HOW PRECISE IS PRECISION MEDICINE?

Precision Medicine: “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person."

The world is changing and fast. We live on the edges of discovery as we always have. Coupled with our computing prowess, things are moving a bit faster. Add that to the knowledge about the double helix that controls and motivates us, life is becoming interesting. And disease is beginning to show vulnerabilities.

Medicine has always been about progress. How to make our lives better, healthier and how we can thwart disease.

Treating patients with some degree of precision has many decades of experience. Although the concept of population medicine was first invoked as similar and only available treatment for most all diseases and blood-letting was it, for any and all disease, understanding real and basic science changed all that. In fact George Washington, the first U.S. president, died after having 3.75 liters of blood removed from his body within a 10 hour period as treatment for a throat infection. Some success in precision medicine goes back to the ABO grouping for blood transfusions. Transfusion reactions are rare nowadays with proper ABO group matching between donor and recipient of the blood.

In 1956 G6PD deficiency was found as the underpinning for favism; toxicity to fave beans and the antimalarial drug primaquine.

As medical research advanced, more interesting phenomena were noted as an impaired CYP2C19 led to Plavix (an anticlotting drug) to become inactive and ineffective. And discovery showed PCSK9 mutation resulted in Lower LDL and consequently people with such mutation had low risk of Cardiovascular Disease. So subsets of humanity with selective gene drivers are making their vulnerabilities and invulnerabilities become known through genomic data.

And that brings me to the…

Human Genome Project (HGP), which cost $3 Billion and 13 years of research. At the time the unflinching desire to have HGP cure most human disease was predicted, wrongly. The concept of one gene equals one disease turns out is untrue except in a tiniest of minorities.

Precision Medicine Initiative: Established a $215 millions in 2016 of which $140 million for cohort group (blood, nail, hair samples and follow through) and $75 million for sequencing the genome/administration of the cohort. many successes and an equal amount of misfires will come from this as well.

Intra-tumoral Diversity: Our understanding of the heterogeneity of tumors (cancer cell cluster) shows that a varied number of cancer cells, normal supporting cells, and transitional cells comprise the whole ball of this disaster. Sub-clones within the tumors grow as a Branching Tree adding new genetic mutations as the growth continues. In addition the tumor cell for its own existence is extremely adaptable and therefore plastic.

Multiple cellular pathways with associated Cross talk. Each cell has many different pathways that carry signals from the surface to the core where the engine of division feeds to replicate. Improper signaling can lead to over exuberant growth as in cancer or an arrest of growth and senescence and death of the cell.

Driver Mutation: In cancer there are many mutations that actually drive the cancer growth. Thus far 50 such mutations are known. Some are noted below:

Actionable mutations

i. HER2neu Overexpression of the HER2 protein appeared to occur in approximately 20-25% of breast cancer cases. Herceptin, a drug manufactured against the protein product of the Her 2neu mutation arrests the growth of the cancer. Additionally a newer drug Perjeta is believed to work by targeting a different part of the HER-protein than Herceptin, resulting in further reduction in growth and survival of HER2-positive breast cancer cells.

ii. BRAF V600E: B-Raf mutation on Chromosome 7 drives cell growth via the RAS-RAF-MEK-ERK-MAP Kinase pathway. Vermurafenib a BRAF V600E inhibitor is also a determinant of sensitivity to Proteasome Inhibitor (CARFILZOMIB). 92% BRAF mutation is actually a T(hymine) - A(denine) nucleotide 1796 switch.

iii. BCR-abl mutation Using Imatinib as the drug of choice in CML. Newer refinements of the drugs have managed to enhance the survival of patient afflicted with the chronic myelogenous leukemia.
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Ponatinib (Iclusig)

iv. In Lung Cancer EGFR mutation in 50%, Treated with Erlotinib and Geftinib directed against exon 19 deletion, exon 21 L858R, and exon 18 G719X, and Afatinib worked against exon 20 T790M mutation. KRAS mutation in 25% without any specific inhibitors and ALK-EML4 mutation 5-7% of patients with NSCLung Cancer respond well to Crizotinib and Ceritinib.

Passenger Mutation: When certain known driver mutations are located in the part of the DNA that is not proximate to the signaling source, their function is reduced and the risk exposure to the cancer is reduced. BRCA gene is author suppressor gene that overrides any anomalies of organ (breast) cell, therefore mutation that leads to its dysfunction results in cancer:

a. BRCA mutation: BRCA -1 on Chromosome 17 q21.2 

19,581 patients: 

46% had Breast Cancer,
12% Ovarian Cancer,
5% Both
37% None
(The effect size is based on the specific location of the mutation. JAMA 4/2015)

c. BRCA-2 on Chromosome13
11,900 patients: 

52% Breast Cancer,
6% Ovarian Cancer,
2% Both,
40% None

c. DiGeorge Syndrome or 22q11.2 deletion syndrome: In this disease, location matters. A slight shift in the placement of this mutation can lead to none of the learning disabilities, congenital heart issues or other disabling anomalies.

d. Cystic Fibrosis: Loss of function mutation as in G551D mutation carrier may not have Cystic Fibrosis but a higher risk of infection…Invacaftor (Kalydeco) helps 4-5% of CF cases.

Not all Mutations are functional (as in location next to the driver gene or further away)or actionable (therapy may be ineffective since the action directed against the wrong gene). JAMA September 2016 article.

Clinical Trials in Precision Medicine (PM):

a. SHIVA Trial: (n=195) No Progression Free Survival or Hazard Ratio differences in genetically matched vs. unmatched.

b. SAFIR-01 Trial: (n=55) 4 Partial Responses and 9 stable disease cases noted in the trial.

c. IMPACT-COMPACT Trial: (n=84) 20% Response Rate in molecular matched vs. 11% in unmatched

d. Basket Trial of 122 patients suggested a BRAF mutation alongside of RAS mutations found in Malignant melanoma, Colorectal and Ovarian Cancers. So the mutations exist not only in selective cancers but these mutations are also shared among other cancers as well. Using Vermurafenib a BRAF V600E inhibitor in these cancer yielded activity.

e. MAP( Molecular Analysis for Personalised Therapy (MAP) conference)Trial: Results from the trial, which took place at the Gustave Roussy Cancer Campus in Paris, found that 199 out of 1110 patients with advanced heavily treated cancer, who had their genes mapped and their treatment tailored, had around 30 per cent longer survival benefit before their cancer started growing again compared to any of the previous therapies the patients had tried. This ranged from between 5 and 32 months.The patients on this trial had diverse types of advanced cancer including lung, breast, head and neck, prostate, bladder, bowel and stomach cancer.

Cost of Precision Drugs

1. As of 2015,150 FDA Approved drugs based on DNA mutations

a. Cystic Fibrosis Drug effective in 5% patients with specific CFTR mutation cost $300,000/year

b. Duchene Muscular Dystrophy: Eteplirsen cost $300,000/ year and recently approved by FDA due to advocacy.

c. A well known debacle in the last decade brought to light a product called Provenge for prostate cancer at a cost of $114,000 that forestalled disease by only 4 months.

These and other costly medications are sticky issues when there are alarm bells sounding on the cost of healthcare. Yet humanity needs to be helped. Reducing administrative and other management costs and redirecting finances to research will auger new advances. As long as a third party insurer dictates the price and governmental policies prevent negotiation of costs, precision medicine may remain a dream for most patients.

Multiple Signal Transduction Pathways.

Example of a single PI3Kinase pathway

a. All such treatments based on Biologics have limiting successes. The major one is the plasticity and adaptability of the cancer cells. Cancer cells as normal cells have multiple signaling pathways between the surface and the core and as one is shut down, the cancer cell adapts to create a Cross talk bridge with another pathway to keep the core fed and growing. That is why the response to Biologics are time limited and eventually cancers after an initial regression start to grow. This same mechanism is elicited with resistance to chemotherapy also.

CTCs, Cell Free DNA (cfDNA) and their potential in PM. Although the CTCs and cfDNA have the potential to diagnose and detect abnormal genetic mutations in cancer cells broken free in the blood stream, the problem remains that the mutation noted maybe from part of that branched tree where the cancer has been destroyed but the other branches with ewer mutations might be alive and well. This leads to a conundrum of appropriate therapy as you can surmise.

CTC analyzers

Layered Information: The answer might be in layering information together rather than in piece-meal approaches. One can use the Family history, layer with the genetic mutation, add to that the lifestyle behaviors, which modulate the genome (via an epigenome, as in miRNA) add that to the gut bacterial genome and its impact on the protein production products of said gene modification and there you have a better handle on the disease and its present and future impact. Layering via:
a. Genome
b. Epigenome
c. Microbiome
d. Proteome

NIH in partnership with the FDA and the Biomarkers Consortium embarked on a iSPY 2 Trial where driver mutations in observed sets of patients will be used to treat other sets of patients. this is an attempt to accelerate and advance the process of cancer medicine.

"ANOTHER DAY, ANOTHER DREAM"

Hope Springs Eternal!

He leaned into the curtains to see who was there. The crowds were milling around. Some taking to their seats, others standing and observing others, still others wanting to be noticed cast their eyes hither and yon for recognition. The porcelain white skinned women gowned and beautified hovered on the arms of their escorts while some with their noses pitched slightly higher walked alone. Their aloneness a symbol of their success as men gathered around them, showering them with cheek to cheek fake kisses. These, he thought were the famously rich people and he, an off the street hobo had been cast to play a part in the play. This was going to be the answers to his prayers. Who knows, he thought, I might be able to mingle with them someday. His prayers had been answered.



The crowd stilled in their seats. The lights dimmed. A trumpet sounded and then all was abuzz with stagehands, actors and set mobility. He was told as he had rehearsed many times now to appear in his native clothing of the smelly rags that had seen the street water, rain water and other unnatural fluids dried and permanently stained on the brown threadbare cloak. His face unshaven with a dark stubble and his mind was set to memorize the few words he was supposed to speak. He went over and over them in his mind, half reciting to himself and to the walls and curtains around him.




Time speeded and slowed as he watched with admiration, the efficiency and alacrity of the stagehands changing the set to keep the spectators mesmerized to the underlying theme of the play. The lights brightened, then dimmed and then brightened again in cycles to keep the spectators memorized by the mirage. The actors laughed, cried, showed anger and disgust and it all appeared real. He was transfixed. From his eyes that had seen a stainless steel pen fall from the pocket of a man on a fast gallop on the street, late for work, he had called out to him as he retrieved it from the street corner for him, the man had turned, looked at him and the offering and shook his head after seeing his pen clasped in dirty hands and walked on, to now in front of these wealthy and important people, all under the same majestic canopy. He still had the pen. He considered it his good fortune, since it was the same afternoon, when another well dressed man had asked him if he would be interested to play a part in a play for money.

The curtain was lit up once again as the intermission ended and the shuffling crowd gathered in their seats. The middle act created the scene of playful elegance and chivalry on stage.

He could hear his breathing and the faint whistle of years long exposure to the pollutants from the automobile exhausts as he sat begging for food on the street corners. The fume had taken some toll on his bronchioles. He was unable to walk the entire street without stopping and catching his breath. His pulse quickened as the play continued to hurtle towards the end and the gasps and muted sounds of disbelief in this suspended disbelief echoed through the large auditorium. He could from his perch see the two mezzanines filled with awestruck spectators watched spellbound as his moment of fame approached.

His moment had come. He walked on to the stage, the bright lights dimmed and he shuffled on the staged street corner where he was meant to stand. The streetlamp overhead on the spot lit the floor brightly encircling him in its lumens. All else was dark. He could not see beyond the first row of the spectators. He shuffled to the spot near the lamp and leaned against it for a few seconds as he and been told. He looked down on the floor and picked up a coin placed strategically for him to acquire. He rubbed the coin against his ragged clothes and uttered the words he had memorized.

“Another day, another dream.” As he pocketed the coin, he collapsed on the stage floor. The streetlamp light dimmed to dark. He got up as the stagehands scurried past him.

The stage brightened and the an actor took center stage, “To the last syllable of recorded time, “And all our yesterdays have lighted fools the way to dusty death. Out, out, brief candle!

Life’s but a walking shadow, a poor player that struts and frets his hour upon the stage and then is heard no more. It is a tale told by an idiot, full of sound and fury, signifying nothing.” 

A thunderous ovation broke out as the crimson gilded curtain came down and swallowed the stage. He felt his heart swell with pride. His moment in life had come.

The man who had asked him to play the part appeared from nowhere, “Thank you. You were great,” he says. He hands him two hundred dollar bills. “This should help you,” as he looks back towards someone unseen, “Joe” he points out to a stagehand, “could you please walk him to where he has to go.” And he was gone.

Back out on the cold street, he watches the limousines gorging themselves with people covered in satins and silks as the parade of the beautiful people leaves the theater. Soon the normal late night bustle begins to take over and he is left staring at the marquee.

He realizes, he is the idiot. His minute of glory was to bring a real wretched down trodden from the street to magnify the imagery and pretense of the play. The rich and famous were back clinking glasses in some expensive restaurants or brick lined carpeted homes pretending to diminish the evils of poverty in society as they absolved themselves off their guilty pleasures. “Did you see that poor wretched person in the end. He was so real!” they would claim. “Nah! he was a high paid actor! its Broadway after all, dear.” “Either case,” a slightly corpulent gentleman confided, “don’t look at me, I empty my pockets to all the beggars on the street every day.” Alas discussing the wretched  distilled away the humor in the air and made everyone uneasy and restless.

“Yeah John,” the young financial district upstart chimed, “only with quarters and nickels?” The fat man ignored the slant, “Hey, doesn't anyone know the borough politician, I think having beggars lowers the real estate values and doesn’t look good either.” A general consensus of nodding heads followed. Silence broke out for a while. Someone argued about taxes and the conversation shifted to vacation homes, yachts and airplanes.

A muted repentance of hypocrisy, well, is still hypocrisy.

PHYSICIAN SUICIDE

PHYSICIAN SUICIDE
&
The misshapen chaos of well seeming forms

Were I a soldier in an infinite army of like minded individuals, I might march to the same beat, move the limbs in the slow and sculpted movement of experienced sinews, hold my head in the temperate form paralleling the majesty of the uniform, sing to the tunes of the collective, view the world from the same pulpit as the preacher and file away the dreams of my youth in the forbidden corners of my imprisoned personal vanity. All semblance of me buried in the form of a single line made of the infinite numbers of similar dots.

But I am not a wanton of simplistic pleasures of agreeability or contextually. I am not the victim of the mind that seeks to swim in the collective tank. I am the unum that desires to seek the fortunes of knowledge, not the pecuniary one but the enlightened angel that hides behind the soft covers of group think beast.

The misshapen chaos of the well seeming forms have come to haunt us. They disguise in the costumes so appealing and seemingly enduring that the lust for the luster and desire for the hues overpowers the senses. These chaotic circles envelope us in our entirety casting a stranglehold on our imagination, our essence, our individuality and our thoughts.

Such is the price we pay for these well seeming forms that caress and cajole our minds. A price too steep, I think, that threatens our very humanity.

Does the calculated mind that oversees such calamity not understand the consequence of its actions? I dare say, it does not. For even as it displeases, it continues to erect newer barriers and rings of confusion around the substance of those well meaning forms. The barriers get higher and higher as their depth gets deeper and deeper, becoming fortresses within fortresses all encased in the realm of meaning well.

Forms such as these, so cruel to the touch that they freeze the fingers, which probe. So dense that they repel the thought that dares and so vicious that they resort to violence against the mind that wonders, captivatingly ossifying any inkling that might threaten them.

These forms take human lives in the form of suicide. Physician suicides. Doctor losses arising from the untimely frost on the wisest minds that roam. These forms bury the architecture of experiential wisdom under the guise of “think not, do,” a form so beguiling that baser natures cannot repudiate. So what if a few die, so what if the many don't get what they should, in the end there is no readiness.

The chaos that ensues destroys the very foundation of the structure that once stood for health and happiness guarded by the wiser angels amongst us. Now the ruins spread like a conflagration, destroying everything but leaving behind a trail of embers; the charred remains of a once polite and very human loving thought.

Physicians take their own lives, mentally shattered from the compressive force of bureaucracy that claims other’s safety by erecting maze upon maze of uncertainty and demand. The maze so clever that exits are all but closed after the entry. Only the solid wall of policies, regulations and mandates exist as you run through the maze, constantly reaching dead ends that never seem to end. Retracing steps to see where one went wrong only to find another dead end. In these hurdles, faced with the never ceasing complexity of the demands, the mind gives up. The center ceases to fathom and cannot hold together the psyche made so fragile by the fear that grinds at the root of every measured step taken. No one is the wiser of the scars that never felt the wound. it seems that no one cares.

When 300-400 physicians commit suicide and female physicians have a 250-400% increased risk of suicides as compared to females in other professions, and 9.4% of the final year medical students are dazed and lost to this monster annually, something is terribly wrong! Something rots at the core of this accelerating phenomenon.

Medicine is complex, Medical care is an art and less of a science than what is believed in the current reductionist society, so tempered with the lust of prediction and probability. The demise of good medical care is near and continues to collapse at the periphery under the erected weighty barriers and threatens one day soon to collapse the center as well. It is humanity’s Hadrian wall.

What resurfaces from this creative destruction is a future of disembodied humans, of virtual machines, of deprivation and an unimaginable lust for the shiny object that will fail to define the better angels of our humanity.

“Virtue itself turns vice, being misapplied
And vice sometimes by action dignified”

Am I a nihilist? I often wonder. But the recent past has been accelerating at breakneck speed for me to be otherwise. We have arrived at the misshapen chaos that no one seems to understand all erected on the foundation of well seeming forms!

THE ECONOMIC SUBSTRATE

The Ultimate Substrate of Economic Health is embodied in what happens to any life. How the person takes care of himself or herself, how the family and society support that person. Overtime it appears that we in the western world have devolved from personal responsibility to blaming every pitfall on others. Some use it to benefit themselves, others use it to absolve themselves of guilt. The pattern remains the same. The cycle renews and has renewed for many generations, ultimately to be replaced by a new cycle.

One cycle appears to be coming to an end and where the next cycle begins is anyone’s guess?

The fundamentals define our future. In this complex world of finance in the United States, there are 320 million players who have an intimate stake in the outcome. The young ones who will create a new future, the middle aged who are functioning on maintaining the current paradigm and the elderly who hope to remain comfortable in their waning years.

The complex colorful origami is still made of paper in the end and fundamentals still matter for any outcome.

So here is a short rendering of the forces that are currently in play that create our economic futures. This by no means is a dystopian future, nor is it a utopian Shangdi-La. It is.

Where the future might lead is another Mind Map yet to come…but will come!

Please comment… it will make for a better conversation. 

IMAGINE

Imagine if you will, you are lying on a field of grass in an open meadow, the declining sun casting its golden hue that you are not aware of, except with the brightness cast on the cloaked retina. Imagine the thoughts of the preceding days clashing within the mind. Imagine that some thoughts cling on to others, like glue, while others fall away in a dried heap. Imagine further that the links between the glued thoughts grow firm and attract others together. Imagine the smell of the grass wafts in like a catalyst opening bonds and closing others between those thoughts. Those inaccessible thoughts stacked into layers of consciousness can suddenly be accessed by the prudence of a relational dynamic insight. Imagine all that and what do you suppose would happen?

Some have solved problems while buoyed by water, others have allowed the miseries of an industrial London to form the basis of classic literature while still others have surprised themselves after being trapped in a hopeless spiral of confusion and colliding thoughts with an answer while resting or awakening from a deep sleep. 

To say that every idea or innovation comes from such bonding would be erroneous. Not having experienced such a transformative explosion of thought confluence or not having entertained any weighty matters or simply having being confined to the empiricism of reductive thoughts, it is difficult to imagine, such a concept. As one such mathematician named Evariste Galois claimed, “Science progresses by a series of combinations where chance plays not even the smallest of parts.” Unfortunate for Galois, he died at the age of 21 in a duel, never recognized by his contemporaries including Poisson for the genius within. Imagine had he lived…there would have been more time, more reflection, more layers of contextual content and more eurekas?

The wonders of free thought is the wonder of finding solutions. After working on a problem over many days trying to find if a straight line that did not meet the vertices of a triangle could not intersect the sides of that triangle, Roland Dobrushin determined he could not solve the problem, because he did not understand “the straight line.” He won the mathematic prize with that comment. Imagine that, stepping down the rungs of the ladder into the deep, dark hole and finding no light replied as he did. All answers seemed to lead to the “mystery within Euclid’s geometry.”

The question then arises, “Does knowledge flow downwards, or does it boil up from the depths?” It is a question long forgotten by the modern minds. Knowledge to them is a series of concatenations inspired by "their applied wisdom." This follows in such things as curricula where Chapter One precedes Chapter Two and after Chapter Twenty the student is no wiser for it. The teacher reads the written words, answers the questions contained from the instructor cheat sheets and the student grades are graphed on the Gaussian curve. From outlier to outlier, no one steps back to understand the motive behind the year spent. What was Hazard Ratio or the Regression Line supposed to represent? What made Galois go on a duel the night before, fearing his death, pen his thoughts and experiments and send to his friend? What was Archimedes’ “Eureka” moment and what significance did it have for whom and why? 

As the candle extinguishes and the hand that holds the pen losses it’s grip, ink falls on the paper below creating the ink-splotch, the morning sun might reveal an answer to the problems from the splotch itself and another “Eureka” moment arrives. Such are the moments that explode from the merger of ideas when the mind is freed from conjecture. As Friedrich August Kekulé von Stradonitz found out that the ring structure of benzene came to him in a dream where a snake was eating its own tail or Newton seeing an apple fall discovered gravity, are examples of those eureka moments that defy plod through a problem mechanism, and arriving at the truth, redefines the need for cerebral lateralization to conjure up links in the peace of rest.

Gavin Weightman in “Eureka; how invention happens” states, “But time and again, even in the twentieth century, those innovations which have transformed our lives have been pioneered not by the big guns of established industries or the laboratories of the most brilliant scientists but by a few visionaries who had the temerity to imagine they could make the impossible possible.”

Modern day educating is about “crossing the Ts and dotting the Is.” The mind is never encouraged to expand the horizons of understanding. The written word is forced as the crucible of knowledge. One wonders even to this day how those that create and innovate do so given the mountains of busywork in learning?

The answer comes from the few who have expanded the largest spheres of knowledge and understanding; Steve Jobs (Apple), Bill Gates (Microsoft), Mark Zuckerberg (Facebook), Michael Dell (Dell Computer), Julian Assange (Wikileaks Founder) and Evan Williams (Twitter). Most times it is the slow boil of an idea that curriculum cannot address, which becomes the new paradigm. Other times it is an experiment that succeeds accidentally at a scale not fathomed and still other times it is the ingenuity of cobbling up parts to make and distribute hardware from a dorm that breaks the mold. Indeed, as Johann Heinrich Pestalozzi wondered; the heart, gives the sense of union, the mind, a sense of reflection and the hand, work through action, sequentially and concurrently as they conspire to create innovations and advance human thought. All imagined! All inductive! All creations, sans curriculum! 

Imagine what you can do with an idle moment of thought?