Finding Bandwidth

 The art of simplicity is a puzzle of complexity. ~ Douglas Horton

It is a whispering metaphor like the curling smoke from a snuffed candle, lazy, aromatic and constantly evolving, this thought about genes and cancer. Yet the burnt wick and the ethereal smoke are real.

Back in 1948 a quiet man by the name of Claude Shannon  and another by the name of Ralph Hartley arrived at a law for Information Theory  that would hold Moore's Law hostage. they opined that communicating information would reach a limit because of two things; bandwidth and the Gaussian noise. By noise they meant distortion in its simplest terms. But bandwidth, now that was a surprise. While Moore had suggested the doubling of storage capacity of a computer chip every 18 months without limits, the funneling of that data was  through "narrow conduits." In other words it would be the "bottleneck" that would limit idea dispersion and not the density of ideas.

Kurzweil's extended dimensions of the Moore's Law

 Image from Discover Magazine by Mihaela Pertea and Steven L Salzberg.

And now we seem to be finding the same bottleneck in Genetics. Humans have a library of about 22,333 functional genes, this culled down from its ancient reminder that there were supposedly 100,000 of these on, off switches that make us, humans twitch.

 Image from Discover Magazine by Mihaela Pertea and Steven L Salzberg.

Everyday there is a new discovery of "this gene mutation leads to that." If one goes combing the various pathways within a single cell that get turned on and off on the whims of one, two or a multitude of genes, the computational algorithms become monumental. 

Furthering the dilemma is the interaction of the epigenetic influence via the microRNAs adds another layer of complexity to an already challenging incoherency in knowledge. And adding to that is the whole other "jumping gene" or "transposons" that hop around to find more diversity and a"fitter" state of being.

The intricate web of the miRNA 

We are left with so many triggers that it boggles the mind. I believe that is why Barbie of Ken's flame, famously said, "Math is difficult, let's go shopping."

Now before we go exploring this further, let me suggest a  metaphor that will help simplify a very complex web of interactions. Imagine if you will, a car. It is made out of many, many parts, like the sterling wheel, which, too has many different parts. But the beauty is that the combined efforts of all these parts, works. 

VW disassembled parts

You get in the car, turn the key or press a button and voila the engine comes alive. You shift the transmission to "Drive" and presto, you are on our way. Not forgetting that the engine itself is composed of many parts too, like the pistons, valves, combustion cylinders, spark plugs etc. And the you press the accelerator and with the flow of fuel into the cylinders, ignited by the spark from the plugs a combustion occurs that push the cylinders, that move the drive-train and the car goes in motion. Okay now that you have the concept, just imagine a few issues that might arise; if the radio doesn't work, it doesn't hamper the drive but the entertainment, if the horn doesn't work, the car still moves but there s a potential for an accident, if the power window doesn't work, well too bad, especially on a hot day, however if the starter didn't work the entire car would be useless and if the brake failed while the accelerator got stuck, then you would have a potentially bad day.

Okay now let's translate that into the genetic business. As mentioned there are several triggers that can create mischief in the human body but some of them are just a nuisance and not necessarily disaster, for example; a very wise scientist named Koch discovered that a single allelic (gene homologue on opposite arms of same chromosome) mutation of the RB gene does not create a disease. It does however weaken the defense against disease should some environmental shard of wrath come hurling out of nowhere and damage the remaining allele (like, an errant gamma ray of cosmic radiation).

Proving Koch's Postulate

So, what with all these shenanigans that the genes conspire, or are conspired upon, what exactly happens? The genes have both accelerators and brakes. As long as the brake-pads are not worn out , as happens with old age or with chronic immune deficiency state, the system works well. The brake-pads prevent a runaway scenario. Genes switch the circuit breakers on for accelerated growth as need by the tissue due to damage, replacement etc, the signal sifts through a maze of parallel intertwined pathways to arrive at the nucleus (the cell center). Here the resulting signal brings with it gobs of protein (the required building blocks ~ like Lego blocks) to create two from one. Once the proliferative mechanism is in place the cell divides and creates two identical daughter cells. After the feed-back loop mechanism signals back the lack of further need, the genes are notified and they either stop sending the signal for further multiplication or send the antagonistic signal to shut down the growth process, in other words apply the "brakes."

In cancer, however the accelerator mechanism can get stuck and thus override the brakes, the brakes may fail or both work and the cancer moves along slowly, surreptitiously at a timid but competent pace. In cancer, the accelerator mechanism is propagated by the "Oncogenes"  while the brake mechanism is activated by the "Tumor Suppressor" genes.

It is quite obvious that there are very, very few diseases (cancer not one of them) that one gene disruption causes the one disease for that gene or one bad gene = one disease. Considering that, it would be therefore impossible to known the many switches that exist for most cancers. Therefore it would be difficult to target them simultaneously and even if we were to do so, we wouldn't know the unintended consequences of messing with all those genes to the human body in its totality.

Medicine therefore has taken a different tack; why not attack the pathways that the genes trigger? A noble thought, wouldn't you say?

Well... And you knew this was coming...

I had mentioned that most pathways are parallel and arching with sprouting interconnections in between so these synapses of activity go to and from and back and forth between the various pathways. If one gets jammed, the other takes over. In cancer the latest venture as I mentioned is to target these pathways, but what we are finding is the ingenuity of signal transduction within the cell. If you block one pathway, the cancer slows down, goes into a temporary remission, even regresses to an unobservable entity, only to take wings and rise again. So what do we do? Attack some or a combination of pathways? or even all of them? Should we for instance hit them all concurrently or sequentially and if so in what sequence? There lies the conundrum, yet to be solved. But you see normal cells need the pathways too, to continue for their function and shutting them down will cause a problem for them too and in turn us, hence the deepening, disquieting dilemma.

One more thing to ponder then, while we are at it. Is it of great import to know your genome and will it serve the purpose of forewarning and fore arming against disease? Since genes cannot predict outcomes with 100% probability, the chaos in the mind would be up for grabs. 

However selective genetic knowledge for example knowing the BRCA I & II can potentially be life-saving for an individual who can mitigate the crisis with prophylactic bilateral mastectomies (breast removal) and oopherectomy (ovary removal). Maybe in the future we will be able to transfect the body with wild-type BRCA tumor suppressor genes via viral vectors, or use microRNAs to silence the mutated versions, that would obviate the need for radical surgeries. Now there's a thought!

Hope, human thought and ingenuity spring eternal!

Kinase pathways

Remember, I began with Shannon? The plethora of genetic signaling triggers  get bottlenecked at the known limited pathways within the cells. The triggers are many, but the paths are few and it will take an awful lot of hypothesis testing to use the right set of tools to enable some and disable others in this verity.

From time immemorial, man has desired to comprehend the complexity of nature in terms of as few elementary concepts as possible. ~ Abdus Salam

THE CURIOUS MIND

A rock pile ceases to be a rock pile the moment a single man contemplates it, bearing within him the image of a cathedral.~Antoine de Saint-Exupery

As I walked through the mind of the curious the other day, I thought, life isn’t like this. No not that but this. The trees, the grass, the flowers the buildings, none of this is like that.

Everything has structure, or so it seems. The trees that arise from the seed stretch out into the air in three dimensions. With sleep and rebirth year after year, as the tiny buds keep blooming every spring and lend a helping hand to occupy more space, they grow. Why yes, that is the this, that I know, not that; this is the colossal unyielding, unmoving giant with a million hands looking out for the sun, shaking incessantly with the breeze in a manner saying “no” to the forces beyond its control, but steadfast in its resolve to weather the storm. In that fight these mighty giants get sculpted into a different form. Nature bends them in order not to break, but always retains their character. They would seem as if they wanted to flee from the oppressor and exposing their soft underbelly of stark scaffolding that herald them up to the sky, yet, even with that exposure, they remain rooted in their foothold. Determined and resolved to persevere. 

But what of this thought. Imagination, isn’t it? How wonderful to see what the “discerning" eye cannot. How wonderful it is to behold a different perspective invited by the magic of thought. How simply magnificent!

The magnolia bloom littering the grass with its pink and purple color flowers readying itself for a rebirth, growth and expansion in a neatly arranged thought of cause and effect is not this. But that, another perspective as it taints it differently. Is it not the death of many a rabbit with the landscape littered with bunny-ears.? No, no, of course it isn’t the remains of a genocide of the rabbit population, but the fearful unrestrained emotional expanse of a blossoming mind. These are all the discarded thoughts fallen to the ground to find nourishment and fashion a rebirth of newer better more elaborate thoughts. Indeed the essence of a differing perspective. This view of the world is from a two-feet-six-inches rather than six-foot-two.

And no the large bush flowering Hibiscus plant is nothing more than that, a view to bring joy to the sight for mere mortals. The flowers are perfectly chiseled out of evocative red with elongated skinny styles and stigmata to attract the bees. But those tiny tongues are more like mockers, mocking the world as they “hang-out,” aren’t they? “Nah, nana, nah, nah!” No, these flowers with their bright colors are nothing more then dissatisfied, disenfranchised floral kingdom’s cast of actors that keep the world close to their saner angels. They teach us to stop looking at the stark sanity of the wretched and mull it over with the gifted cues of fairies and goblins. There is something more to that Hibiscus flower within that plant life. Isn’t there? There are gremlins amidst the colorful splendor. Indeed there is enchantment. It is a wonderland to behold. These are the actors on the stage strutting their stuff in colorful overtones, observing, sometime even laughing but always mocking our very stark, "as is" view of the world.

That stretch of green grass, with blades cut to the right length, is there to provide a softer cushion to the stepping feet, to lounge around on a summer’s day or play catch-ball or even stick-ball should the urge grab you. Or maybe not. The green chlorophyll exchanges of carbon dioxide for oxygen remains the valued asset for life’s survival on this planet. But no, these are natural canopies of great strength for the tiny little beasts that live under the green grass. These tiny beasts, the ants, worms and fleas all rework the earth to constantly feed the dynamics of mother-nature to renew more armies and even larger canopies. It is a constant rebirth beneath our feet. This is the underground economy of life that renews, reshapes and is reborn annually.

And oh the stories there are to tell when lost beneath the blades of grass. Prince Cornelius is no where to be found as Thumbelina looks for her beau in the vast green jungle where animals come to life and tiny streams serve as might rivers difficult to cross unless you have wings. Oh my the sheer magic of it all!

How little we know, I thought. Tinker Bell and her pixie dust do exist! This mind of a three-year old without the wink of confusion, or the nod of dissent has created a rule for the world as she sees it. There is nary a hesitation. Life is simply a game of shadows. There are actors who strut about in masks to hide their real faces and parade on the stage voicing the predetermined eloquence of written lyrical emotions. They are and yet not. But beneath it all is the vast undercurrent of thought that colors and re-colors our life that we work hard to deny. And yet, it is in that very essence of imagination that a process is born, a process to reshape our future. There is a story to tell and to this open minded beautiful child with Grace, the world has revealed its other more beautiful and powerful essence, its core of cores, its heart of hearts, its mystery of mysteries, it had unfolded its very soul of existence!

The fairy tale is indeed here for all of us. Sometime in the quiet confines of our own thoughts, when twilight alights and you let that concrete view imbue the essence of the otherworld, a change takes place that forces us to see the black and white transformed by the sprinkled hues of darkened color onto the drab and dreary into this magical kingdom. From that figment, come the spark of curiosity and a cataract of action, that changes us all. Oh for that tiny speck of imagination! Oh for that openness of the mind! Oh for the world through the filter-less, imaginative view of a three-year-old! But for that, the dimensions of ingenuity collapse into the flatter-land of this, our bleak existence.

Like the three-year-old, let your imagination soar and you might just throw some color into your own life and the lives of the rest of the world and make the future a better place for all.

 Can you imagine what I would do if I could do all I can? ~Sun Tzu

BAPTISM UNDER FIRE

Back in the days, you know those days, when time was irrelevant, nights merged into days and once in a while you saw the sun. The rest of the time was underneath fluorescent lights and walking past those germ repellent UV lights caressing the corridors. All you heard was “Paging Dr. So and So,” and visiting little children would laugh when they made up stuff amongst themselves for the garbled overhead announcements. The corridors were clean without any mechanistic large devices that regurgitated medicines upon a directive from the screen above, nor were there large covered shelves with clean laundry awaiting immediacy due to a spill. There were housekeepers that were quick on the call and nurses who mostly tended to the call-light overhead the patient-room door. The nursing floors were mostly empty save for the Ward Secretary who answered the calls and triaged them to appropriate personnel. The nurses were busy doing what they were trained to do, provide nursing care and not spending time documenting every hiss of the opening and closing door.

During those Shangri-La moments there were pulses of great chaos too. The Emergency Room was always filled with wounds, diseases and sudden illnesses. Coughs and Colds rarely wasted their time visiting.

On such a Thursday evening, when the shifts were changing and bodies moving from work to leisure and shoulders relaxing to shed the burden, I found myself on the side of a very sick lady. I was the medical resident and this one had arrived with severe abdominal pain. She was pale with fear, her eyes were wide open in pain and her body writhing without relief from the calamity within.

There are moments that are not quite ripe in memory. My next recollection is walking beside the gurney with the chief surgical resident on the other side and three nurses holding various equipments that proclaimed life had not escaped the host. The anesthesiology resident was astride the patient’s head as he ventilated her through an endo-tracheal tube and everyone’s eyes were glued to the monitor for the rapid blips that signified a beating heart. The next thing I remembered was my right hand inside her belly clamping the pulsating aorta. The surgical resident had determined that she might not make it to the Operating Room where we were headed in a frenzy, so rather than wait, he did what he had to do and needless to say, my gloved hands were there feeling the weakening pulsations of the aorta. Her posterior penetrating gastric ulcer had eroded into her aorta. The rest of everything was a blur. I remember seeing the UV light on the wall and then I remember standing in the operating Room for a long, long time. 

The attending physicians and the rest of the elite crew arrived and brows were mopped off the sweat, The smell of blood and guts was everywhere, the fading and strengthening heart monitor and the arterial pulse pressures, the pints of blood dripping furiously down the tubing, IV saline rushing through wide-bore angio-catheters into the subclavian vein like open faucets and the race to save a life was on. The clocks seemed frozen in time. The long arm stayed at the 12 O’clock while the short arm circumnavigated its face. One moment it was ten o’clock at night and then one o’clock in the morning and the next time I looked up it was six o’clock in the morning. I had a morning “Intake Conference” to present before the medical department an hour later. I did. I don’t exactly know what I said or how the audience received it. Sleep came with difficulty that night as time replayed itself in a frenzy. What was, what could have been and what should have been.

A few weeks later, on call for the night, I walked into the Emergency Room and found myself face to face with a young 19-year old girl. She was sweating and throwing up at the same time. She looked tired, worried, and fretful. After an evaluation and the appropriate tests an hour later, I determined that she was pregnant. A happy occasion, I thought, as I approached her with the news. She sobbed hysterically into a convulsive heap. Fortunately the nurse was there to handle the raw emotions. After tending to a few other easy patients, I took the shortcut and walked from the Emergency Room to the Resident quarters, which were across the doctors parking lot. The moon was out and everything was a silvery bright. From the corner of my eye, I saw a flash and turned quickly to see what that was. I saw a tall, rather large man brandishing a shotgun in his arms. He approached me from the side and said in the most menacing voice one can hear, “Doc, my girlfriend ain’t pregnant! You hear me. She ain’t pregnant! Now you go and do what you have to do, or I’ll make sure of a few things.” What do you do in a circumstance like that? I said, “Okay” as best as I could muster the air out of my lungs and through the vocal cords, and walked slowly back to the emergency room with him following at a short distance behind. I remember my insides shaking, actually convulsing, feeling that any moment a flash of light would be it. I walked as best as I could although my knees were buckling from fear. The muscles had absolutely no power and the bones felt heavy. I made it to the automatic sliding door and as I stepped in and felt the door close behind me, a sigh of relief escaped. I remember not looking back. I remember going to security and reporting the incident. I remember walking into the corridor past the emergency room and collapsing against the wall. I remember hearing some commotion in the emergency room and then all was silence. No reports, no police, no nothing. And then, “Hey, had a tough ER call?” from a fellow intern. "Just ducky." I thought.

On the Tuesday before Halloween, I was scrubbed holding a retractor while the surgeon attempted to pull the diseased gallbladder out. His hands were steady but he had a voice that would make you shiver and sweat. “Pull here,” he would say and after showing what he wanted with the retractor, he expected you to follow and then imagine what he was thinking for his next move. If you didn’t, then the invectives flew. Somewhere during that surgery, I saw the oozing blood in the surgical field turn a darker shade of red. Mind you, I was a lowly intern. So in the bravest of brave tones, I said, “That blood looks dark.”

“Shut up. Who asked your opinion?” Moments later the patient’s heart rate rose and the dinging from the monitor portended bad tidings. The anesthesiologist’s eyes grew wide, the surgeon’s hands showed a little tremor and they all anticipated what was next to happen. And it did. The patient had a cardiac arrest. I remember being pushed aside to the walls of the operating room and there, I stood and watched the bizarre pantomime. Everyone worked in unison. Not a motion was wasted. After an hour of this and that, the monitor blips came back in full vigor; the surgical pads in the stainless steel bowl became colorfully red again. Finally I remember walking into the recovery room as the patient opened her eyes. All was well with the world but for those frightful moments when she was asleep.

These moments are a few from the many that make a doctor arrive at his chosen destination of caring for the sick, the infirm, the unhealthy. There is more to it than meets the eye of an insurer or a bureaucrat isolated in the trepidations of a large governmental building. Learning medicine comes after you have given a bit of yourself. You as a physician realize, there is more to life than medicine, that people other than doctors are oblivious to the red oxygenated pulsating blood from the aorta, the convulsive moment of life and death, of humanity’s trigger from fear and apprehension, of anger and pain, of betrayal, of humility and finally of real purpose. 

The world that steadfastly conspires to denigrate this noble of profession, should consider otherwise. The trials and tribulations that precede becoming a doctor and then being one for life exacts a toll on them. Give these few dedicated men and women, what they deserve, a little respect.

HARMONICS

There is something about a heartbeat. The soft rhythmic melody that flows beneath the breastbone, harkens life. It is the quintessence of our being. The “lub” gathers the momentum and passion of the human soul and carries the weight for a fraction of a second and then with a Spartan precision throws the even-keeled burden into the deafening blow of the consummating “dub.” How wonderful to be able to hear it in its glory with your ears to the chest of another being. The beautiful rhythm, the repetitive melody and the soothing timbre all conspire to comfort a crying infant to her mother’s heartbeat.

The harmonics of the blood flow within the chambers and then the muscular force that beats in unison to drive the elixir of life far and beyond its reaches, is the consummate reflection of our being.

http://youtu.be/qYBtchCqPao

Not to far in the past I lost a couple of friends to unknown causes. They both collapsed into a lifeless heap. The first one in his fifties was trimming the tree branches with a electric trimmer and the other one was using the leaf-blower and hedge trimmer. Both collapsed in mid-movement and were gone. What happened? What brought on the calamities of these two disparate individuals. There was no known illness in either. Both physicians of quality and integrity and both lost to the world.

It dawned upon me that the commonness of these two events might have something to do with harmonics. I cannot prove it, I can only surmise.

Harmonics.

Ever sit down to the calming arpeggio laden. “Prelude in C-Major” by J.S.Bach.

http://youtu.be/zlAic9aPoqs

Listening to it you will find a certain comfort to want to listen to it again and again. The beauty of the notes of the cords played in different octaves is like a soothing, enchanting high priestess of comfort, massaging away the tight muscles of living.

In recent day music, Coldplay, a musical group has encompassed that beautifully in many of its songs; “Viva La Vida”

http://youtu.be/vOxfNxzBGBU

The rhythm and resonance of the large audience symbolizes the connection to their souls.

or, listen to the equally wonderful, “Every teardrop is a waterfall.”

http://youtu.be/1Kf_6BWcOOg

This is another beautiful melody that shimmers just above the undercurrent of a warm harmony. It keeps you tapping to its even beat.

There is something about music, which is proprietary in its finesse. When listening to it, all extraneous movement is arrested voluntarily. The listener’s focus and attention gets directed inwards. The doors to the chamber of thought are closed and the echo of the melody takes over. It resonates with the harmonics of the soul. All extraneous reference is rendered moot, cast away with abandon. It is only the melody and the harmonics within that remain.

If you listen and not just hear music you will find the ghosts of Christmas past and with them, all the joys, smiles, laughter merging with the tears to become one. The line between good and great is crossed. There are such beautiful musical creations that invoke feelings like this within. The classical fugue is the Concertos for two Violins by J.S.Back where point and counterpoint keep you alert and alive to the harmonic dialogue. If you listen carefully the background melody is repeated as the foreground melody counters both itself and the product of the background. It is fascinating in its creation and only a master could have managed to hold together this variegated castle of incredible beauty. Listen to it and rejoice in it. It will fill your soul. But through it all this music with the rub of the strings will resonate with the rhythm of your heart.

http://youtu.be/Fo0K_n3VLG4

But then, there is the violent side of music that jars. It compels all our essence to hide behind itself. The violence is not tempered, the notes thrash at each other, the harsh dissonance increases and makes one uneasy. It raises the blood pressure and the heart rate. It evokes sentiments of anger. We listen to it and it puts us in a disjointed frame of reference. It is music of another mindset. Yet it is music, of another culture for another culture. Seeking harmony and comfort is not in it. This is designed for a different purpose. It violates comfort. It awakens. It brings out emotions of despair and anger.

http://youtu.be/K_1hLiqwq7c

  

So you might agree that music affects us all in many ways. The harmonics are everything. Precisely there is where it got me thinking. Maybe the harmonics of the two instruments that my friends were using clashed with those of their heart rhythms and that clash caused the final act. Maybe the clash of the harmonics created a sudden change in the harmonics of the heartbeat and a convulsive ventricular tachycardia emerged, turned into a fibrillation from the resonance and blood ceased to flow? Maybe, the dys-arrhythmia played a role, because autopsy of one showed no direct or indirect causation. But this is just a hypothetical and we will never know. But maybe, just maybe, given how music affects us all, harmonics were at play.

Let me take you down another lane of thought. An interesting study conducted on succcessive monitoring of the R-R intervals of EKGs over 24-hour period as stated on the website: "The time series belonging to the first two groups (healthy and congestive heart failure) are all in sinus rhythm. Those in the third group (a1rr, a2rr, a3rr, a4rr, and a5rr) are provided as examples of a cardiac rhythm that is not sinus rhythm; in that group, the rhythm is atrial fibrillation (AF), an atrial arrhythmia producing an erratic and typically rapid ventricular response. All of the time series were derived from continuous ambulatory (Holter) electrocardiograms (ECGs)" show interesting rhythmic intervals between a resting hear rate that has a flow and balance to it as compared to one with congestive heart failure where 2% premature beats were recorded and a exaggerated baroreflexive state and atrial fibrillation.
The recorded views are presented below:

Normal EKG r-r interval

Congestive Heart Failure r-r intervals

Atrial Fibrillation r-r intervals

One immediately notices the stark differences in the three rhythm scenarios. 

We all live in the constant feed of doubt and I am sure there is plenty here for you to mull over. But below is a beautiful melody crafted on the harmonics of a heartbeat. Listen to this and allow your heartbeat to slow down. Soul cleansing!

http://youtu.be/btk5gAU9tQo

Music therapy has become an especially important feature to control psychosomatic side effects to medical managements and Bettermann and colleagues in their paper, “Musical rhythms in heat period dynamics,” (http://ajpheart.physiology.org/content/277/5/H1762.full) argue,” …experiments should include percussion (at least finger tapping) or dance to reproduce the rhythms and should pursue the question whether distinct physiological rhythms can be specifically amplified. This positive physioacoustic feedback or rhythmic resonance may be of great potential use, in particular, for the evaluation of music therapies.” They go on to say that African music is the heart beat of music per se, stating bluntly, “From the point of view of African cultures, music rises directly from the inner dynamic of human beings, which is symbolized and brought forth by the human heartbeat.”

http://youtu.be/9o0aRe1LpMY

Speaking about the convergence of music across continents and platforms, the essence remains the same. The beauty of the Seven Notes that create the magic is evident in this phenomenal musical video of Peter Gabriel and Nusrat Fateh Ali Khan. The melody shifts, reaches, falls and then is reborn while the harmony lingers long after the song is over. There is definitely something about music that reverberates in the human soul. There is something magical.

http://youtu.be/3eq2st8e_IQ

Don’t you think?

PD-1 and CANCER

We are the human race, the quintessence of dust, and the paragon of all life. We build bridges, roadways, industries and castles. Some of the castles we build are fortified with steel, mortar and bricks, while others are more in the mind. We build the ones in our minds with reason. This reason is based on an interplay between known and imagined, hypothesis and evidence, now and then, emotion and cognition. In these castles we house all our plans for the future. Barring the wrongly placed beams and windowsills that open into other facades without a hint of any landscape, where we can get crushed under or trip over and never come face to face with ourselves, here in this nebulous world, we are also vulnerable to high praise and effusiveness.

The first salvo against the Immune Checkpoint pathway was directed against the CTCL-4 cells in Malignant Melanoma with a drug called Yervoy (ipilimumab). This resulted in spectacular results in metastatic melanomas unseen previously with other concoctions of chemotherapy, hormones and Cytokines. That was and is worthy of praise. This is a follow through to that story. 

Imagine then my delight upon hearing about this new glint of miracles called the PD-1 and PD-L1.  New and novel targets to arrest, handcuff and incarcerate the ugly beast called cancer. Now here is a castle worth building.

So what are PD-1 and PD-L1:

Programmed cell death 1 ligand 1

Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production. PD-1, which stands for Programmed Death 1, is another compound in the CTLA4 family.  

Flowcytometric data

PD-1 is, for all practical purposes a “programmed cell death” receptor present on the Immune cell, a T helper (CD8) lymphocyte.  Okay, so why does this get my brain to sing?

Because...

Back in the yesteryears when sophistication was just a word and it implied what a woman wore to a party and how she behaved, today it has many different meanings. The ongoing rhetoric then was that certain cancers seem to follow a surprisingly different mode of action. For instance, Malignant Melanoma a deadly skin cancer would present itself, be cut out of its habitat on the human skin and then many years later it would surprise everyone especially the patient with a recurrence in a different organ. A similar scenario played out with Renal Cell carcinoma or Kidney cancer. The surgeon would take the kidney out and all would be well, until it wasn’t. 

Immune surveillance by T helper type 1 (TH1) cells is (not only) critical for the host response to tumors and infection…

Something did not sit well with the specialty of then, modern oncology. They suspected it had  to do with immunity and with little in their arsenal, threw everything available at it ~to subjugate it. In both of these above mentioned illnesses a concoction of Interferon and IL2 (Interleukin-2) were used. These are cytokines derived naturally (mass produced in the labs later) from a human host in response to a viral infection. Well in a small percentage of patients (less than 14%) it worked, but no one could put their finger on the "why".

Cell-mediated immune responses are initiated by T lymphocytes that are themselves stimulated by cognate peptides bound to MHC molecules on antigen-presenting cells (APC). T-cell activation is generally self-limited as activated T cells express receptors such as PD-1 (also known as PDCD-1) that mediate inhibitory signals from the APC. PD-1 can bind two different but related ligands, PDL-1 and PDL-2. PDL-1 is a B7-related protein that inhibits cell-mediated immune responses by reducing the secretion of IL-2 and IL-10 from memory T cells. This suggests that PDL-1 may be useful in reducing allogenic CD4+ memory T-cell responses to endothelial cells, thereby reducing the likelihood of host immune responses to allografts. At least two isoforms of PDL-1 are known to exist; this antibody is specific to the larger isoform. PDL-1 antibody has no cross-reactivity to PDL-2.

Immunohistochemistry of PD-1

Anyway not to belabor that issue, early this summer the scientists came up with antibodies to the PD-1 receptor and its Ligand (a mirror image that fits like a puzzle piece onto the PD-1 called PD-L1 or (“programmed cell death Ligand”) Interesting as it might seem that some cancer cells carry this Ligand protein on their surface (like bees to honey); A most surreptitious mechanism to evade immunity employed by the cancer cells. An ingenious self-protective act, this, most interesting of unities shuts down the immune pathway for surveillance against infection and cancer.

Immunofluorescent Flowcytometry

The programmed death-1 (PD-1) pathway has emerged as an important tumor-evasion mechanism. The two principal components of the PD-1 pathway are PD-1, an inhibitory receptor expressed on the surface of activated T cells, and programmed death ligand-1 (PDL-1), which is expressed on cancer cells. When PD-1 and PDL-1 join together, the T cell’s ability to target the tumor cell is disarmed. Thus, targeting either PD-1 or PDL-1 can stimulate the immune system and enhance T cells’ ability to lyse tumor cells.

Cellular proliferation model via PD-1 pathway

Using mice as models to establish the link between immunity and recovery from infection, the PD-1/PD-L1 complex so used, resulted in florid infections and the clearing of the infectious organism from the body was markedly delayed, hence the infectious organism grew within the mouse at a rapid rate. And if cancer was introduced into this mouse model, it also grew at a fairly vicious unchecked rate. This implied and with good reason that the cancer cell growth as well as the infectious organism was uninhibited by the “lack of” immunity in the mouse when the complex was added. This implication has been previously confirmed and ratified from several differing sources, indicated strongly that immunity puts the cuffs on cancer growth and infection, until it, the immunity, gets overwhelmed or side-stepped via deviant mechanisms. But here came the reasoning also why the cancer cell was able to escape this prison cell of body’s manifest resources. An analogy would be; the cancer cell surreptitiously using a clever tool/key was able to lock the room where the guards slept and continue to ravage the house.

Immuno-blockade of the PD-1

To everyone’s delight, came this news of an Anti PD-1 antibody (created in the lab) that is directed specifically against the Immune cell’s PD-1 surface protein that prevents the immune surveillance from being restrained. The data from recent studies proved that if one was able to unlock the door to the guard room, the guards would defend the fort. And they did! Lacking that as if adding the PD-1 antibody, things went awry. Patients who participated in the BMS-936558 (the PD-1 antibody) study and were given the PD-1 antibody (to unblock the T(helper) cells) had longer survivals and durable responses compared to those who did not receive this magic bullet. Voila, here was the clinical translational evidence of a scientific hypothesis. We still however, had to deal with the beams and the windowsills though.

Cancer cells and the T-Cell/APC interaction

There were a total pf 296 patients accrued in the study. Objective responses, as measured by standard RECIST criteria, were observed in patients treated with BMS-936558 across dose cohorts and across the NSCLC (6% to 32%), metastatic melanoma (19% to 41%) and RCC (6% to 32%) tumor types. Most responses were durable with response durations = 1 year in 65% of responders with = 1 year follow-up. The most common side effects were fatigue (24%) rash, (12%) and diarrhea, (11%). A First in human Phase I trial of the BMS-936559 against PDL-1 has shown durable responses with increased disease stabilization in heavily pretreated patients.

Infectious virus and the Immune mechanism of action

However there were two deaths that were directly related to the use of this PD-1 antibody. Both the deaths were due to florid pneumonia. That may seem unreasonable at first blush but looking at the mechanism of action, it becomes obvious.

Studies have demonstrated that PD-L1 on APCs (antigen presenting cells) can control peripheral tolerance and anergy Interestingly, PD-L1 expression on tissue parenchyma can protect against autoimmune pathology in diabetes models. The PD-1/PD-L1 pathway plays an important role in influencing T cell dysfunction and viral clearance during chronic viral infection.

Interrupting the immune surveillance will prevent the normal human host defense against an infectious bacterial agents and parasites as well. And that is exactly what also happened.

In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.

The difference between the anti PD-1 antibody therapy was that there were delayed cases of Autoimmune disease. This implied that blocking the PD-1 leads to an “overjazzed” immune surveillance later, that targets normal body cells downstream, whereas the anti PDL-1 antibody restricts immediate protection against the infectious organisms. We are learning where the badly placed beams and the windowsills are. We need  more experimentation to find the rest of these misplaced architectural anomalies.

PD-1 and PDL-1 antagonists in Production and Trials

The obvious question that lurks in the mind is, what is the future for this Anti PDL-1 and anti PD-1 antibody? The answer is simple; it is another piece to the anti-cancer puzzle. We can still one disease at the risk of inciting another one. Since the interlocking mechanisms of the body's modus operandi are fitted so cleverly by nature, harnessing one and not the other or the other can and does have unintended consequences. Having said that, the unintended consequences are hazards, once known become identifiable risks that can be mitigated. So moderate speed ahead as we carefully untangle the vines across the many paths that lead to this dreaded disease.

How substance, action and mode unite,

Fused, so to speak, together in such wise

That this I tell is one simple light. ~ Dante from The Divine Comedy

References:

Scott N. Mueller, PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice J Clin Invest. 2010;120(7):2508–2515.

Butler NS, et al.Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol. 2011 Dec 11;13(2):188-95.

Shoba Amarnath The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells. Sci Transl Med 30 November 2011: Vol. 3, Issue 111, p. 111ra120

LaGier J and Pober JS. Immune accessory functions of human endothelial cells are modulated by overexpression of B7-H1 (PDL1). Hum. Immunol. 2006; 67:568-78.

http://chicago2012.asco.org/ASCODailyNews/CRA2509.aspx

Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6(3):280–286.

Tsushima F, et al. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood. 2007;110(1):180–185.

Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–895.

Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–245.

Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–687.

RIPPLE

The pulse and fade of the blooming ripple

The consequence of the structured and concrete mind is that it fails to dethrone the mystical powers of the reigning thought. No mater how much of a force is applied to it, it repels and happily continues on the path of ignorance. Some say it is strength of conviction, others think it is stubbornness of ideals. The gulf between the two remains wide. It is possible it is neither.

I came across an interesting story the other day. It propounded the theory that rabbits were causing a disease in humans. The disease was laced with all sorts of physical ailments. Looking deeper into the illness it appeared that the rabbits had nothing to do with the malady. It was the mere proximity of the rabbits to the humans. There was no established Koch’s postulate of cause and effect. So after rethinking the headlines, I came to the conclusion that the author had merely looked at the most superficial of matters and finding the premise of his prejudiced thought, he had launched into the headliner.

As the hours ticked by after the story broke, more and more people with little thought started tripping over each other to get a ticket on the sycophant train and inserted their opinion. All opinions added to the magic and mystique of this new found correlate. A few opined against the concept but they were quickly drowned out or laughed at or snuffed into submission. The chorus of accord grew and enveloped the whole state and then the neighboring states and then ultimately the whole world. Even the far reaches of civilized society found the rabbits as an abhorrent creature not worthy to feed the starving.

Headlines upon headlines sold countless newspapers. The rabbit population was hunted down and placed in sanctuaries, then annihilated, away from the humans. Their population dwindled and inevitable so did the owls, hawks and bobcats in certain regions of the world. The little fluffy bunnies on the shop shelves were packed in boxes and sent to the incinerator never to be redeemed. It was mandated that “the children psyche was a very fragile thing and the society must do everything to preserve and protect it.” The dictate was handed out that all bunny-related cuddly toys must be handed over to the government trucks that would drive by through the neighborhoods. Any remaining unreturned bunny toy if found in a household, would be charged to the parent as a violation punishable by prison and removal of the children to a foster home for their protection and safety. “Away from the evil uncaring self-indulgent parent.” The headlines stated.

On a bright sunny Sunday, a baby rabbit hopped out of its little cove beneath the decorative rocks next to a swimming pool and the baby girl playing with her alphabet blocks saw it. She squealed with delight and ran after it. Their ages matched in speed but the human child was more resourceful. Soon the girl had the baby bunny in her arms. She quietly took the bunny back into her room.

The father of that child, was the original author of the bunny paper, and the girl his only child. But closets are not safeguards for secrets, so eventually all things come to light, as they will.

The author now facing a serious personal dilemma of an inconsolable child and the mandate that he himself had articulated, went back to his original premise and found the large voids of ignorance he had propounded. He spent night after night to craft a repudiation of his original work.

The publication was greeted with great clamor and soon the high and the mighty weighed in stating that they had never believed in the original study and that the author must be barred from future studies. And so it was.

The fervor died down and the dwindled population of bunny rabbits like the tulips in Holland, became the latest greatest craze of the civilization across the globe. There were television shows, showing the rabbits with photo-shopped softened images, appealing to the human heart. The emotional appeal bled into every heart that saw the story unfold before their very eyes. The newspapers began advocating the wonders of owning the animal and the virtues of ownership, which lengthened human survival due to the contact between the two species. The fever pitch peaked and the rabbit once again became the Easter bunny to the children’s delight. The chocolate eggs were once again consumed in excess.

The tides had changed. The ripples of enthusiasm had shifted. The pendulum had struck its limit and reversed course. All this because of the shapeless, formless ignorance of one man, his personal ambition, glory and then, inevitable fall from grace due to his love for his own child. The “evil” scientist was imprisoned in his own personal hell and all was well with the rest of the world that found the culprit and exercised the punishment.

Once the minority opinion had dethroned common sense, now the innocence of a child had forced it back in again.

Like the ripples, the dream faded.

So it is in this world, that one might consider all points of view in any ideological debate, the story serves up an interesting challenge. We hail the latest greatest achievement, or so we think, and blinded by the success we conform ourselves into a closed impenetrable and unyielding boxes, to any opposing idea. We stand on the soapboxes and hurl invectives at any contrary opinion. We rile the masses into agreement, some with thought and a purpose but most without. If not for the contrary opinions, humankind would have evolved into a self-deluding race capable of a quicker self-destruction. If not for individual thought most would blindly and cheerfully be led to extinction. If not for thought, life would be in unbearable chains. Maybe that is what it means to "think outside the box."

So cheer the contrary opinion. Cheer the individual thought. Cheer another’s ideas. Find the truth or flaw in it with honest vigor before vilifying the messenger. There is much truth in truth and much flaw in prejudice.

The foolish are like ripples on water, For whatsoever they do is quickly effaced; But the righteous are like carvings upon stone, For their smallest act is durable ~ Horace