As far as I know, drug in HIV patients are managed based on sequence of HIV drug targets. Can we extend same approach for other diseases

An interesting paper pointing on potential limits of targeted cancer therapy, other than development of resistance, has been published in March 2012 in NEJM: "Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing by" by Gerlinger et al

There is a confusion between personalized medicine and targeted therapy. If a drug works majority in patients but happens not to work in a few patients (usually high toxicity), you tend to genotype/phenotype the patients with drug metabolism and drug transporter genes. With this method you can adjust the dose well and make it work for 100% of patients. Several examples are there in the literature with regard to pharmacogenetics of drug metabolism (white paper or ADME pharmacogenomics published in 2007/2008; in clinical pharmacology journal, I am one of the co-authors representing JNJ along with several other authors from other big pharma companies). CYP2D6, CYP2C9 and CYP23C19 and UGT1A1 and a few other DM enzymes are involved in variabitity due to drug metabolism.

Targeted therapy on the other hand involves understanding the genetic variations on a particular gene responsible for the disease. This is still a naive area although a good number of drugs are already on the market. Example herceptin for Her2 mutation in breast cancer, tamoxifen for estrogen related breast cancers and many others. I can pull out the list.

For many cancers, as pointed earlier - is a complex disease - multiple targets play different roles in different stages of cancers. OMICS technologies including genomics, transcriptomics, proteomics and metabolomics all need to be combined to map the different aberrant pathways that are causing cell proliferation and that knowledge need to be used to appropriately target the specific genes/proteins for effective therapy...

In a nut shell, I feel like the human genome project has just emphasized how important the role of environmental factors are in influencing gene expression, particularly the microbiome which we know so little about.

To understand the role of a gene is one thing but it means little when isolated.

Put another way- we have described a piano, linked certain keys to certain sounds... but we still have no idea how to play music.

Well Juliet, the human genome was definitely a landmark but the major issue is to understand the functions of all genes and more importantly understand the cross-talks between many genes which are under tight feedback control. The amazing network circuits of genome-transcriptome-proteome-metabolome need to be understood in more depth the genotype-phenotype correlations. Today we have more questions than answers. If there are about 25,000 - 30,000 genes why are there more than million proteins. Post-translational events or overlapping genes with multiple protein products also do not explain the 1:40 ratio of genes to proteins. So we have a lot of work cut out for us to understand the systems biology. Focusing on genome alone will not provide the answers we are looking for. Of course, I agree with your anology of piano but it is lot more complicated than that. Just one quick example, although the same 30,000 genes are present in every cell of your body, not all genes are utilized in all organs. The selecting silencing and upregulation of certain genes over other genes is what makes a liver different from brain.......

I agree with Juliet on the role of the environment. I further believe genomics turns treatment on its head. Genomics now makes it clear that a univariate linear approach – one mechanism one disease – accounts for 5-10% of the causes of disease and environment and lifestyle for 90-95%. That explains why “usual medical care” has produced such mediocre results to date. What we now know is that genes are only the predisposition while environment, lifestyle and habits are the triggers that push us over the tipping point. There is no train with all the cars lined up in a neat single file that lead to a caboose containing a “silver bullet.” We are now at a Las Vegas craps table where every throw of the dice changes the odds of the next roll. The implication is should continue chasing single “mechanisms” of disease, or should we instead pursue creating the conditions of the highest level of integrated functioning possible in individual patients (typically return-to-work). We have found that relevant, optimal functioning – since it is clearly incompatible with chronic disease behavior, habits and lifestyle – produced statistically significant decreases in the biomarkers of chronic disease. Here’s the critical experiment: select patients with a representative chronic disease, easiest being early diagnosed DM2 where we often find 1-2 other comorbidities. The Control Group gets usual care (Metformin) but no lifestyle interventions. The Experimental Group gets personalized operant lifestyle modification aimed at restoring RTW. Treatment requires a qualified operant lifestyle modification provider with: (a) formal training in operant conditioning to the doctoral level, (b) at least 5 years clinical experience treating medical disorders, and (c) 3 years clinical experience treating chronic disease. Collect basic biomarkers at baseline and at 90 days: chol, trig, HDL, LDL, HS-CRP, and FG. Stats: nothing fancy, just cross-tabs. Null hypothesis: The Experimental Group will post biomarkers that are statistically significantly improved relative to the the Control Group. The implication is that integrated higher-order behavioral and molecular functioning – which is incompatible with dysfunction of the individual mechanisms of DM2 or their other comorbid chronic diseases – supersedes dysfunction of any one single disease mechanism. Enjoy.

Dr. A-F

Sorry, the Null Hypothesis should read: The Experimental Group will NOT post biomarkers that are statistically significantly improved relative to the the Control Group.

Dr. A-F

Great discussion. Very enjoyable indeed. "What we now know is that genes are only the predisposition while environment, lifestyle and habits are the triggers that push us over the tipping point." Yes, I agree with this statement.

Here are some major issues with genomics. Back in 1980s when I was a biochem PhD student, I was taught one gene-one protein hypothesis. Now it no longer holds true. With human genome sequencing we think there are about 25,000 - 30,000 genes but it appears that we have more than one million proteins (1:40 ratio from gene to protein). This complicates everything. Another complexiy to the dimension, we know there are only 5,000 - 7,000 metabolites (

Thank you Subrahmanyan. You extended the scope of the discussion even further. I’m reminded of the scene in Amadeus when Salieri clumsily tries to keep up with Mozart while he dictates his Requiem Mass to Salieri as he lies dying in his bed. That moment’s glimpse of total genius was breath taking. The scope, depth, speed and unity of Mozart’s view in time and space, contrasted radically with Salieri’s linear, clumsy step-by-step plodding thought process. Medicine’s clumsy paradigm of health and disease we now know is no different than Salieri’s, clumsy, narrow, infantile perspective. The medical paradigm never grasped the breath-taking wonder of the inner universe at work within us and that paradigm now seems no different than Salieri’s linear, clumsy step-by-step plodding process. Astronomy developed the math that gives us a measure of control of the interactions at work in the universe, and physics developed the math of quantum mechanics that replaced Newton’s classical mechanics. The math that can provide a modicum of control of the massive permutations at work in our genetic-behavioral-molecular-lifestyle-disease interactions simply doesn’t exist yet, even though next-generation sequencing gives us some idea of the distance that method will be relative to the current paradigm. That’s why, it appears, when usual care of diabetes with Metformin was compared to lifestyle intervention, Metformin only reduced DM2 biomarkers by 32% and the simplest lifestyle intervention by 58% (New Eng J of Med, Feb 7 2002;346:6:393-403). That’s also why Subrahmanyan is probably right that personal medicine will require “diagnostics [that will] have to be based on a much broader perspective that includes genomics, transcriptomics, proteomics and metabolomics and, of course, clinical symptoms.”

Thanks Henry. Well said. i like your analogies. Simplest preventive mechanism for many disease is a healthy lifestyle and a healthy unpolluted environment surrounding us. Unfortunately, we as humans are looking for that magic pill to cure all our diseases which is a sad state of lifestyle today but definitely helps pharmaceutical industry to keep going...........,

Single word answer "selectivity"

None of us know what the future will hold,thus we would be wise to keep an open mind,to focus very much on competence and fitness to practice,and to develop a strong evidence base, as we travel this important topic of pharmacology in clinical application