Why Watson Didn't Want His ApoE4 Results.

Alzheimer's disease (AD) afflicts about 10% of persons over 65 and almost half of those over 85.

When Jim Watson had his genome sequenced he asked not to have his ApoE4 status revealed. Why??

Dr Watson did not want to know his genotype status because although twin studies suggest that there are several susceptibility genes which, along with the APOE 4 allele, contribute to up to 80% of LOAD (Late Onset Alzheimer's Disease) cases, the story is nowhere near being finished. Not everyone with APOE4 gets Alzheimer's. In fact, the majority do not......

But the picture for those predisposed is getting clearer.

This last week a study was released by the team at TGen (Translational Genomics) in the journal Neuron. According to the study:

"...suggests that the gene - called GAB2 - modifies an individual's risk when associated with other genes, including APOE4. The study results appear in the June 7 issue of the prestigious peer-reviewed journal, Neuron."

"The team screened the DNA from 1,400 individuals who had been clinically assessed with Alzheimer's prior death, and simultaneously examined more than 500,000 SNPs or genetic variations to characterize and confirm additional LOAD susceptibility genes. The search revealed GAB2."

The polymoprhism is known as SNP rs2373115 . It interacts with APO epsilon 4 to prevent neurofibrillary tangles. This protein is over expressed normally in APOE4 afflicted brain cells.

So what does this mean? GAB2 normally acts like your mother. Remember when you made a mess of your room? If you were lucky, your mother cleaned up the mess. You kept making more of a mess and she kept cleaning up. If your mother didn't clean up, then your room was a constant mess. Even worse, you couldn't find anything in your room that you needed. Much like the way an Alzheimers patient can't find their memories.

In the end a Non-cleaning mother and a really messy kid led to a very dirty room. Just like the combination of GAB2's SNP and APOE4 lead to an odds risk of 4.06 a 400% increased risk.

The Sherpa Says: I agree with Jim. ApoE4 testing can often be uninformative with only 25% of those with the gene polymorphisms going on to get Alzheimers. I think family history will have to lead the way. At least until we have a GAB2/ApoE-4/new gene panel that puts together the picture much more clearly.

Not all drugs benefit all man!

While Bertalan Mesko at ScienceRoll is introducing us to the best medicine 2.0 tools, i am reviewing some results from the American Society of Clinical Oncology meeting last week.

In another example of how we need to examine patients pharmacogenomics prior to instituting therapy the SWOG (South Western Oncology Group) in the U.S. releases results of a collaborative effort with two clinical groups in Japan (Japan Multinational Trial Organization).

The researchers were interested in how these different groups metabolized certain chemotherapeutic agents Paclitaxel and Carboplatin. Now what is interesting about this study presented at the ASCO conference is the fact that they were able to isolate two gene polymorphisms responsible for these effects.

In patients with certain variations in the CYP3A4 gene, it took 2.75 times longer for their lung cancer to progress than in patients without the variations. A variation in another gene, ERCC2, appeared to interfere with how well patients responded to treatment.

The problems with this type of analysis are threefold.

1. The study was too small a size to not need replication


2. The study did not involve the genome of the tumors (Perhaps the DNA repair mechanisms in the Caucasian tumors were better. This would like to decreased cell death i.e. response to chemo. As with the tumors and ERCC1)


3. The dose of chemo was not controlled (although the lower dose worked better in the Japanese)

The Sherpa Says: In order to make useful sense of Personalized Oncology we must look at genomes of both the cancer and the person. I feel that we are introducing erroneous data to confuse us. I hope The Cancer Genome Atlas will show us some better data!

Part 3 of the Personalized Medicine Revolution

The third post of the conference at Brown will cover a round table. This forum was moderated by Professor Charles Ogletree of Harvard Law School. The following persons were involved in the forum:

• Healthcare Translation – Daniel J. Wattendorf, MD, MAJ, MC, USAF, Keesler Air Force Base
• Ethics – Thomas H. Murray, PhD, President & CEO, The Hastings Center
• Patient Advocacy – Sharon F. Terry, MA, President & CEO, Genetic Alliance
• Privacy – Joy L. Pritts, JD, Research Associate Professor, Health Policy Institute, Georgetown University
• Research – FrancisS. Collins, MD, PhD Director, National Human Genome Research Institute
• Institutional Review Board – P. Pearl O’Rourke, MD, Director, Human Research Affairs, ESCRO Chair, Partners Healthcare; Associate Professor, Harvard Medical School
• Legal – Richard A. Johnson, JD, MS, Senior Partner, Arnold & Porter LLP
• Economics – Edward Abrahams, PhD, Executive Director, Personalized Medicine Coalition
• Media – Jonathan D. Rockoff, Reporter (Washington Bureau), Baltimore Sun
• Insurance – James E.Purcell, JD, President, Blue Cross Blue Shield, RI
• Hospital – Joseph F. Amaral, MD, FACS President and CEO, Rhode Island Hospital
• Pharmaceutical Industry – Patrice M. Milos, PhD, Executive Director, Pfizer
• Politics – Paul T. Kim, AB, MPP, JD, Partner, Foley Haog LLP

Professor Ogletree posed the following situation. "Terry is a 25 year old woman who has just used Google's Health Kit and searched her family's history. She finds 2 maternal aunts with heart attacks in their forties. Who does that matter to?"

First he asked her PMD. "Does this matter?" The PMD representative was a physician from the Air Force. He said-"I don't have any guidelines on second degree relatives. I don't know what to do" Obviously he didn't read Maren Scheuner's articles.

Next Dr. Ogletree asks what other tools might she have used. Dr Collins answers that there is a study going on at Harvard where all employees were encouraged to input and utilize a family history tool. There will be an evaluation of pedigrees and risks.

Dr Ogltree then asks "What are the discrimination risks?" That is when the panel caught fire. Joy Pritts starts by stating that each state have different regulations, and that these regulations are filled with loopholes. She also states that Rhode Island has some of the best protections available. "Don't ever move! Because your protections don't follow you!" "I hope she doesn't work for Wal-Mart she says" Mr Kim then chimes in...."What's in the google box? What are they doing with your data? How protected is it?"

Professor Ogletree then shifts gears "This 25 year old woman receives an email from a Pfizer clinical trial coordinator offering enrollment. Should she join? What about protections?"

It is becoming evident that the existing legislation throws you to the wolves. Patrick Kennedy seated quietly in the crowd can barely contain himself and starts shouting at the crowd. He says HIPAA doesn't protect you. In fact if your provider or company utilizing your data (i.e. for research) goes bankrupt that your data is no longer protected.

Dr Milos of Pfizer then chimes in....."I don't think Pfizer is going bankrupt any time soon. She should enroll." Then Dr Collins quips "Who wants to place bets on that?" The crowd erupts into laughter.

The Sherpa Says: The moral of this roundtable was that there are online companies offering services. Who is to say that they won't go bankrupt and put your info out there. Only medical practices actually have the kind of protections a patient needs. No DTC company can be held liable for "losing/selling" your data, especially if they go bankrupt. In addition we learn that most PMDs are unaware of the significant role family history plays. The take home point is that the medical infrastructure is ill suited for this next transformation in medicine and Google is likely to give you more information about genetics in medicne.

Coumadin and Buccal Swabs!!!

Prior to posting part 3 of the Brown conference I had to put Kimball Genetics on the Radar! The have devised a test to help with the scourge of Adverse Drug Reactions and Coumadin! Coumadin/Warfarin is designed to thin the blood and prevent clots causing stroke and pulmonary embolism. The test detects specific variations in the CYP2C9 and VKORC1 genes, the presence of which result in lower dose requirements for warfarin/coumadin. To help with implementation the nice people at Washington University, St Louis. The interactive website at warfarindosing.org has been developed by Brian F. Gage, MD,MSc, colleagues and is ideal for this purpose.

With every test their is the Good, The Bad, and the Ugly.

• The Bad? Turnaround time is a day. At the American College of Cardiology conference there was a claim of 1 hour turnaround time with an unspecified test!


• The Ugly? Will physicians know to advise patients of the familial implications of these tests? And will the 2 million plus people on coumadin be able to understand the counseling?


• The Good? This test is 99.9% sensitive and accounts for over 35% of coumadin metabolism variation

The Sherpa Says: I have to go tell it on the mountain....but I will be back to go over coumadin metabolism and this test in a finer detail. For now, hold tight and get some help with test interpretation if you plan to use it.

Dr Collins reports from the Front Lines

In the second of my 3 maybe 4 part post I will detail Dr Collins' report from the Front Lines of the Revolution!


First some notable quotes

• "2007 is going to be a landmark year in Genomics and Medicine"


• "We all have ticking timebombs in our genome, you could guess most of them from family history.........But not all of them"


• "We shall have the major genetic risk factors for common diseases in 2-3 years or less"

Without further ado I will break his talk down into sections. Dr Collins', feel free to correct anything in this.

"Notes From the Front Lines"

1. DNA sequencing is undergoing a revolution. I almost felt that he had been reading The Sherpa prior to giving this lecture. I had commented on 454 recently. On powerpoint he showed the technology behind 454 and Illumina. he did not comment on nanopore, but I think that's because it is not ready for prime time. In addition he did not comment on RainDance..............I feel he knows something big is going to happen in sequencing real soon.


2. Common Disease gene discovery is skyrocketing. In this subset Dr Collins draws our attention to several great discoveries. He talked about GWAS (genome wide association studies). He even mentioned the numbers and power required to get a decent study. I am always amazed by how the public and physicians think this type of stuff is easy! He made mention of the macular degeneration studies which implicate 2 gene polymorphisms in over 50% of the disease!!! He spoke about Diabetes, something that he has been studying for 14 years. He did not metion DNADirect and DeCode's TCF7L2 testing via DTC........ I think this is a hot topic. Especially because Sharon Terry was at the conference. A great woman who is now advising DNADirect. She is a patient advocate in the truest sense. Without her GINA would not be around.


3. Diagnostic capability is advancing. In this subgroup Dr Collins mentions Abacvir toxicity and pharmacogenomics testing. He also give us some insight into the pharmacogenomics process and how we can use these tests. By this time my teams' heads are spinning. I am reminded of my prior post. Coumadin was mentioned by Dr Collins too, the 1 hour test was not. Trust me, this flank is moving full speed ahead!


4. ELSI needs to be addressed “Will we increasingly think of ourselves as hapless victims of our genotype?.......Attention to ethical, legal and social issues is more important than ever,” Dr Collins aptly points out the fact that we have some serious loopholes in our legal protection. In addition, we have to think about ALL of the uses and misuses of this information. Later on I'll tell how Representative Kennedy is super focused on this topic.

The Sherpa Says: Ok, this is too much info. Let's digest this and move on later today..... Oh and Francis is the Man!!!

Watson, Francis.....and The SHERPA!!!!!

Remember how I said that June is going to be one heck of a ride? Well, what a way to kick it off. Yesterday I attended the "Personalized Medicine Revolution" at Brown University. My team drove 3 hours from NYC to Rhode Island to attend and trust me....It was worth it. I want to recap in some coherent and readable fashion so I will break it into 3 posts throughout the day.

Post 1 The Welcoming Remarks by Dean of Brown Medical School Eli Adashi and Rep. Patrick Kennedy.

I find it interesting that the introductory remarks are given by an REI specialist. Especially after what was disclosed to me.

"Future Pundit talks about the role of Preimplantation Genetic Diagnosis and its ever expanding uses. The specter of looks and intelligence for PGD rears its ugly head. Do I think this is a slippery slope, you bet. Especially when at the REI conference this April there were comments such as "We are the new geneticists" and "We determine mankind's fate" were heard by my Specialist friend. Yikes here comes Aldous........"

In addition, the lack of REI oversight in this country was addressed by Dr Thomas Murray PhD CEO of the Hastings Center . But I will save that for a later post. Dr Adashi did make a funny though. He showed a slide of Jim Watson receiving a copy of his genome on CD from Jonathan Rothberg. Dr Adashi said "I am happy to say I just received my copy from Netflix!" to the laughter of the crowd. Lastly he closed with a comparison many of us make. "Just like the microbiology revolution...........Genome based medicine is inevitable and It's here today."

Still, the welcome was warm and the stage was set for an exciting day of "Personalized Medicine!"

The next comments came from the sponsor of the conference, US Representative Patrick Kennedy. First I would like to say I have no political attachment to either party so what follows is merely my observations as a citizen of the United States.

At first it was difficult to understand his accent. Second it was tough to listen to his ummmms and uhhhhs. Thirdly he had a tendency to say "you know". But once I got past the "nerves/Billy Madison-isms" what he had to say was pretty amazing. Representative Kennedy is a huge ally in the fight for the right drug, for the right person, at the right dose. He went on to detail how proud of Rhode Island he was, he talked about his mental health initiatives and how personalized medicine will help those with mental illness. Frankly, I was very impressed with what support and knowledge came from his mouth.

Next post............Francis Collins and "Reports from the Front Lines of the Revolution!!!"

The Sherpa Says: Viva La Revolucion!

June comes Crashing In!

I am sorry it has been 2 days since my last post. Things have gotten crazy recently. I started with the launch of my personalized medicine practice. We are busy dotting the i's and crossing the t's. We have a truly "flat" organization and are able to grow at a moment's notice. This is great news for the patients! Several things are happening in this week and I want to share all of them with you.

1. My wife, daughter and myself were involved in a car crash. I want to remind everyone to please wear your seat belts. If you have children please make sure they are in the appropriate car seat for their age. These simple things allowed us to walk away unharmed. Sometimes it is all about the prevention.
   


2. At Brown University there is a conference being held, Frontiers of Medicine. My team from Helix Health of Connecticut will be up there listening to notable speakers, including Dr. Francis Collins. I look forward to him accepting a position on our scientific advisory board.
   


3. Hsien has posted on a subject I feel very passionate about, predictive, preventative medicine. If PTC-124 works out the way everyone feels it will, then we are looking at adjusting environment to avoid disease. I think this is precisely why the co-funding at NHGRI and NIEHS is so important. Because once we find predisposition we need to find out all the environmental effects. Otherwise we just know you are at risk.
   
4. Lastly, the Gene Genie is coming. I would like to thank Hsien for hosting this month's edition and Berci for motivating me to post. Have a look at Eye on DNA!

The Sherpa Says: Buckle up. June is gonna be one heck of a ride!