I guess that's why they skipped the Institutional Review Board. Haven't we seen that before?

The Gene Sherpa Says:

Pollyana get a grip, take of the rose colored glasses and smell the thorns. For us to reap the benefits of genomic health, we need public education, physician education. What these corporate genomics companies need is some ethics classes, an IRB review course, and some restraint. I look forward to seeing how Navigenics moves thorugh this maze. I am certain it will be better than giving away free kits to steal your genome. Disruptive technologies require an ability for the public to utilize them rather quickly....I am not certain this is that case. Which brings me back to Genome Boy's point. "Just because we can sequence doesn't me we should......or shouldn't do it. We just need to lower our expectations of what 600k or a million SNPs can tell us."

Interesting Readers

Over the last week I have been working on a little personal genome search project. I was contacted by one of my readers to help her find someone to "donate" her genome to. Initially I was surprised to receive such a request. Especially because I have railed against using the genome for a crystal ball.

But she was vehement that she wanted to donate her genome. Now I Have to tell you that I was then convinced of her altruism. She didn't know where to turn so we began with the usual suspects Dr Church, Dr Collins, Dr Rothberg, Hodosh. But when we were turned away a window opened.

I turns out Dr Venter's Institute is looking to turn out 10k genomes in 10 years. The perfect project.....provided these subjects have appropriate care providers to help out......

Since Helix Health of Connecticut is taking patients now, it seems only natural that we take her on as a patient.

I wouldn't have it any other way.

On another interesting note Dr Robison at OmicsOmics posts on yet another whole genome player who is entering the Archon X Prize.

Base4 (Real Cute) Innovations is pretty young and Keith covers it nicely.

Formed in 2007 with support from the University of Warwick and Warwick Ventures, base4 innovation is a group of highly talented and innovative biologists and physicists from the University of Warwick and Oxford and Cambridge Universities specialising in molecular biology, single photon detection, and nanotechnology.We are developing a new high-speed, low-cost method of DNA sequencing which combines well-known techniques such as photon detection and fluorescent labelling with nanostructures and cutting-edge methods of nanofabrication.

X Prize team leader and base4innovation founder Cameron Alexander Frayling is a researcher at the University of Warwick and the inventor of the innovative method behind this sequencing technology.

The Sherpa Says: This wonderful woman wanted to donate her genome and was turned away. I wonder who would have bit if she was willing to pay. What a shame!

An Attorney General, A Genetic Counselor and Gap Phase

Today my phone blew up. I had five different Venture Capital firms call me to pick my brain about "The New deal with Illumina" as well as "Viability of Microarrays in Pharmaceuticals"

I must say thank you to those who called. I look forward to speaking with each of your esteemed groups.

That being said......I must say that there is a general consensus of the physician side that the time for whole genome analysis for your health is not now. I agree. An excellent scientist Dr Bettinger over at the Genetic Genealogist posed a great question.

"What is your opinion on Gap Phase?....."

"that inevitably long period of time between (1) the availability of inexpensive whole-genome sequencing, and (2) the point when the medical field produces enough specialists in genetics to handle the work load."

Well....I don't think that is what gap phase is. Currently there are less than 1300 geneticists for the WHOLE country. In addition. If we expect personalized medicine to affect things like Coumadin, a drug which is dosed by adult doctors primarily, then shouldn't we have some adult geneticists? There are less than 100 of these doctors in the US. LESS THAN 100!!!!!!! Even scarier, there were less physicians sitting for the genetics boards this year than 5 years ago.

I don't think Gap phase has anything to do with these people. I think GAP phase has to do with literature and evidence based medicine. In medicine, doctors try not to do anything without good data that shows long term outcomes. When they veer from this path you get train wrecks like drug eluting stent mishaps and Vioxx!!!! Soon to be Avandia!!

So what do we do with the gap? We mind it!! We don't jump blindly without looking out for the fall that it may cause. Overselling genomics could destroy personalized medicine's promise! I will not let some overzealous "Let's do it because the technology is there, and so cool" people ruin our future. Even for a quick set of chromosomes!

As for trained professional shortage....When we have fighting between lab companies and the people who traditionally order tests, then we have a problem. Which is the case with Myriad.

There is a great NPR spot coming up. A colleague and teacher of mine Ellen Matloff. She will be on there with Attorney General Richard Blumenthal discussing the controversial Myriad advertisement campaign that is now running in CT, MA and NY. You can listen in online Sunday Evenings at 6:00 PM http://www.wnpr.org/

Ellen is the bane of Myriad's existence and because of this the genetic counselor is notably absent from the Myriad commercials.....hmmmmmm

She has started an online petition to start asking state's attorney generals to investigate misrepresentation in genetic testing. My genetic counselor has a wonderful take on this whole thing. BRCA testing is NOT in Gap Phase, unlike whole genome sequencing for healthcare. It has significant amounts of data and studies. It is clinically useful and can be of benefit when used properly. The problem.....The Fox is watching the Hen house. Lab reps are probably not the best people to be teaching physicians about using these tests, trained counselors and Geneticists are.

I am scared for physicians and this should serve as a warning call.

MYRIAD/23andME/Navigenics/futureunnamedbiotech are saying, "if you aren't with us, then you're against us, AND WE WILL REPLACE YOU WITH COMPUTERS!!"

The Sherpa Says: When my phone blew up today, the question was not, how can we invest in a safe product and service that will benefit people's medical care. It was..."How can we make this scalable?"......The answer does not lie in training genetics professionals....that takes at least 9 years after college. The Answer......All roads lead to Google.......Too bad the data is not there and computer guys haven't been burned as bad as those Vioxx doctors......

Gene Genie and George's Blog

First....Gene Genie is up at Cancer Genetics. Thanks to Ramunas who put up an excellent edition!!

Second and even more importantly......My excellent Chief of Genetic Counseling brought George Church's blog to my attention. My gosh....

His evaluation is right on point. His question is a wonderful one...... Great now we have genomes....so what. How do we get to systems biology? Once we have systems biology on point, we will then have truly personalized medicine. We will be able to manipulate the systems....and physicians will become engineers, systems analysts....

So when will we get there? How will we get there? My gut says there are 25 different signalling systems and perhaps four different common pathways....these will corroborate with the 4 humours........ Welcome back Galen and great to see you again Hippocrates.

The Sherpa Says: Stick around for 2010 it's gonna be huge! I am a firm believer in systems biology. I feel that be understanding cellular signalling pathways, we will see the link between previously unrelated disease. For an example if this take a look at this NYT article.

What good is a map?

Imagine being stranded on a raft......An object is floating in the water. You paddle hard to get it. Once you do, you realize its a map. Hooray, you can finally find some land. Or can you?

There are some significant questions to ask yourself prior to having any utility gained from that map.

1. Can you read the map? I used to be in the Navy. We learned how to read nautical maps. But my father, a retired colonel in the Army, would have no clue where to begin. Imagine someone who had no training......


2. Where are you on that map? If you have no orientation, how could you hope to navigate. Where does the sun rise? Simple question. However, when asked almost 15% of Americans do not know the answer.


3. What is on the land you will be paddling to? If you paddle hard to get there only to find out that there are man eating natives, how good was your choice? Did you really want to find that land?

A map of your personal genome is much the same. Jason Bobe over at the Personal Genome comments on some of these topics. Who should be able to read the map? Should everyone have a Tom-Tom or Garmin? Should there be age limits on querying ability. And what if we find out something we didn't want to know? These are serious questions.

The Sherpa Says:

There will soon be a personal genome option. Everyone will be able to have an economically priced copy. We need some guidance on its interpretation. Personally, computers can only do so much. With all apologies to my colleauge Tim Arimond, we cannot program our way out of needing human interpretation. A computer cannot tell when you are scared, confused, upset......yet. I think that personal genome sequencing holds tremendous promise.........But it is only a map.

Why Can't We Be Friends?

A recent study in the New England Journal of medicine implicated a gene called FTO (Fatso) in increased risk of obesity. If you had one copy, then you had a 33% increased risk of being obese. 2 copies? 67% increased risk. On average people with FTO weighed 7 pounds more.

It is true that we know of some increased risk due to genetics. However, a study published this week in the NEJM suggests perhaps your friends may play a larger role than your genes.

In this study, if you listed someone as your friend, and your friend became obese during the time they were studied, then your risk of becoming obese would be 171%. Much greater than the risk of carrying 2 copies of FTO.

What about the 6 degrees of separation effect? Wht if it was a friend of a friend? Well they found that the increased risk was less than that of FTO's effect. However, there still was increased risk.

The Sherpa Says: This study was performed on the famed Framingham Heart Study offspring. They attempted to control environment by evaluating neighbors. It does turn out that there is no relation between neighbors and obesity.....Unless they are friends...This tells us that social networking is an indicator of risk of disease. Intuitively this makes sense. Smokers hang together, as do illicit drug users, and perhaps as this study shows over-eaters. Why can't we be friends? Because you are fat.