" HELLO "

The current zeitgeist in medicine encompasses a wide range of “DO NOTs.” The kind that limits a physician’s input in the care of the patient. Without the shade of a thought that medical evaluation is being reduced to a set of guidelines; the “DO’s.” It all stems from the mantra that was proffered some time ago, “Hospital Stupidity Costs 85,000 Lives and $35 Billion Per Year.” After the much ballyhooed report there were fixes attached to the follies that created the problem of these “premature deaths” Everyone in the bureaucratic industry ran amuck with the paper in hand and started pointing fingers and laying blame across the threshold of sanity. The bureaucratic jungle is a flourishing canopy of protective veil that hides its own flaws to the detriment of all. The medical world was stunned, actually stunned by the reporting and not having any numerical values of their own, starting nodding their heads in unison when the media poured out their venom by using simple arithmetic to get higher ratings with the likes of “Medical errors kill enough people to fill four jumbo jets a week.” 

The foothold had been granted and the bureaucratic “dogs of war” had been unleashed. The entire medical care industry was soon tied up in knots with regulatory fiat. Many well-wishing physicians started to move in lock-step with the mandates and guidelines and other entrepreneurial spirited ones devised their own schemes to rip a page off the book of the incipient collective thought and created the terminology of the “public good.” One such entity; The American Board of Internal Medicine ABIM organization added to their once a lifetime certification examination the process of a 10-year recertification process and as the bureaucratic voices within grew their penchant for luxurious items and high salaries grew as well and they added the Maintenance of Certification process; a biannual process that reaped more than $130 million in 7 years.

While these spectacular shenanigans were going on the bureaucrats, policy wonks and legislators wanted to quantify every communication between patient and physician in a “meaningful” way through coding for billing. The CMS or Centers for Medicare and Medicaid Services gave the dog and pony show to the American Medical Association to come up with more lipstick on the pig with the ICD coding system. The ICD-9 codes numbered in the 17,000 for all medical diseases and each coded was fitted with an “appropriate payment.” Seeing a potential for a follow up revenue to the tune of $200+ million the AMA upped the ante by creating the 70,000+ coded-ways to describe medical illnesses with the ICD-10 coding system. This was a bonanza for the AMA, whose survival no longer seemed to depend on membership of physicians but on its alliance with the industry, governmental affairs cash cow and the data mining wonks. This coding system, they surmised would help the medical insurance industry to actually see how and when and where the illnesses occurred, maybe in the hopes that further legislations would help create more checklists and legislations for the common folk with the “DO NOTs” and give the insurance legitimacy in payment denials to the physicians and other care givers. A win-win for all they said.

Meanwhile the patient and physicians started to see barriers erected in the empty space that existed between them. Once the physician would sit and listen to the patient, eyes locked, hands touching to determine the malady, a soothing voice to comfort against the pathos of the cellular machinery now suddenly the space had thick walls of checklists, guidance, warnings, etc. erected between them.
Communication, once a simple process of speaking and listening, soon became a legal verbose jungle that had to be done for the perfect patient understanding of the expressed information. The voice that once said, “Hello Mrs. Smith” now was broken down into the nuance of implied meanings in the word “Hello!” Was there any implied empathy expressed in that word or was their implied coercion or threat? What was the meaning of the word "is" soon took reins. Empathy leaders sprung up all over the medical education landscape to fill that chasm. Linguistic experts were hired to determine the shades of the meaning within the meaning of the word itself. Meanwhile as the sentence was being analyzed by the billion-line codes of the software algorithm, the payment for services rendered by the physician was being held in abeyance till resolution was reached. Ah! no empathy...no claim...denied! Each step of the communication with its many turns and twists had to be carefully scrutinized. Any deviation from the norm coded into the algorithm was rejected and the physician reprimanded for his behavior. At that point payment was not even on the physician’s mind because a much higher fine could be imposed for such a misdeed. This is where we find ourselves today. Ignorance is no bliss.

The universality of error-making, the inevitability of it and the humanness of it are now a forgotten knowledge. What remains is the “DO NOTs” and the “DO’s.” We have ceased to learn from errors. We only need the errors to find fault and point fingers of blame, because it soothes the bureaucratic mind to do so. The bureaucrats and other wonks seem to think that the current knowledge is the last drop from the fountain of wisdom and there are no more springs or pools of knowledge left to behold. That, what is, is IT! What they don’t understand that today’s knowledge will be supplanted by tomorrow’s discoveries and become laughable if not outright disdained. As they print out their mandates and grind to a halt the very machinery of human excellence, a hefty price will have to be paid, someday soon. Economics teaches us the same thing. Forever tinkering with fiscal policy will have its day of reckoning. Sometime the illogic of the rampant bureaucracy blunts even the Occam’s razor with its layers of Matryoshka Russian nesting dolls approach.

The rabbit hole has gotten deeper and deeper as more blinding rain water flows through it. The deluge from the bureaucratic mindset has flooded the lands and only an Arc will save us now.

ME and YOU

If you did not read, would these words have meaning?
I write this in hopes that you might read.
You read and comment in hopes to further thought.
Our very being, presupposes an eye, an ear, a mind, comprehension!
So then dear reader are we linked for our existence?
If we are, then does not our existence imply mutuality?

Heisenberg's duality exists.

Count you out
Is counting me out.
Particle or wave,
we are linked,
through sight.
My presence is through your eyes
My absence in yours.
Our desperate lives, lived in hope
Of connection.

Eve had Adam
To sooth his aching cage.
Shakespeare's idiot, his spectators and stage

My words persuade you to comment;
We are connected.
In your words, I find existential happiness.
In your absence a deeper sorrow.
The art of belonging is the art of love.
The art of neglect, a demented loneliness.

Without you, I am not me
And without me, are you?
Ambiguity lives
And then it is no more
Schrödinger's cat lives!

The CURIOS CASE of UNCERTAINTY

There is an inimical power distribution curve that covers a lot of area and devours all thought’s food. It is the charade of certainty. The power exudes directly from the certainty of the word “certainty.” Projecting something with the net of realism and a confined future within certain artificial bounds is tantamount to being a prophet. And there are a lot of prophets to behold. In fact prophesizing has now reached epic proportions in the 21^st Century.

Let us look at some of them with a critical eye.

 1. Life Expectancy: In the United States, an adult male expects a life expectancy of 80 years. Barring all the other natural shocks that the flesh is heir to, that might not be too certain. Things happen. There is no certainty here, except that projected and demanded by the experts and lawyers. “ He should have lived…”

      2. Regulations are for the Public Good:  Nancy Thorner wrote about the Dodd-Frank Bill; “Its purpose was to create a sound Economic Foundation to grow jobs, protect consumers, rein in Wall Street and big bonuses, end bailouts, and "too big to fail," as well as prevent another financial crisis.” Paul Atkins stated, “…the 2,319 page bill is basically rubbish. Dodd-Frank created thirteen new offices and agencies, the government only got rid of one agency.” And according to Oversight and Investigation Subcommittee Committee Chairman Rep. McHenry, "Rather than institute market discipline and a clear rules-based regime, four years later Dodd-Frank's failed policies have only worsened the risks within the financial system and recklessly handed financial regulators a blank check for taxpayer-funded bailouts." 

    

      3. Quantitative Easing will prevent a financial Crisis: Thus far the wealth of the nation has increased with fiat money and aggregated in the 1% population. The median income and wealth effect has diminished steadily since 2009. The United States Debt has ballooned to almost $19 Trillion (around 108% of GDP) and counting. Someone will have to pay in some form or another. Food hyper- inflation that matters to an average individual is eating away at his or her meager earnings while adding energy and electronics into the calculations makes the inflation picture appear tame for the time being to the politicians and the economists. All good for the forecasting experts. Hey if you cannot afford food, you can always take a selfie. “We have continued economic recovery…”

      4. ACA is a boon for Healthcare in the United States: 9 million souls are covered by the ACA while 33 million still have no insurance, this from five-thirty eight. Meanwhile those that had personal or private coverage have had to relinquish their insurance and are forced into a substandard coverage with high deductibles and higher co-Pays. Insurance denials are rampant and “Less is More” is the mantra of the experts. The tail has wagged the dog into a state of panic. The experts keep drumming the virtues of a failed system while the ordinary citizens walk around dazed and confused. The countercoup injury to reason appears devastating at present. “The Affordable Care Act!”

       

      5. ACA affords Quality Medical Care: Physicians are burdened by the morass of paperwork where they spend more time trying the “Meaningful Use” of a computerized binary logic of medicine in an uncertain human pathology, while the patient gets less and less time of meaningful encounters. How does one measure “Quality” is the question asked often. The answer still evades even the most sophisticates. Using metrics of cost and time and resource usage is one way this is being calculated currently. “Call it the stupidity of the American voter or whatever…”

      6. Patients are getting quality Care: Patients who are newly forced into the Medicaid system are unable to find doctors who participate in the overly regulated Medicaid environment and thus are left seeking help many miles away from home, leading to delay and detrimental care. If that is quality, there is a bridge in Brooklyn ready for sale. “If you like your doctor, you can keep your doctor…”

      7.  Electronic Medical Records: A physician’s time is spent trying to get reimbursed for rendered care so as to continue feeding the managerial beast of burdensome regulations within their private and hospital practice. The demands by the regulatory body for compliance and the need for the hospitals to make a profit to pay for the 3000+% increased managerial staff pits the doctor against the patient in providing the best care. All that time spent in clerical computerized tasks is, time away from the patient; time is wasted in the bureaucratic jungle. "Initially you drop about 30 percent [of productivity following an EHR implementation], sometimes more.” John Rodgers MD.

8. A Purell in every corner to arrest spread of germs: When did washing hands become a rarity in everyday life before eating? The simplest and best form of defense against acquiring infections from others is still Agnes Simmelwies’ well documented and proven “Washing hands to prevent transmission of infections,”  in “Die Aetiologie, der Begriff und die Prophylaxis des Kindbettfiebers” (“The Etiology, the Concept, and the Prophylaxis of Childbed Fever”) Purell unlike hand-washing might have unintended consequences; might help mutate the exposed bacteria at a faster rate to gain access to the human body. The dream for another antibiotic is kept alive. Just a thought, take it for what it’s worth. Purell in every Walmart and Grocery store.

9. Vaccination will lead to eradication of viruses: Although vaccination is an important landmark in population health against disease, it crackles the imagination that a virus will acquiesce and lay down its arms for survival against this sea of defense. Viruses mutate and they will, to find a foothold again. Eradication is impossibility, because paramount in the viral code is its own survival. Polio virus keeps making a comeback as does the tuberculosis bacterium, the devastating mycobacterium. The human immunity learns to live over time with microbial adversaries. The elusive dream of certainty remains elusive. "There is no cure for polio, it can only be prevented." - World Health Organization. Unfortunately pockets of Poliomyelitis still exist but with a more virulent mutated form of the virus. (here)

10. The Food Pyramid:  That pyramid was responsible for the current obesity rate in the world to a large extent! It was a well-meaning platform by some health experts. What it touted was the fairly excessive use of carbohydrates. The hunter gatherer had not so easily transitioned from the meats to the carbs so quickly and storage of excess not-utilized carbs turned into fats for later use. The human girth exploded as a consequence. Since there was little chance of a famine given the burgeoning racks of food varieties in the supermarket, more and more fat storage occurred that is now threatening chronic illnesses, heart disease and cancer in 36% of the population? The Big Gulp addiction continues. Again an ill-advised certainty gathered on the shoulders of giants in the academia has now become the bane of existence. And a new industry is born; wearables! The uncertainty of human certainty creates a new uncertainty!

11. Volkswagen: The bosses were almost certain that the cool software that fooled the emission standards software was undetectable, were proven wrong once again. Back to the Enron days a similar set of rules were used and we know what happened there. The confirmation bias exists only in the mind and uncertainty has a habit of redressing it. "I personally am deeply sorry that we have broken the trust of our customers and the public,"- Martin Winterkorn, Volkswagen's CEO."

We live in a world defined by the Fallacy of Anecdotal Evidence used as a surrogate for certainty. An anecdote is cited and the drumbeat follows. The poor are richer by world standards in the United States but they are told they are poorer. Healthcare in the United States has spawned the most innovation and continues to do so yet we are told that we have the worst care in the developed world by using some arbitrary metrics that satisfy the academia and the politicians for their personal fortunes. Even Heisenberg's Uncertainty Principle about Nature's fuzziness seems to have escaped the minds of the elite to their own peril.

There appears only one certainty in this world today and that is the certainty of invoking fear. The media is complicit. The politicians love it. The experts spawn it and the populace drinks their Kool-Aid. Disaster looms at the sound of daylight. Fear rides at the tick of the second and citizen helplessness is the all-encompassing fait accompli. Entitlements abound, hope is touted, change is demanded and through all this the human dignity suffers a little with each passing moment. The only certainty in life is death. Life is a terminal disease.

Maybe we might consider that certainty in an uncertain world is the utopian creed. Chaos is the norm, admit it! Certainty is a human mind construct to feed it’s sense of security. After all it is in the uncertainty that innovation is made and progress stimulated. In certainty, life becomes a mournful indignity, a known, known; an exposed drudgery.

“We sail within a vast sphere, ever drifting in uncertainty, driven from end to end.” – Blaise Pascal

CRISPR, GENE EDITING & CANCER

There are more things in heaven and earth, Horatio,Than are dreamt of in your philosophy. - Hamlet

Funny you should ask about CRISPR. It is the most talked about latest technology to hit the media. In fact the two ladies; Jennifer Doudna and Emmanuelle Charpentier were nominated for a potential Nobel Prize in Chemistry. So that brings us to the question, what’s the buzz about?

It is a big as in B I G buzzy development! Let us look at where this CRISPR came from first and then address how it might help us down the stretch.

Bacteria and viruses happen to have survived on this planet much longer than humans. Those two microbes have developed a relationship with each other. Since no one wants to be vanquished by another, the bacteria have developed a strategy to prevent the viruses from using its cellular interior from being used as a factory for producing more viruses and then discarding it to the “file cabinet.” You see, viruses that infect bacteria are called bacteriophages and in so doing, they insert their DNA into the bacteria to circumvent the bacterial machinery so they can produce more of their own progeny. Kind of like your in-laws visiting your home, staying in it for a long time and eventually by proxy taking over the ownership.  

Bacteria for obvious reasons don’t like that. It is akin to the Hepatitis virus infecting the human liver cell and using it for its own propagation to the detriment of the host cell, causing inflammation of the liver as a whole and sometime death of the infected individual; Infect a cell, multiply within (CCCs) and then infect more cells and the parade goes on until the immune system kicks in and the fight leads to the hepatic inflammation.

Okay, so the bacteriophage (virus) has attached itself to the bacterium surface and injected its DNA within it. The Bacterium also happens to have its own piece of coded DNA in place and within it is this nifty fragment called the CRISPR (clustered regularly interspaced short palindromic repeats). These repeats are so called “Spacers” (25-30 nucleotides) and sandwiched within these repeated palindromic segments of nucleic acids are cleaved portions of the infecting virus’s selected DNA fragment. There are many such repeats and bottled in between two CRISPRs is a unique fragment of the viral DNA. Multiple fragments from the same virus or one or two from many different viruses reside here.

One can look at it as a “Guest House” All guests visiting the Great House must live in there. Each guest has a bodyguard on duty, where, if they are noted to have mischief in their DNA will be handled swiftly by the bodyguards and delivered to the police (in this case Cas9 protein) without harming the owners of the great house beyond.

As I was saying, the CRISPR holds these fragments in check and when a similar virus happens to stroll along that has previously caused mischief by injecting its DNA to cause harm, the CRISPR goes into full throttle, slashing and killing the deadly DNA.

The CRISPR segment creates a messenger RNA that merges with the single strand of the DNA of the double-stranded virus (guide RNA or gRNA) and then is rapidly segmented further by being cleaved containing multiple smaller strands each containing a viral DNA fragment and the CRISPR spacer called the crRNA. These fragments attach to the transactivated RNA or tracrRNA and that helps bind to the Cas9 protein and then the orgy begins.

The Cas9 protein cleaves (cuts) away all the crRNA that are attached to the viral DNA in exactly the spots where they are attached thus fragmenting the viral DNA and rendering it useless from further replication! Imagine the simple ingenuity of the Bacterium. But here is the kicker, the viruses don’t sit back and take this kind of bullying within the CRISPR Guest House either. They perform Single Nucleotide Polymorphisms (SNP) or colloquially, single point mutations and thus try to hoodwink the bacterium from recognizing the DNA strand. That single SNP is enough to throw the whole game asunder. And it does. But the slow-poke bacterium compared to the Ferrari driven viruses adapt albeit slowly and incorporate the new segment within and thus the battle for survival and supremacy proceeds anew. When the bacterium divides the latest CRISPR information also goes with it to the daughter cells to help protect them. And the species survives!

And you might ask, how does this help us?

And rightly you ask the most daunting of questions. The answer is simpler than you think. If we can use the nuclease enzyme to cut out a bad portion or multiple bad portions of the human DNA and insert the healthy version into the stem cell, Voila, we have a healthy being! But before you go drinking and smoking hoping for the CRISPR to save your DNA mutations, consider this, we are a long way away from using this technology in humans. The unintended consequences in tinkering with a single gene insertion for a single gene = single disease paradigm might be low but inserting mRNAs that enhance or suppress gene functions and placing them as lords over the genome might have serious pitfalls. You might cure the cancer and kill the patient with some other evil. Happens!  As you are aware that “the hip bone is connected to the leg bone…”and so on, a change here might make a big change there. If you are into the butterfly effect the analogy fits well here. Reminds me also of the Lorentz strange attractor, but we will leave that for another day.

We certainly can keep this wonderful technology in the laboratory and mess around till we have more data to configure the monster of Lamarckian twists that lurk within this technology. Many hundreds if not thousands of experiments are needed to evaluate the hypothesis in a controlled environment and after validation, with trepidation move ever so slowly in the human sphere. But those in love with the “Disruption” fall madly in love and leave caution to the wind. And the wind can be destructive. There are pernicious consequences in the split between what is and what could be. So careful out there, girls and boys!

In cancer for instance, one might snip away a mutated oncogene or have a RNAi sitting adjacent to and enhancing a tumor suppressor gene to shut down the cancer process. The possibilities are endless. Similarly Infectious Diseases could be rendered moot by vaccinating individuals at risk with a CRISPR Cas9 system to destroy the invading bacteria.

Speaking of vaccinations, this is nature’s way of vaccinating against an invader. Plug in the coordinates and destroy the target. Mission Possible!

The mechanism and the understanding are not as daunting as one might think, but using them without safeguards is akin to future genetic disasters. Just sayin!

We have infectious diseases, cancers, chronic illnesses, hereditary genetic misfortunes to consider in alleviating the burdens on humans but we have time and some hard work ahead.

https://youtu.be/2pp17E4E-O8

PRECISION MEDICINE

Precision Medicine is an strange term. It invokes an image of carefully crafted exactness rather than the reality: medicine is an inexact science - bounded in humility. So those of us looking around the corner for the Golden Age of Medicine need to calm their caffeinated jitters.

Articles abound in scientific literature and increasingly in the lay publications. Authors are doing cartwheels and stepping over each other in the trail of this magically transforming triumphant approach to treatment of human disease. Some claim that human illness will soon be eradicated. The hubris astounds.

Let us look at some of the pitfalls for now, not to be distracted by an anecdote of how this or that person was cured from an incurable malady. Plenty of that anecdotal material can be found in the New York Times and other papers.

The human body has about 25,000 functioning genes, made from the linkage of four nucleic acids Adenine, Thymine, Guanine and Cytosine or A,T,G,C. From these humble beginning a population of 7.1 billion diverse human beings currently occupies the planet. (Malhus must be turning over by now). Each individual, shares the same genetic structure but there are subtle changes in each human being’s DNA that give us our looks, morphology (body structure), intellect, nuanced behavior and other things that are nurtured by the environment. And thus, although monozygotic twins share a 100% of their DNA they too have subtle differences in their gene structures over time based on difference of life experience – the Lamarckian twist!

So in a population of say 1000 people who are not related to each other what is the probability that they will share identical genomic signatures for a given disease. The answer comes from various studies including the one carried out by Mary Claire King looking at the prevalence of BRCA (BReast CAncer gene) mutations. These mutations are at best in 14% of the population and seem to be more prevalent in for example the Ashkenazi Jewish population subset.

Another study in Lung Cancer determined that EGFR (Epidermal Growth Factor Receptor) mutations are found in 15% of the population, or the ALK (Anaplastic Lymphoma Kinase) mutation in the same patients with lung cancer occurred in 5% of the cohort studied.

So then the saying goes, well, if we find the genetic structure we can treat effectively. Effectively, yes. But cure a disease? Not so quick my dear Watson. One might think that if we can study these genomic discrepancies, and then devise therapy selectively for the cohort with the anomalous findings. Ah but here is the $64,000 conundrum: What epigenetic signatures modify the behavior of those genetic signatures still remains unknown. So one might have the SNP (Single Nucleotide Polymorphisms) or CNV (copy number variations) or a substitution of A for C in the DNA but how that is expressed might be in the hands of a lesser known but equally strong power called the micro RNA that might be perched around the gene to mess with its behavior.  Or even the semi fluid control of the Transposons, the genes that jump for the sake of strengthening the survival of the DNA and can inadvertently sit and silence a tumor suppressor gene or over-express a proto-oncogene to accelerate cancer growth. So responses even with known gene abnormalities differ as a consequence of the epigenetic deliverance. Not to forget that the cancer cell within its interior has multiple pathways, which govern the behavior of the nuclear proliferation and hence doubling of the cell. So silencing a gene that provokes the proliferation pathway may be silenced temporarily by an antidote (monoclonal antibody or mAb) that attacks the functional protein product of the gene only to be thwarted by an overactive collateral pathway that gets recruited to continue the wayward cell growth.

Recently reported scientists have discovered a gene called GNAS c.393C;T that seems to cause Ventricular arrhythmogenesis (causing arrhythmia or irregular heart rhythm) and is now thought to be associated with sudden cardiac death. With a HR of 1.2 and a P-value of 0.039, clearly more study needs to be done before we start inserting pacer/defibrillators in people with this genetic anomaly.

A study in the NEJM recently showed that targeting a select molecule (BRAF) in different cancers where its expression is evident yields mixed results at best. and goes to the original Shakespearean premise that "there are more things in this heaven and earth (Horatio) than are dreamt of in (y)our philosophy."

So precision is imprecise at best. Before we start building models of costs, quality and exactness, a tincture of humility might also be in order. Such bravado needs some careful reckoning before we hail the next coming of sliced bread. You know, it would be nice to just call it Medicine for now!