Sunday, August 24, 2014


When one comes up on two diametrically opposing views, it turns into a learning experience of how both sides cannot proverbially see the forest of the trees? When one side claims and tugs and pushes its viewpoint to the point of abstraction and the other emulates with equal passion somewhere in that monologue from either side lies the seed for a dialog, a seed, that neither one sees. Don’t you think?

Two households both alike in dignity, are drawn to ancient grudge to bring proof of their supreme excellence. The Epidemiological house derides the Randomized Controlled Trial house as too focused and limited in scope due to its optimized conditions, which does not meet the requirements of the large populations. And that is true to a large extent, even Thomas Bayes, he of the English statistician, philosopher and Presbyterian minister fame would agree that using random samples can only have so much strength and integrity to export validity of a meager sampled experiment to an entire population.

Meanwhile the reductionist household of empiricists are also employing the same war chest. Both sides want to win the argument: Population statistics and results equate at the individual level and small samples of the population equate to the whole population is the new creed of this crude thought. Both sides employing similar tools are being drawn to a similar conclusion: The “missionary” work of the empiricists however would look at it the other way and say, “we, of the reductionist point of view, from deciphering the needs of a few can determine what ails the whole society. Our carefully crafted experiments see the forest as it represents itself !” They however momentarily forget those new saplings and an occasional oak on either side of their 95% curved landscape.

So who is right? Maybe neither!

The Epidemiologists now have a new war chest. The Biggish Data that they are fond of using for proof of their methodology seems to satisfy their needs. They no longer find the need to get their hands dirty. They merely need to ascertain the weight of the compiled digits that someone has keyed into the servers.  Data defines reality for all! Or does it? Is it the data, its selection or its manipulation that defines the concocted reality? One must also remember the Bird Flu A(H1N1) rallied by the World Health Organization as an pandemic in 2009, wasn't! It is a stark reminder of the strong carry-trade of emotional currency, when projections based on math overwhelm logic and reason! Not only was the logic denuded of reliable data but the fear-mongering projections thus mathematically reasoned were accentuated only by the comparisons between the Bird Flu of 2009 to the Influenza of 1918.

From the ePluribus Unum we have arrived at ex multis! John Snow, he of Cholera as a waterborne disease rather than air-borne fame, would be resigned to depression today. After all, epidemiology certainly has a part to play in protecting the population from potential risk, but utilizing the large umbrella of public safety could these experts venture into the habitat of the empiricists without so much as a nod to the causality, except by dint of thought or bias? In other words can the protective umbrella of the epidemiologist wrongfully detract from reality by force-seeking the causality without hurtling through the rigors of the empiricist’s evidence, which are similar in scope and therefore be blinded to project false causality to the whole or a select portion of the citizenry? Ah therein lie the seeds of discord!

Epidemiology studies are a boon for societies as a whole, if they are done correctly to find causal factors of potential vectors of the flame that incite wide-spread epidemics. But using limited data arrived at through statistical torture and casting it as a wide net of causality can prove a detriment to science itself. Today the rigors go so far as to admit and deny the causal factors of an affliction in the same breath. There are a lot of “mays” and “mights” thrown around for full disclosure and future immunity.

The purity of science is in the rigor and not in the shortcuts that one seeks today to publish, gain recognition, make a name for oneself, get a promotion and seek further advancement among one’s peers. That desire of self-aggrandizement, based on the mishmash of the scientific conversations in print seems diametrically at odds with good science. John Iannodis, MD in his article, “Why Most Published Research Findings Are False,” found that more than 50% of the experimental studies were unverifiable! With the 15-minute fame over, the focus of the scientist-statistician moves on towards new mining.

In the world of data-mining from large data-warehouses where any selected digit is a means to an end and reliance upon the statistical methodology so employed a means to a better future, science suffers from such inaccuracies. Both sides are embroiled in the latest rendition of such thought that would compile the argument into a tightly bound Confidence Interval and then determine the 95% probability making all other nuances of differing thoughts, mere distractions.

There is an epidemic of false starts and forced understanding in medical science today. It is time to unwind the clocks and rethink our future otherwise this pleiotropic nature of “one size fits all” will indeed one day end individualism, creativity and innovation. It is time for each side to think its own set of tools and merge the information for a unified theory of existence where real world problems are handled through real world thinking, not some sham-based probabilities!

Monday, August 18, 2014


The crispness of the morning breeze brings with it a shudder to the blanketed-warm skin, its freshness evokes desires and wants for more. Such is with truth, undiluted by the perpetual sea of falsehood, it forces within the mind, a revolution. Away from the interlocking strains of glorified lies, this monastery of reality stands firm against these manipulating truth defying savages.

It is the mark of an educated mind to be able to entertain a thought without accepting it. - Aristotle

The mind, the organ of intuit and reason, the wisp of nothingness that holds within its nebulous architecture, a version of reality, seems oddly the place where reality or for that matter anything should exist. Yet it does and no one has yet been able to decipher, what “mind” is or for that matter where it is?

Is mind a concoction of the human brain, deflecting responsibility of its own action or inaction? Is it the personage of the being? An oddly relevant companion that lurks in the shadows of existence, who no one can see, measure or understand, yet is probed for all things seemingly justified.

The new PET/reporter gene-PET/reporter probes might give this invisible existence, structure one day or may rob us humans of a perfectly legitimate scapegoat for our own misdoings. How then will we ascribe our socially wayward behaviors to the aegis of mind-control? And speaking of mind-control what about the realm of psychic warriors where exactly will their battalion of “seers” end up? If we can see the “mind” in action then the psychic domain becomes a visual for all to see.

This mind probing thing could bring with it an upheaval in human rational thought, couldn’t it? How would one translate, “In my mind there exists…” Yeah, okay, now where would that existence next find habitat?
Conjuring up the next artificial intelligent robot then could we sprinkle a little dust of the “mind” in it so that one day Asimov’s dream would come alive but at what human peril? I shudder to think about the HALs; their next generation! Imagine HAL 10000. “No you may not drink the 16oz big gulp…if you disobey my laser is set on stun.”

Yes but, some might like that idea. Why not empower robots to modify human behavior on the streets, after all those that envision such a life seem to want control and safety against all liberties. It would be well, until the laser is pointed at them.

Indeed life is about to change with 20 petabytes of data emerging every day and being harnessed in “warehouses,” “lakes,” and soon “cities” and “states” appear not too far behind. Analyzing them through the wonders of predictive models will bring the era of machine ordered security of the Jetsons or was it the Flintstones? And might not we humans end up in the “planet of the robots?” Something for Hollywood to consider!

So I ask you dear reader after that first chill of the morning air, a loaded cup of hot coffee and a desire, what would you do differently?

Tuesday, August 12, 2014


Targeting Therapy: Kinase Inhibitors

The human body functions on the backs of proteins called enzymes that modulate cellular behavior. These enzymes act as catalysts for a biochemical reaction within the human body milieu. One such class of enzymes called Kinases has a profound effect on the internal machinery of the cell. The human genome of 25,000 genes has a total of 500 kinase genes that have the ability to modify 30% of the genome.

With the advent of tumor genomics and high throughput machines the gene expression signatures has brought forth an array of medicines to counter malignancies.
Our understanding of the normal function of the kinases has enabled us to realize the pathology within. The governing gene of the kinases and their mutations, rearrangements and copy number variations can thus enhance, inhibit or modify the normal physiological function of the cell by interfering in the cellular signals and create chaos. It is this understanding and our ability to recognize that will help transform cancer care in the very near future.

A Kinase
acts as a mediator to transfer a phosphate moiety from the ATP molecule to a target substrate. A receptor recruited kinase most commonly such as EGFR is activated when the receptor plus ligand dimerizes the receptors and initiates the downstream cascade. The kinase phosphorylate other protein substrates to transduce the signal downstream via pathways directly or indirectly to the nucleus for enhancing proliferation or arresting growth. This act of phosphate transfer is called “phosphorylation.” Kinases have the ability to orient the substrate and the phosphate in such a manner so as to stabilize a high level energy reaction.
Courtesy McGraw Hill Companies

It is this activity that signals the interior of the cells to modify, grow, and self-destruct or cease-function. The kinases govern such initiation, inhibition or disruption of cellular activities, all through the charged phosphoryl-group. This regulatory function of the kinases comes from their ability to have reversible covalent modification of the substrates.
Courtesy McGraw Hill Companies

Such external modifying measures also create allosteric activity (feedback loops) within the interior of the cells that can potentiate and maximize the initial reaction.

Biotechnology companies are creating various Kinase Inhibitors. These inhibitors are used to suppress the kinase turned rouge -due to modification of its function as a forerunner of gene mutation. To prevent the mutated kinase from over-function and excessive uncontrolled cellular proliferation as happens in cancer, the inhibitors shut the signals emanating from the kinase and thus arrest any untoward cellular behavior.

There are a total of 60 Receptor Tyrosine Kinases (RTK) and an additional 30 intracellular Tyrosine Kinases that have been identified. Amongst the RTKs include the well-known families of: EGFR, PDGFR, VEGF, MET and ALK and amongst the non-RTKs included are: ABL, FES, FAK, SRC, IGFR and SCFR(c-kit) and JAK families. The various TKIs thus far developed include: Crizotinib (Xalkori), Dasatinib (Sprycel), Erlotinib (Tarceva), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Sorafenib (Nexavar), Sunitinib (Sutent). Most are familiar with Imatinib against the BCR-ABL mutation in CML, Crizotinib against the ALK mutated lung cancer and Sunitnib against renal cell carcinoma. The list of TKIs in development currently exceeds 38 at this time and future studies will highlight the benefits of these developments.

Aside from the RTKs there are three other kinases worth mentioning: Cycle Dependent kinases (CDKs), Phosphoinositol kinase (PIKs) and Mitogen Activated Protein Kinases (MAPKs).The CDK enzymes regulate the cell cycle in mitosis. CDKs control transcription, metabolism and because of their role in cell division they are vested heavily via mutation in creating malignancies within lymphatic tissue, pancreas and breast tissues. The PIKs phosphorylate the Inositol, which regulates the Insulin signaling pathways and is involved in both cancer and Insulin resistance. The MAPKs are activated by mitogens such as Epidermal growth factor (EGF), platelet derived growth factor (PDGF) and Insulin growth factor (IGF) to initiate a downstream signal transduction into the nucleus via the RAF-MEK-ERK pathway for cellular proliferation. Again kinase mutations cause dysregulation of the cell growth in most cases leading to cancer.

A word of caution
as we explore and enhance our understanding of the new TKIs is that the benefits from TKIs appear to be temporary in most cases.
The reasons are many-fold; the feedback loop mechanism within the cellular interior may abrogate the inhibitor function, cellular cross-talk between different pathways may take over the function of the kinase and cancer controlled degradation of the inhibitor might undermine the kinase inhibitor activity.
A case in point recently featured in the New England Journal of Medicine showed that a mutation of the Bruton Kinase in patients with Chronic Lymphocytic Leukemia (CLL) resulted in resistance to Ibrutinib a BTK inhibitor that is very effective in this disease!

The changing face of Cancer Care...Sustainability, Durability and the hope of longer term survival!

(Hey, I didn't say Science was easy, but it sure the heck beats contemplating the navel!)


Manning G, Whyte DB. et al. (2002). "The protein kinase complement of the human genome". Science 298 (5600): 1912–1934

Higashiyama, Shigeki, Iwabuki, Hidehiko, Morimoto, Chie, Hieda, Miki, Inoue, Hirofumi, Matsushita, Natsuki (February 2008). "Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands". Cancer Science 99 (2): 214–20.

Stout TJ, Foster PG, Matthews DJ (2004).”High throughput structural biology in drug discovery: protein kinases.” Curr. Pharm. Des. 10 (10): 1069–82

Hunter T (1991). "Protein kinase classification". Meth. Enzymol. Methods in Enzymology 200: 3–37

Cantley, Lewis C (2012). "PI 3-kinase and disease". BMC Proceedings 6 (Suppl 3)

Canavese, Miriam; Santo, Loredana; Raje, Noopur (1 May 2012). "Cyclin dependent kinases in cancer: Potential for therapeutic intervention". Cancer Biology & Therapy 13(7): 451–457

Tony S. K. Mok Personalized medicine in lung cancer: what we need to know

Nature Reviews Clinical Oncology 8, 661-668 (November 2 2012).

Jennifer A. Woyach, M.D. et al. Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. N Engl J Med 2014; 370:2286-2294. June 12, 2014