Time & Imprudence

“To-morrow, and to-morrow, and to-morrow,
 creeps in this petty pace from day to day,
 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.” -Macbeth

I am fascinated with time, aren’t you?

Is our time out of joint?

Or is our reference out of frame?

One wonders about time. It is a commodity in short supply. In a blink of an eye the world changes. We don’t see it change, but change it does. The infant you hold in your arms today is walking to school tomorrow and driving the scary red convertible the next day. The tree across the field grows taller and then one day is gone replaced by some form of concrete, or maybe a sapling. The progress through time comes with regress in our thoughts. We miss the past and bemoan the transit. We huddle and muddle and juggle to extract the nectar from within the fruit that dries up as we reach. We laugh away tears and cry out in laughter. All the while, time ticks away the moments into memories. It has a directional flow to it. Such is the linearity of this fickle ghost, like the flight of an arrow, it is drawn, stretching the sinews of life’s bow, with intrepid force and penetrating might, it flies, never relenting and never doubtful until it reaches its mark. And with that it draws to the end.

Remember Mr. Henry Belville of London. Back in the days of 1836 he became the first “time-carrier.” He carried a large chronometer made by the greatest clockmaker in the day, for King George IV’s younger brother. Large as a ”warming-pan,’ he carried it on foot and by rail to divest the information of time to banks, Firms and other wealthy individuals who needed the information for status up-keeping. He changed his name to John Henry later to hide his French origins. After his passing his widow, Maria, carried the mantle of the Greenwich Time and then Ruth their daughter. Finally in 1939 the “time-carriage” ended with the advent of other means of quicker (electrical) transmission. Thus was born this distraction of haste in the echo chambers of the restless human soul, by this most nebulous and fleeting of commodities.

Maria Belville

If you wanted to delve into more ancient play in this mud-filled playground of esoteric remembrances, you would see the 13^th Century water clocks designed by Ibn al-Razzaz al Jazari

 and a hundred years stretch later, in the 14^th century the first clock-tower erected in the city of Milan, Italy to mark the passage of the hour. From then on humans have been planning their lives carefully, with an assortment of sundials and jeweled timepieces that reflect their station in life, into the quiet slumber of their grave.

I remember a taxi ride in Manhattan, NY once. There was a predictable delay on 40^th street as we snaked our way around to get to a Broadway show. Oh yes and I did not want to miss the beginning, I was told, when the humongous chandelier comes crashing down. The second sweep on my watch seemed in a flight of hurry, ticking its way, forcing the minute hand closer and closer to the XII mark. My foot was pressing the invisible accelerator in the backseat urging the taxi to lurch and jump past the car “parking-lot” ahead. It was not to be. That extra reach for a scarf, the misplaced keys to my car, the hurried phone call to the restaurant for reservation and all other unnecessary things that torch the “now” into the past had overtaken and cluttered the mind-space. No, it was predestined and not to be.

And here we are, impatient that the taxi driver is humming a tune when he should be pressing the pedal to the metal, or tapping your feet so that aunt Marge would stop talking about a past that no one knows or cares. Such is the impatience of life. We rush to places that matter least, away from the heart of where contentment lies. We run to jump the highest hurdles, we drive a little faster to get nowhere and wish for the sun to come up or the moon to rise while “tick” in its inexorable advance “tocks.” Is impatience a vice then? Maybe or maybe not, for it is the unreasonable person who shakes the world and it is that impatience with inefficiency, which drives the gears of industry and innovation. So maybe it is imprudence and not impatience that drives us to tailgate, honk behind the other car, throw fits of rage at strangers, throw tennis racquets on the ground and even bend golf clubs in sheer disgust, then.  We want things done yesterday. Considering, that is even possible, we expect perfection when flaws drive the subterranean flow of life’s very existence. Strange, don’t you think, this dichotomy within our existence?

Oh and that little event in the hospital that I can recall, where the brother of a patient continued to interrupt the explanation of the therapy planned for his sibling, constantly interrupting, advancing the conversation to the next step, while he looked anxiously at his watch. He was asking questions but not waiting for answers to fill the space. The patient later apologized for his brother, stating that he was a “Hedge-Fund-Manager” and “his time was in short supply.” Really? Oh well, lets give the poor soul a little break from the debacles that were to face him in later years, sad, but true. Which leads me back to the question, where are we headed?

What is this dichotomous behavior that we humans have such a predilection for; speed to nothing and from nowhere. Passing the day to get to another day for what? Whence will that day just swatted away come back in the form of a bonus of survival? Never! It is gone. Done with. Over! Kaput! The moment ticked and the present has tocked out of existence, a figment only in the memory that the brain later embellishes, belittles, pleads and concedes to the higher principles of self-delusion. Yet the perfectly crafted moment where nothing is gained, except the smell of the air, the view of a field or a flower, a building, a passerby with a strange hat or the man with a briefcase standing perfectly erect at the corner of the street as a bird deposits its waste upon his hat, or a potential thought, is gone, Vaporized!

We ask, is it time, time for what? Should we move on? Move, to where? Must we wait? Ah! Maybe we should. For in that wait lies the wit and code of living. It is that moment of pause, which becomes pregnant with idea and a passing reflection, which may lead to a greater achievement.

Our impatience robs us of our comprehension. We speed and in that blur we forget to learn. Our focus stills a certain future and yet the millions of beautiful and wondrous things, sensations and ideas that embellish the present on this earth and within us are lost in that “zoom.” Creativity, clearly lacks speed, possesses capacity for comprehension and forgets the face of the clock. It bubbles under the boil of subconscious, cannot be rushed, can only brew, for the required time and warrants the idleness of patience.

It was in a carpenter’s workshop where I first encountered this thin weather-lined face, with it’s sun hardened skin, atop a lanky six foot frame. He was a master carpenter in his sixties. His shirt neatly buttoned and his thick black hair smoothed back in a two-sided symmetry. He spoke softly and his movements were ever so measured and confined to the pace of his thought that I kept stepping on his heels as he showed me around. He was slow and methodical, as he hovered over the edges of a chair-leg. He measured and re-measured before he took the burr or the saw or a nail. Watching him was like watching grass grow and yet he was the busiest carpenter in town with a sales chart that would make the CEO of a large corporation blush. He managed to do more in the ten hours of a workday then most people do in a week. He was slow and methodical, yet inventive and prodigiously productive. Time was his employee. He was its master.

I must govern the clock, not be governed by it. – Golda Meir

The joys exist all around us, yet we resort to the runaway wilderness of thought to find it. We define fun and excitement in nebulous terms and reach towards the unreachable. And then having succumbed to the despair of not reaching, we quench that despair in the elixir of mind-numbing spirits. We drive ourselves to distraction and destruction in the rush of it all. All the while for that stillness of the moment where beauty resides, is passed for “something else.”

Speaking of beauty, there was this gardener, who spent an arduous amount of time, in my opinion, weeding the flower-bed. He had white tousled hair with an Einstein sort of flare, wore overalls that were muddied at the knees and carried a collection of gardening tools hanging from every loop on his dungarees. He had a sharp set of eyes, which kept darting from flower to flower and bush to bush in hopes of comforting them from any nature induced peril. He clipped any petals that had a minor infraction of droop. The garden was immaculate, the flowers were robust, beautiful in full bloom and nary a weed to be found. His life revolved around a different perspective, the want to nurture. He was careful, he was measured in his stride and oh what a beautiful enterprise of thought, time and action he created in that slowness of action on that tiny patch of land.

We run to a place and lose sight of the beauty that abounds next to us. We seek the future and find no guarantees there. We hop on a thought without understanding the next step and we speak a word without so much as a thought to its meaning. In that speed of non-thinking the translation of life is lost. It is the present and only the present where truth, beauty and life exist and where the true nectar and essence of life reside. Time, that space has carved for itself is; still, reflective, all encompassing and bundled with the past, present and the future. For in that “Now” moment lie the immortalized truths embellished or sanitized in our hazy, lifetime of memory. After all, it is that second, that minute or the hour, which we need to craft, think, feel and live in! That is our world!

I remember the day my infant son and then my daughter’s tiny hands curled around my little finger. All was well in this world. All present haste devolves to those magical of moments for me, when in anguished thought or deep reverie where action for action’s sake forsakes the real pennant of truth. They are grown up now and my wife and I have been enriched with their blessing, yet those beautiful memories remain in that sweet locket of immortalized time.

The Arrow of Time

Machu Piccu

                      A  fine mist rolls, dipping into the foliage. The flowers lick at the moisture. The sun hides behind the clouds above, the year is 1911. In spite of this quiet, there is much urgency in his footsteps as he ushers through the unmarked trails known only to him through broken limbs, trampled grass and footsteps. The birds sing or whatever they do to create the echo through the forested hills. He is an 11-year-old boy. His skin brown and patchy from the sun, reflects the silvery haze that surrounds. His name is Pablito Alvarez. His bony hand pulls and tugs at his follower, a 36 year-old American historian, a lecturer and a future Senator of the United States, named Hiram Bingham. 

Hiram Bingham

The pace is fast but the energetic legs that carry the 11-year-old have no bounds. The trail is obscured with trees and large foliage of ancient times. The insects and flies hover over the little boy, as he makes his way, but don’t alight on him. He knows the end is near as his feet in an almost a dead run seem not to touch the earth. Meanwhile his follower is out of breath. And then suddenly they are in the open.

All sounds turn into distant echoes. A cold drizzle is falling and the overcast sky seems to dip down and touch the face of the majestic mountains in front of them. “There! There!” the boy cries and knows little else to say in English. His grinning face resting on his slender arm as it points to the broad sweep of ancient terraces. 

They climb some more and beyond the foliage appear the granite walls of the 15^th. Century. The three walled-enclaves are now known as the Royal Tomb, the Main Temple, and the Temple of the Three Windows. The Incas still live in spite of the Spanish Conquistadors.

There in the midst stands the Intihuatana, also known in English as the “Hitching post of the sun.” Here the sun during the winter solstice is astride the “sun-dial” casting no shadow. The Incas had determined the Space-Time co-ordinates for their civilization that fostered in the Peruvian mountains for more than a century.

Intihuatana

Well, now if you were to spend some time listening to the physicists who have time on their hands and a space to sit on, they will start by unfolding the universe into an accordion and then with the magic of mathematics they will claim the many universe states and that each human action predisposes one into a parallel universe where the remainder of the life ensues, until the next action. Even if and I am going out on a limb here, even if a scintilla of credibility can be afforded to this argument with the 7 billion people inhabiting the planet today and each to his or her own cognizance determined a course of action of this not that or vice versa we would have an infinite numbers of universes all jiggling around us. Parallel dimensions not withstanding ask the physicist about time and lo and behold they come up with another wondrous canopy of color, although this has some scientific basis in Einstein’s Theory of Relativity; Time is a dimension, fourth to be exact and the three dimensions of space are folded into the fourth dimension of time. Ok, you ask, like a tuna wrap? No! No! It is more like a book, he replies. So tell me then, how?

Time is pasted just as space is, in three dimensions. In other words if you wanted to look at your status at say age 85 years, you would turn to page 31,025 page and voila there you are all weathered and ready for a space-flight with your bionic this or that. Similarly if you wanted to do a Michael J. Fox, “Back to the Future” trick in a Delorean, you would turn to any page before, then the one you are resting on today. So time is affixed and represented, one just has to turn the page. The Past exists with the Present and all are married to the Future. Funny you think, there is that time paradox somewhere in there, isn’t there, you mutter under your breath. Yet seriously there are minds that are filled with this kind of stuff. And then when you bring up the “Arrow of Time,” the physicist would say well it is in flight. It knows which bow it came from and knows where the target is. The past, present and the future all there in one simple book-form! Right there to behold. If only we could see! Lets move on to more mundane issues in life. Like for instance this aging thing. – A function of time.

The Arrow of Time

Aging is a natural decay of a time-limited vessel. Like the rusted iron, a torn shroud, an exposed mineral on a mountainside, or the aging elderly hobbling with a cane down the road. The sighting from any spectacular or sea level view-stand is the same. The cataclysm of degenerative discord arrives unappreciated at every living cell’s doorstep. Can we affix it to a space as the Incas did with their Intihuatana time clock? Can we? Can we stop the ravaging storms of this linearity”?

There are some technical problems that are like the physics of the aeronautical limits that cannot be transgressed; exceeding the angle of attack will always cause a stall. The first one is the Hayflick Limit. A living cell grown in a culture media will undergo division for “x” number of times and then die. The “x” remains the propriety information of the cell. There is within every cell a coded piece of information residing within the DNA. That information resides at the 5’ terminal end of the DNA and multiple tandem repeats that tell the cell at each division when it will exceed its limit of division and then no more. This information of tandem repeats is called a Telomere. So if the cell has 6 telomeres at the end of its DNA then after the sixth division it will lose its ability to craft out a mitotic spindle and go haywire with cellular dysynchrony or just plain commit suicide. A preprogrammed limit of survival!  The obituary is written in the code at birth. No fuss! No Muss!

Telomere

What about this telomerase enzyme that the germ cells have so they can divide ad infinitum? You ask. Yes and that is true. But the problem is that if some one is harboring a potential precancerous rouge cell, addition of the telomerase enzyme will allow replication of that cell and create cancer, the very thing we are trying to avoid by attempting to live longer. Now if we could starve the cancer cell, which surreptitiously acquires the telomerase and use, it for their nefarious means to grow, and excite the normal cells that have normal functional powers why then we could all live to the golden age of Abraham.

Telomerase

But what about the weathering that goes on through degeneration of the cells; the wrinkling, the patchy skin, the arcus senilis, the crooked noses, the hanging earlobes, the weathered dry skin, the thinning of the bones and the sluggishness of the heart and the mind? Pray, how do we stop that?

Dolly

Interesting pieces of information are emerging that may have a predictable future. Remember Dolly, the sheep. Well when Dolly was cloned she grew at a faster rate and aged rapidly in short order to her mother’s cell limits. So if taking cells from an older person and cloning it leads to an aging clone, why not save/freeze some of your cells at birth. Oh I am not saying to have your head frozen and then one day in some distant future when space hover-boards are available and taxis fly in vertical directions in all dimensions that a perfect body can be cloned and affixed to the head and all those memories come roaring back centuries later and you find your 21^st century mind exposed to the real Star Wars. No that is not what I mean. Simply that if stem cells saved at an early date in life can be used to repopulate the damaged portion of a weathered body and allow normal living, wouldn’t that be great. The problem that has yet to be solved is whether the young stem cells through cross-talk will acquire the wisdom and age of their new older neighborhoods.

In the meantime one can continue the current trends of plastic surgery; the nose job, the facial pull, stretch and smooth, the turkey flesh tug, the transplanted hair and all other such things available today for vanity’s sake. Aside from taking massage with snakes crawling all over your body or heated rocks on the back of your chakras or being kneaded by a 300 pound female on your fragile ribs in some far off place called Rancho Exotico maybe, just maybe, eating healthy foods in limited amounts, not smoking or drinking or too much sunning might help preserve the natural visible enclave of your soul.

So, the Incas knew a thing or two about time and space. Their terraces and the agri-farming of the 15^th century that has been repackaged as today’s new endeavor was and is the state of the art. Their carefully arranged steady streams of natural rain water trickling down via tiny rivulets feeding the burial temples drip by precious drip, exemplified their fascination with fixing time at a certain place. 

The physics of immortality clashes with the limits of Hayflick and that we still try to do as we do and always will, is our curious destiny; to reach for the stars and touch the face of heaven.

References:

Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains". Exp Cell Res 25: 585–621

Hayflick L. (1965). "The limited in vitro lifetime of human diploid cell strains.". Exp. Cell Res. 37 (3): 614–636

Griffith J, Comeau L, Rosenfield S, Stansel R, Bianchi A, Moss H, de Lange T (1999). "Mammalian telomeres end in a large duplex loop". Cell 97 (4): 503–14

Eisenberg DTA (2011). "An evolutionary review of human telomere biology: The thrifty telomere hypothesis and notes on potential adaptive paternal effects". American Journal of Human Biology 23 (2): 149–167

I Remember the fall~9/11

I remember the fall,
I remember the feel.

It was the wrench,
It was the reel,
It was the hurt
And then the appeal;

It lifted the spirit
And raised the brow
That pulled the soul
From the deluged bow.

The waves all crashing,
The cries all haunting,
The eyes all wet
The hearts all wanting.

The feet all running
The smell of dust
The eyes all dry
The color of rust.


The smoke all rising
And lives all falling
The end is near,
The end is not.

What evil this is
That lives in hearts
All black,
All dark,
Riddled and cursed.


We think,
We love,
In Grace and heal.

I remember the fall,

I remember the feel.

Barriers in Communication

The evening had slipped hurriedly into the night. The street lamps outside had brightened their glow, their brown amber halos splashed onto the ground. like liquid gold  From where we stood in the hallway of the fifth floor of the hospital, business as usual was in progress in the external world. On the street across from the hospital, cars were buzzing by in their hurry to deliver their occupants, where they had been intentioned. And were I in one of the cars below, I would have thought the same business as usual was going on inside this giant well-lit hospital building. But no, I would be wrong.

My colleagues and I were standing in that hallway after encountering what could only be described as a “train wreck.” The patient was a elderly man who had a ruptured diverticulum in his bowel and he had progressed rapidly into a “shock-like” state. The bacteria from his bowels were teeming into his abdomen (peritoneal cavity) and through ruptured capillaries, filing directly into the blood stream. His life was staggering over the precipice looking down into a dark abyss called “septic shock,” - the event horizon from where half of those afflicted never come back to breathe another breath. The hallway was quiet, save for our muted conversation and the infrequent hum of the compressed and conditioned air as it crawled its way through the ducts in an a-periodic frequency to shake the decorative window-blinds from their reverie.

Surgeon: “You should have seen his interior, purulent and messy. Every tiny capillary was oozing. I found the source tic, though! And in feeling through his bowel we found an incidental colon tumor. It was the size of a golf ball. The frozen path suggests a carcinoid. That is the least of this chap’s problems unfortunately.”

Infectious Disease: “Well, I think he is going to need Broad Spectrum stuff and we will throw in some fourth generation for good measure till the C and S are back.”

Hematologist: “The poor guy is in DIC. Got to figure on treating that. Hope we can stop it or you might have to go back in there to evacuate blood, which as you know can further propagate the DIC in a vicious cycle.”

Surgeon: I don’t want to even think of going back in. It’s a nightmare in there right now and Heaven knows what it will be later. Especially with that Disseminated Intravascular Coagulation of yours that is going on.”

Nephrologist: “I got him on Bicarbonate and added some Calcium. I’ll watch the acid-base data in three hours and make changes. His Creat is 4. Might need Kayexalate for his K and maybe a temp dialysis too.”

Surgeon: “No PD. His peritoneum is teeming!”

Hematologist: “Fix that acid-base stuff and the DIC might calm down. Those damn endotoxins in the abdomen are wreaking havoc. I checked the parameters; both PT and PTT are high and the platelets are dropping as the FDPs rise from all the clotting that is ongoing. So I’ve got him on Fresh frozen and ordered platelet infusions for now.” Then addressing the surgeon, “Did you run your hand over his liver. Feel any mets?”

Surgeon: “I did, the liver was slightly nodular, but when and if he stabilizes, we will have to scan him.”

Pulmonologist: “I am worried about his third-spacing. I will need the central line to monitor his pressures. Did you put one in?” And with only a pause in his breath he stated, “We also need a heart guy involved. His ticker appears time-limited.”

Surgeon: “Yup. Anticipated and done!”

Pulomonologist: “We’ve got to get an endocrinologist to monitor his diabetes. He is very fragile based on the history from his family. He has Type II.”

Surgeon: “Get someone of your choice. Ok guys! stay posted. I’ve got another one to follow in the OR. See you later. And thanks for your help!”

We all disbanded a few minutes later. But as we did so, I noticed a young 20s something guy lurking. I had noticed him fiddle with the vending machine before and now again noticed him staring at it. His eyes were fixed but his mind, one could see, was wandering. He raised his eyebrow and a sigh escaped from between his tight lips. He couldn’t fool me. There was a sense of desperation in it. A warm wisp of moisture, just barely enough to cover the glass panel of the vending machine escaped, as he tossed a look that seem to suggest a conundrum between choices E4, a peanut M&M packet or F6, a Snickers chocolate bar. Neither, however could or would satiate the desperation behind his saddened eyes.

“Can I help you?” I asked.

“No, no, just looking.”

“Oh! ok. Sorry.”

“Oh! Maybe you can.”

“Sure.”

“What were you doctors all talking about?”

“That is privileged.”

“No, I mean you speak in some language that is so difficult to comprehend.”

“We were discussing medical issues about a patient.”

“Yes, I know, but when I was in the room with my grandmother and the doctor came in to tell us about what was going on with her. He used these highfalutin words that none of us in the room understood.” He paused a moment and then finished with a deeper sigh, “He might have been speaking in Latin.”

“I am sorry to hear that.” I offered, but the words were hollow, even to me. “Maybe I can help?” I said, not knowing what I was getting into. He tried to explain his grandmother’s malady and I listened and tried to help as best, I could, but my hands were tied by the ethical and legal constraints of speaking with another physician’s patient’s family member. The best I could do was not good enough.

We parted company shortly thereafter, both parties dismayed, unsatisfied and filled with an emptiness that spoke volumes about the dilemma. This young man’s anguish was about a monologue instead of a dialog. Maybe, and I am quite certain of that, maybe the doctor had discussed it in a medical terminology unable to unburden it in layman’s version. He might have used “medical lingo” to describe the disease, its manifestation and the treatment that he or she was envisioning and fully expecting a complete understanding by the recipient. As patients sometime are wont to nod to hide their ignorance, the conversational gulf expands. The flow of those descriptive words however might not seemed to have bridged the gulf. The recipient’s slate remained blank and yet managed to get stained from a frustration and miscommunication. The power of the words for them might have been reduced to a barrage of indecipherable syllables and consonants. Even though words had been uttered with the greatest of  energetic emphasis, they failed to crossover, comfort and explain.

Physicians are constantly involved, coping with the burden of disease, thinking, speaking as specifically and accurately to one another about the management and they will sometimes continue that expressive dialogue with the patients and their family. Yet in the emotive, expressive, urgency of the disease and the nuances of proposed therapy the "expressive" reveals itself over the more controlled, conventional watered-down version of the explanation, meant for the patient. As physicians we tend to hold everyone to the same degree of understanding and that can be form the barrier in communication with patients and families. It is akin to a biologist speaking with an astrophysicist or an artist speaking to a Physicist about Quantum Mechanics (Something that he -the physicist, probably doesn’t understand either and then has to explain in metaphors), where the facts get bundled in the complexity of the detail. Sit down with the patients and their families, face to face and mete out the difficulties one by one.

Patience is a virtue for all things underneath this wide canopy of blue. A polite conversationalist never interrupts. So it behooves a physician to listen, direct a conversation to pertinent issues and never hide ignorance behind medical dictionaries. Somewhere in the vast literature of spilled ink is a statement that extols the virtues of honesty. That is good for both, patient and the healer. Recent graduates and others with some years under their belt should NOT emulate TV actors in House MD as models for communication. It is good drama but bad bedside manners.

To all things complex such as a consolidation of multiple diseases, a measure of simplicity and a dose of commonness is needed in discussing the ramifications of the malady with the patients and their family. Look them in the eye and behold the lack of understanding and then explain, until the glint and glimmer of “Aha!” is achieved. Understanding involves bringing the patients and their families into the circle of awareness. With that awareness comes the recognition of the complexity and the efforts that are being undertaken on the patient’s behalf to conquer the disease and save his or her life. Communicate with exquisite thoroughness and with mastery of each spoken word! The listeners are hanging on every nuance and word uttered by their physician. Make your words worthy of their attention. There is a difference between a robotic reciting of medical science and a human discussion, the same as there is a difference between a guideline-algorithm and excellence of care.

Understanding Cancer Metastasis

A dividing cancer cell

A Cancer cell is a pale cast of thought, pregnant with desire, packed with motive and reasoning more murderous then all ill-intent!

It was a cool dark night. Not a chirp from a bird or a howl from an owl. The trees were still. The flowers limp with dew. Not a soul inhabited the streets, save one dark shadow. The face masked and with gloves to cover all skin only the windows to his cloaked soul shone through. He weaved in and around the trees after stepping out of his bungalow; lurking behind the walls of other homes, seeking opportunity and stealth. He let out a soft bird-call that was answered immediately from beyond and another shadowy figure emerged and as quickly disappeared into the thicket of darkness. The game was afoot. The object of their desire was the wealth in one lone house perched amidst the weeping willows and the might oaks. That house was silent. The dog lay sleeping in its little abode guarding only its midnight dreams. One of the robber crossed the street and with speed and an artful craft making nary a sound, he jumped the fence with ease, crossed over and threw a half-eaten steak in front of the dog that barely stirred, to rob him off his scent. He then proceeded carefully, using the dexterity of his fingers and the learned manipulation of a simple right-angled tool and opened the multi-pronged door lock. A hiss sounded and then a low tone. The place was alarmed. The other robber appeared from beyond the shadows and moved to the opposing wall panel that housed the brains of the alarm system and using a cell phone and two wires hijacked the system into quiet obedience. Again with light-footed efficiency and agility one walked straight to the library, unhinged the gold-framed photo of the owner and behind it exposed the safe – the heart of the owner’s life-long enterprise. The safe was no match to his ingenuity. It opened without a squeal or clamor. The other robber surreptitiously and without so much as a sound gathered other valuables. A life was undone.

Imagine the cloaked robbers as cancer cells. It is the same sociopathic behavior of ingratiation without lack of empathy for the host and a constant self-perpetuating desire. That same motivation feeds both. It is how cancer spread (metastasizes) occurs. Surprised? You shouldn’t be. Let us take a short journey into the fledgling field of metastasis.

The cancer cell, like the masked, cloaked robber uses similar stealth and tact to circumvent the host defense, for there are many hurdles that favor the normal organs against the spread of disease and all have to be neutralized one by one. [Italics represent quotes from various studies listed below in references]

Spread: A. Primary tumor, B. Local invasion E, Lymphatics D. Blood vessel, F. Fascia

First Hurdle: The cancer cell has to grow and multiply. For this, it co-opts the vascular system (blood supply) and releases hormones in its environs. It also, through communications within the normal surrounding community of cells via cross-talk, establishes a quid-pro-quo relationships in the form of, “I am here, you are here, lets be friends” kind of way. 

Soon having established the groundwork for attaining the nutrients for itself to grow, it manipulates its neighbors into transitioning from their normal functioning selves into cells that unknowingly and inadvertently help in the choreographed dance of stealth and duplicity. There is a close relationship between the metabolic needs of the cancer cells and that of the host micro environment. Not only do the metabolic needs of the cancer cell but those of the host human plays a significant role in perpetuation and progression of this disastrous of all maladies, they also enhance or suppress it:

“Genetic alterations that are associated with cancer often occur in these same signalling pathways, which suggests that both environmental and genetic factors influence the metabolic heterogeneity that is present across tumours… Indeed clinical studies have linked altered whole-body metabolism to cancer development, progression and poor treatment outcomes. Indeed, obesity, hyperglycaemia and insulin resistance are all associated with an increased risk of developing cancer and are associated with worse clinical outcomes in patients with cancer… Increased circulating levels of insulin and insulin-like growth factor (IGF) have been linked with cancer pro-gression, which suggests that obesity and insulin resistance promote cancer at least in part by activating signalling pathways that drive cell growth. These same signalling pathways also drive nutrient uptake into cells and regulate enzymes in glycolysis, which implies that hormonal changes can have important indirect effects of cancer. Furthermore, elevated levels of glucose alone may promote increased glucose uptake in some cells, and lower circulating levels of glucose are associated with better cancer treatment outcomes”

The well known Warburg effect after Otto Heinrich Warburg, who hypothesized that the cancer cell needs two pathways for survival: the glycolytic pathway whereby the cell breaks down the glucose to obtain energy and the Lactic Acid pathway, whereby the cancer cell needs to eliminate the excess byproduct of glucose consumption (waste product), is alive and well. Targeting both sides and not affecting the normal cell is a challenge that consumes many in the field of oncology.

In the same context, Insulin Growth Factors (IGFs) are shown to increase tumor proliferation by activating the phosphoinositide 3-kinase (P13-K) pathway. This pathway is affected by the nutrient availability and the pathway signaling inhibition by drugs downstream can be impeded by the excess of nutrients, thus the signal once impeded by such an overabundance of resource, may not reach the target inside the nucleus to initiate growth. An agent that seems to influence the m-TOR, a downstream path, of the P13-K pathway is a drug called, Rapamycin. However in the presence of excess nutrients, such as, glucose the efficacy of Rapamycin is compromised. It is thus important for the human host not to indulge in food and therefore obesity. Excess food and thus obesity are confounding factors that help the robbers rob!

In a recently discovered entity dubbed the Epithelial-Mesenchymal-Transition or EMT, the E to M phase transition can also go from M to E  (MET) and indicates the fluid flow of cells morphing by desire and motivation, by acquiring properties of others that have better abilities to migrate, invade and spread.  All of these phase transitions within the cancer environment occur for the sole purpose of mitigating any difficulties for escaping the firewalls erected by the basement membranes and other fascia as defenses  within the host.

Some cancers like the alveolar cell carcinoma of the lung and the clear cell carcinoma of the ovary have a field day in “spreading” due to their proximity to an “open-field.” Both types of cancers also manipulate various cytokines and enzymes and by promoting such, they are able to modify the epigenetic system to abrogate the tumor-suppression algorithms within the DNA code from coming on board. The Phase transition, EMT is an aberrant activation of a latent embryonic Program encoded within the cells. This very deterministic behavior lends to self-renewal capability, antigenic expression and later, resistance to therapy and is the object of recent scrutiny.

“It is increasingly acknowledged that aberrant activation of a latent embryonic program - known as the epithelial-mesenchymal transition (EMT) - can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence [1-3]. Moreover, several lines of evidence have converged in recent years to support the notion that not all cancer cells within a given tumor are equal in terms of their tumor-initiating potential. The emerging paradigm posits that tumor progression is driven by a small subpopulation of cancer cells - termed cancer stem cells (CSCs) or tumor-initiating cells - that exhibit two defining characteristics: the ability to self-renew and the ability to regenerate the phenotypic heterogeneity of the parental tumor [4]. CSCs have thus been implicated both in initiating and sustaining primary tumor growth and in driving the seeding and establishment of metastases at distal sites… During normal embryonic development, EMT serves to loosen cell-cell contacts and to enhance intrinsic cell motility, thus paving the way for the extensive cell movements required for gastrulation and organogenesis… EMT can be induced by a plethora of extracellular stimuli, including hepatocyte growth factor, epidermal growth factor, platelet-derived growth factor, Wnt, Notch, Sonic hedgehog and transforming growth factor beta (TGFβ) as well as components of the extracellular matrix such as collagen and hyaluronic acid and adverse conditions such as hypoxia [1,3]. These diverse stimuli trigger a multitude of signal transduction pathways that converge on several EMT-inducing TFs, including Snail, Slug, Zeb1, Zeb2, Twist, FoxC2 and Goosecoid, many of which are frequently overexpressed in breast cancers”

The breast, it may be reminded, is an organ worthy of considerable study because it undergoes expansion and then involution for each pregnancy cycle and thereby provides us with an indirect indication of the presence of breast stem cells that undergo morphogenetic branching via many transcriptional factors during these single or multiple pregnant phases. Additionally, a family of Metastatic Tumor Antigens (MTA1-3) proteins that are also involved in the spread of breast cancer:

“The metastasis tumor antigen (MTA) family of proteins, MTA1, MTA2, and MTA3, are components of chromatin remodeling pathways with potential roles in breast cancer.” 

Using the genetic profiles of breast cancers, six different subtype populations of differing molecular signatures have been identified; luminal A, luminal B, HER2+, basal-like and  claude-like. Most chemotherapy drugs attack the cancer cells but do not address the de-novo or phase transitioned cancer stem cells that have evolved. An anti diabetic drug “Metformin” seems to address that directly by killing Cancer Stem Cells (CSCs). Now, that might be a direction towards cure should further studies confirm this violate action as being a true representative of going after the “culprit!” Imagine destroying the menagerie of propagating cancer cells with chemotherapy, targeted biologic therapy and then going after the sociopath itself! Thus based on the predicate, which stipulates that the primary tumor is governed by different sets of molecular rules from those of the metastatic cancer elucidates the realm of differential therapy with multiple “medical” and “surgical” scalpels. Better yet, if one can choke off the system completely without affecting the normal cells remains the holy-grail! Refining the sociopath and changing his or her motivation is a daunting path since it is difficult to determine who is who. It is a difficult task indeed. But understanding the needs and depriving the aggressor may be the simplest preventative measure towards success. We might just have to live by “Dunkin Broccoli rather than Donuts.”

Got you out of the comfort zone, didn’t I? Sorry. Let us walk a little slower. Smell the fresh air and take a deep breath once again. The entire orchestral symphony played by the cancer cell is a strategy for self-renewal and thus self-perpetuation. The cancer cell wants to survive and propagate. That is the code writ in its code. It thus manipulates its environs to suit its own needs. Just like the unmasked, and uncloaked man is a perceived normal functioning member of his household and of the larger community, yet lurking within him is the unseen evil betrayal. No one is aware, or even concerned that this mild-mannered sociopath is a burglar, aiding and abetting others to join his league. Acquiring these traits of using enzymes to cut through the jungle of basement membranes, fatty tissue, fascia and a dense arborized collection of capillaries and supporting cellular network, is like the prince hacking at the forest in search for Snow White, only this is not the prince but the witch using her unlimited powers to dissolve and destroy so she can govern and control the purity. The cancer cell makes its escape by recruiting host micro environment features, such as the Tumor Associated Macrophages or (TAMs) to help make the break through the jungle. TAMs have the ability to secrete various dissolving enzymes to clear the path for the progress of the cancer cell and confuse its own immunity police. Macrophages thus become the unwitting accomplices in the robbery.

Primary cancer, CTCs and distant Metastasis

Second Hurdle: The cell, having found a perch, now has to migrate longer distances to reach a source of easier nutrition and better residence. For that it has to find a vehicle of transportation. Various means are available for just such purposes. There is the lymphatic chain - slow, thin-walled easily invaded system. Cancers originating in the Colon, Breast, Melanomas and Lung are adept at such invasive coercions. Their travel through the lymphatics establishes new sites for growth and residence -in places wherever those lymphatic chains end – the lymph nodes (gateway of the lymphatic system). These lymph nodes, process the defense and measure of the cancer cell by using the elaborate mechanisms of immune surveillance and serve as the primary protective gate-keepers. They try to destroy and prevent the cancer cell from laying a foundation and a foot-hold.  It is by sheer misinformation and some disinformation that the cancer cell “fools” the host immune cells. Sometime it just uses sheer physical force of a large army to subdue and claim victory, as in leukemia. The more aggressive cancer cells find means to kill the joys of defense by insinuating themselves into blood vessels directly, mostly the venous system, since the veins are less thick-walled then the arteries. They reach the widespread circulation in the vascular system, traveling miles in minutes. 

Main Lymphatic System

The Main lymphatic system originating in the abdomen also ends up in the vascular system eventually, it is called the Cisterna Chylii and dumps its lymph via the thoracic duct into the large subclavian venous system on the left side of the neck. This is why there is a revitalized interest in the CTCs (Circulating Tumor Cells). The presence of the CTCs is object of renewed interest to try to detect their presence and decipher their vulnerabilities. 40% of all comers with breast cancer have spread of cancer cells in the bone marrow and an equal number of lung cancer in early stage I state have cancer cells in the pleural sac that lines the lung. No wonder there is recurrence in early stage disease at a later date. The “cat had already climbed out of the bag.”

One can detect their (CTCs) (cancer cells) genomic make up and fire targeted therapies at them in an attempt to cure. Although it may seem that the cancer cell has it all in its favor. Not so! Another hurdle for the free-floating CTCs in the blood-stream is that having lost cell to cell adhesion, in their free-floating mode, they rapidly undergo anoikis (apoptosis or cell death) When observed morphologically, it is unknown if these CTCs are alive, playing possum or just dead and effete waiting for the dirt heap. The cancer cell “Mission Impossible” smart, adaptive and self-protective, capability has devised elaborate special anti-apoptotic mechanisms by expressing Bcl-2, Bcl-XL or FAK genes, to keep itself alive from death till it finds a host tissue organ. The self-destruct message is not invoked that easily. No poof! Only more smoke and mirrors. Some of these cells may live in the body undetected for months to years and resurface again. It is well known that years later the same cancer, considered cured, can raise its ugly head and new molecular data seems to shed some light on this phenomenon. The argument remains whether it is the cell that clicks its machinery into action or the abrogation of responsibility by a taxed immune system that allows such spread, no one is certain just yet.

Third Hurdle: From the blood vessels migrating back into an organ is another deterrent for the cancer cell. There are two issues with this hurdle: One, for the cancer cell to re-invade the endothelial and muscular layers of the blood vessel wall to reach the outside reference of the vascular system is difficult and, two, to find a location where the cell is comfortable in its existence. (Someone who loves the beach will want a beachfront property and those desiring mountaintop abodes will find their destinies). So there is a “soil” issue that remains to be resolved. Oh yes these cancer cells are picky! The cancer cell has protrusions on its surface that look for target sites on the organs. For instance colon spreads to the lymph nodes and the liver, breast cancer spreads to the lymph nodes and the bones, prostate cancer spreads mainly to the bones. All these predilections are based on the “homing devices” the cancer cells carry on their surfaces. Not to say that the cancers do not deviate and attack other organs, they do, but the majority, behave in the fashion elicited for a reason. A transcription factor 3-gene being an adaptive-response gene may serve to integrate stromal signals from the tumor micro environment and in so doing bring the invader to its selected host site. Or in other words the signals from the host organ are received and processed by the cancer cell and appropriate obfuscating response is given to the host to confuse and thus allow easy access. (It is akin to throwing a steak to the dog). In Osteosarcoma (A sarcoma (cancer) of the bone) where 20% of patients have metastases at the time of initial diagnosis and 40% in later stage, 80% of the metastases are to the lung! Thus a special proclivity to spread to the lung tissue exists in osteosarcoma cancer cell.

“The metastatic behaviour of OS (Osteosarcoma) is very distinct as over 80% of all metastases arise in the lungs and other organs usually remain unaffected. This suggests that the circulating tumour cell specifically ‘homes’ to distinct molecules that are expressed on the endothelium of the organ of preference”

Fourth Hurdle: Once inside the organ, the cancer cell has to fight off the natural defense of cellular density (cramped quarters) within the organ of its desire. Again the EMT and MET come into play at the host site.

 “A critical molecular event underpinning the dissolution of cell-cell contacts during EMT is the loss of E-cadherin, a key component of adherens junctions… The loss of E-cadherin releases β-catenin into the cytosol and elicits activation of the canonical Wnt signaling pathway [1,3]. Moreover, the impairment of E-cadherin function, together with the downregulation of components of tight junctions and desmosomes (for example, claudins, occludins, desmogleins and desmocollins) and polarity genes, contributes to the dissolution of inter-cellular contacts and the loss of apico-basal polarity… The ensuing reorganization of the actin cytoskeleton and the intermediate filament network and the acquisition of front-back polarity dramatically alter the cellular architecture, while the secretion of extracellular matrix components and matrix metalloproteinases remodels the extracellular matrix. Collectively, these changes disrupt the contiguity of the tissue epithelium and render the cells intrinsically able to migrate - independent of one another - and to invade the underlying stromal compartment by breaching the basement membrane”

It does so by “talking” to its neighbors and coercing them into allowing residence and ultimately though vascular fiat of co-opting the vascular endothelial factor release it finds itself a stream of palatable nutrition (Employing the same previously well-managed method). Cancer cells also block the immune network by sending alternate and confusing signals to the immune cells, (T and B lymphocytes, Dendritic Cells and the macrophages). While the first robber is decoding codes of protection, the second robber is sighting, gathering up the valuables and laying bare the foundations of an existence.

Dendritic Cell

“Tumour cells, either circulating or at the site of metastases, can modulate the immune system of the host in order to achieve a survival advantage. Down-regulation of cell surface receptor HLA class 1 is one of such mechanisms. This impairs the recognition of tumour cells by the host cytotoxic T-lymphocytes. Tumour cells can also induce the production of immunosuppressive molecules such as IL-10… Fas also plays a role in immune evasion. Fas expression leads to recognition by, and activation of cytotoxic natural killer (NK) cells and promotes elimination from the circulation by the host immune system.”

Additionally they send out alarms of inflammatory signals throughout the blood system. (IL18, NFkB, TNFa etc.) These cytokines have the ability to modulate the genetic makeup of the immune cells by bringing them in full force to bear on the enemy (in this case the cancer cell) and then by disinformation and direct assault causing attrition forcing the defensive host army to laying down the arms and capitulating. Thus the cancer cell kills the immune-surveillance for the single and simple act of self-perpetuation.

Hypoxic (low oxygen) environments are not conducive to most cells. Metastatic cancer cells reap the rewards in a low oxygen environment where they find themselves frequently, both in the initial phases when the framework of blood vessels have not yet been established and late stages of growth, where there are too many cancer cells in the center of the tumor where the co-opted blood vessels cannot reach by distilling out HIFs. They use hypoxia as a mediator to release (Hypoxia Inducible Factor) s HIFs to force other signaling proteins to modify the DNA to build more bridges over breached dams for their own survival.

“Low oxygen tension in the primary tumour is associated with metastasis in soft tissue sarcoma, cervix carcinoma and carcinoma of the head and neck. Multiple mechanisms may be involved in hypoxia-induced metastasis. Thus, hypoxia followed by reoxygenation may induce point mutations and DNA strand breakage leading to deletions, amplifications and genomic instability…Moreover, hypoxia may induce a temporary increase in the expression of gene products involved in the metastatic cascade, either through gene amplifications or through normal physiological processes by activating oxygen sensors, hypoxia signal transduction pathways and DNA transcription factors”

Every line of defense proposed by the host is subject to mitigation and denial of sustainability by the cancer cell. This co-opting mechanism is the hard and tedious work of Darwin’s old adage, “The survival of the fittest.” The cancer cell having acquired devious means, wants to survive. The cancer cell is unfortunately better equipped since it has understood the molecular machinery of survival better then the host has determined new adaptive lines of defense. There is more tit than tat. The fight between the host and its cargo of renegades, is a battle of intense planning, scrutiny, subterfuge and all out assault that rages in deft silence.

Therapeutic Options for metastases exist currently in the form of surgery (metastatectomy), radiation therapy, chemotherapy and biologic therapy. The former is surgical removal of the metastatic sites. There is proof at least in Osteosarcoma, and in Colon cancer where known only-metastatic cancer sites when removed (osteosarcoma metastases to lung and colon cancer metastases to the liver (in colon cancer, as long as no intervening spread or in-transit spread into lymph nodes has occurred)) yield better survival.  It is also well known that patients with concurrent metastases have a worse survival then sequential ones. The precept being that the cancer cell has already achieved multiple DNA transgressions in the former and acquires them later in the latter. The steps needed for metastases to occur in osteosarcoma specifically are detailed in the table below: (listed in references):

Steps of metastasis	Molecular involvement
Migration and invasion	MMPs
	m-Calpain
	Wnt
	Src
	Notch
(a) Anoikis resistance	PI3K/Akt
	Src/PI3k/Akt
	Src/Ras/MAPK
	NF-κB
	Wnt/β-catenin
	BcL family
(b) Apoptosis resistance	Src
	NF-κB
	Wnt/β-catenin
	Fas/FasL
Evasion of immune system	HLA-1
	IL-10
	Fas
Arrest and extravasation	CXCR4-CXCL12
	CXCR3-CXCL9-11
	CXCR4/MMPs
	CXCR3-4/Erk/NF-κB
Adherence	Ezrin/MAPK/Akt
	Ezrin/β4-Integrin/PI3K
	CD44/Akt/mTOR
Dormancy	Integrin-α5β1
	Integrin-α5β1/Erk/p38
	Bcl-XL
	IGF/PI3K
	ECM
Angiogenesis and proliferation	EGFR. PDGFR, VEGF, IGFR, TGF-β
	MMPs
	VEGF/Erk/NF-κB
	VEGF/PI3K
	EGFR/Src/Ras/MAPK/STAT3
	Src
	Integrin/PI3K/Erk1-2
	Wnt/β-catenin/CyclinD-Survivin

Understanding of this elaborate and intricate fabric woven together by a rag-tag group of wayward cells is the difference between life and death. The matters remain intricate and more and more complexity continues to be added to this heavy tome of discussion. The answer may lie at fundamental levels. There may be a final common pathway, or as we now know, there may be many layers to the finite bottom of this “rabbit hole.” Each step and each experiment brings us closer and sometimes inadvertently leads us further from the truth through the minutia of “discussions.” We will uncover that truth eventually and relegate it at some intermediate level of a “chronic disease’ and eventually to the vast heap of “past maladies.” Whenever the end-result, the journey is far from over and ripe for the taking.

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Matthew G. Vander Heiden Targeting cancer metabolism: a therapeutic window opens Nature Reviews Drug Discovery 10, 671-684 (September 2011) | doi:10.1038/nrd3504