Monday, May 30, 2011

Trim your way into Comfort and Efficiency

Long before there were chain link barriers at the airports and long before there were restricted Airspaces popping up at will, there was a moment in time when all was well in the world of flight. You poured in the valuable fluid from the hose and it did not break the bank. You climbed into your personal airliner and more then one person winked at you expressing pleasure for your achievement. That was a heady time crafted within limits of sanity and unabashed in its desire to please any adventurer in his or her adventure. You wanted to fly and you did.

It was on one such day with an overhead cast of light and dark grey clouds that I set out for a flight of 60 nautical miles to take a trip on a multi-axis simulator.

I know you are probably anxious for me to describe what happened during that flight. Happily nothing at all. What did happen was when I walked in, head bowed into the confined space, buzzing with electronic equipment. The simulator was designed for a heavy jet, a Falcon 2000 replete with all the bells and whistles.
Falcon 2000

I sat down in the left seat as is the purview of the trainee in a disaster-free, non-scary, totally controlled situation of a simulator. Here is where you feel the Whoaas and the Ooohs, the whumps and bumps, the whoosh and thuds without the risk. Yup there is no risk of breaking a thing on this gigantically spacious (from a cockpit point of view) confine called a simulator. There is however the very real risk of pouring gallons of sweat, racing your heartbeat to the limits of the internal natural pacemaker and pulling off a neck-strain that one would, lifting the Empire State Building. Okay that was a minor exaggeration, but you get the point, don’t you? All because once you are in it, you are in it! It feels very, very real!
Falcon 2000 Cockpit

So I sat there all comfortable and tingling with excitement as the computer screens came online. Within minutes if not seconds, I was transported into that world of artificially real flying. Jazzing the juice of the make-believe kerosene into the engines that existed and were revving only in my mind, I took my feet of the brakes and with the gentlest of lurches I felt the forward motion. My back against the seat and I was leaving terra firma at a 15 degree pitch angle. The feeling was ecstatic. It was like flying my Mooney that I had flown in, only a thousand times more exhilarating. The smooth climb out as the altimeter tacked away the feet of altitude beneath me. I passed through some white puffs of happy and sincere clouds that made the drama of motion complete. “Wow!” is all I could say. My vocabulary was stunted to a three-letter word of exclamation.

After reaching the desired altitude of FL 350, I leveled off and happily made some gentle turns left and right. I caught my instructor smiling, I couldn’t smile anymore since my cheeks were pegged in maximally deflected grin mode, any more would strain the tissues at the corners of my mouth.

He (my instructor) said, “Take your hands off the yoke and see what she does”. I looked at him in disbelief. I wanted to fly it for the entire one-hour -every ticking second. But given his superior CFI over my then puny Instrument certificate, I yielded. What happened next (I know you were waiting for this) is a debacle of unprecedented proportions. You know when you have come to think like in those short few minutes, I had come to, of how wonderful things are and how terrific this ability to control this huge dynamo of aluminum from this cockpit and that I really should consider flying for an airline in my spare time and they, the airlines wouldn’t have to spend a nickel to train me and how I would wow them with my superior techniques, Well! The cockpit took a nosedive. The altimeter that had leveled at FL350 give or take a few hundred feet of vacillations that I believed were due to the kinks in the software, started to unwind at 3000feet per minute and that accelerated to 6000 feet per minute, until I whooaah-ed it and pulled on the yoke to bring it back into a positive climb.

So what happened? I looked at my instructor and he must have seen the big orbs of fright reflecting back his own image. While my grin had changed into some monstrous look of fear, disbelief and frustration all admixed with frown lines and dry open mouth ugliness, for his face seemed to have grown brighter and his smile now mimicked some diabolical grin. 
Elevator and Rudder placement and motion

“You see what happens when you don’t trim the aircraft?”
“Ah Huh?” I said.
“Well, in a rarified atmosphere or even at low altitudes the most efficient way to fly an airplane whether it is 3000 pounds or a 100,000 tons is to have it fully trimmed. That is why all airlines fly autopilot except for take-off and landing. The autopilot continuously monitors the external pressures, the winds and matches them move-for-move in keeping the aircraft trimmed. If they flew manually imagine the plight of the passengers.” He paused a minute for that to sink into my clouded brain. “And,” continuing on his monologue, “if you were to carefully trim the aircraft in non-turbulent conditions at any altitude the results would be efficiency and comfort.” There was a deafening silence except for the whirring and whizzing of the electronic equipment that now seemed commonplace. After an interminable silence, I was finally able to put one word in front of another and speak, “comfort, I can understand very well. What about efficiency?”
“An aircraft out of trim will constantly require the elevator and ailerons to adjust its flight path, right?”
Air separation from sudden motion due to changes in (AOA)
Angle of Attack

I nodded in agreement. Simple concepts are quite simple when spoken with simple eloquence aren’t they?
“Right!” I said.
“Well, every time you adjust the elevator up or down you create a momentary drag which robs efficiency. The drag slows you down and that increases your time in the air which robs you of the extra gas that is required.” His frugal conscience was ahead of its time by a few years. “Same thing happens when you constantly perform uncoordinated banks in the aircraft or yaw the rudder out of the desired slipstream.” He touched his cheek in repose and then continued, “Air is a fluid and the rigid body of an aircraft, though it may appear rigid deforms to the pressures exerted upon it. This boundary between the air and the aircraft is the aero-elastic boundary. This zone is constantly under attack by the aerodynamic forces in an attempt to maintain perfect flow and efficient symmetry. A poorly trimmed aircraft induces a greater degree of drag, which consequently slows it down. So imagine a fish as it glides through the water with a damaged fin? Not only can it not glide properly it becomes lunch or dinner for a predator.
The Fish as an Airfoil with (CM) as Center of Mass and (CB) as Center of Body

“Fish,” he goes on to say, “have the innate ability to utilize turbulence and vortices in the water to their advantage by maneuvering with their body, tail and dorsal fins. Fish are inherently unstable in the water and need constant state of propulsion to maintain the glide or the hover. 

Pectoral Fin of a Fish

Any damage or misalignment to the dorsal fins will prevent hovering and maneuvering, creating a more chaotic struggling motion that brings in the predators.”  He looked over and said, “I was in the Fishery Dynamics business before I considered flying.” Oh that explained a lot. I know how to swim a little but it was flying I was mostly concerned with. Yet with that metaphor he had made a point. I did not want to be a fodder for nature’s wrath in robbing me of my fuel in getting to my destination! Smarty pants got his message across! (Notice, I use the word glide. It is very apropos to the function of drag created by an aircraft in air and a fish in sea). "To maneuver through any medium," he went on to say, "you have to glide as effortlessly as possible with the least "foot-print" (aeroelastic boundary) exposed and like airplanes, fish create similar vortices in their wake. So why not use them metaphorically to understand." This was an educated instructor!
Vortices behind a Fish

Plankton's vortices

The “Ah!” escaped out of my mouth without the “huh.”
I went about quickly trimming the aircraft into a stable flight. I had learned a valuable lesson. And then all of a sudden, hell broke loose! His hands were hovering around the circuit breakers! But that is for another day.

Flying back home that day with my blue colored shirt rigid in places with streaks of white salt, I hand-flew my trimmed Mooney as it slipped under the belly of the thick overcast at 10,000 feet. It was a new beginning! Ecstasy!

The lessons learnt were far more intense and etched some where deep in my brain. All I had to do was establish the “rut” in my memory banks to prevent it from fading.

And that leads me to the very simplistic of all arguments; practicing procedures is how you develop the “rut” in the brain. It is quite similar to the ruts that develop in ski races. So, when ever, I fly, I look to make it the smoothest most efficient and comfortable flight.

I sit in the right seat some of the times as I gently probe the efficiency of the left-seat pilot trainee. Oh but for the pleasures of teaching a lesson learnt!

So next time you find an incarnation of me in the right seat show him or her the hands-off flying you can do. You will make him or her delight in your ability and maybe allow you to become a “teacher” of the teacher for that moment in time.


George V. Lauder, Peter G. A. Madden Learning from Fish: Kinematics and Experimental Hydrodynamics for Roboticists International Journal of Automation and Computing 4 (2006) 325-335 Museum of Comparative Zoology, Harvard University, Cambridge, MA 02138, USA

Friday, May 27, 2011

AVASTIN and Judah Folkman’s Persistence.

Judah Folmann once said, “There is a fine line between persistence and obstinacy. I have come to realize the key is to choose a problem that is worth persistent effort,” He followed it with:  "Science goes where you imagine it."
Judah Folkman, MD

He spent his scientific lifetime imagining the concept of vascularity and cancer – or does cancer require additional blood supply to keep it humming? The answer to that question he got from his research was an unqualified yes and still is.

Perseverance... keeps honor bright:  to have done, is to hang quite out of fashion, like a rusty nail in monumental mockery.  ~William Shakespeare

Cancer cells need blood supply to grow and prosper in their own right. Since the growth of cancer cells is progressive, they outstrip the normal blood supply of their host -an example may be colon cancer. So once the blood supply limit of the host , in the case of colon for instance, has been reached, the cancer cells have an ingenious regulator called VEGF Vascular Endothelial Growth Factor) abbreviated to “Veggef” that they liberate into the blood stream. (The VEGFs are Glycoproteins consisting of A-, B-, C-, D-, E- forms and Placenta Growth Factor (PLGF)). 

The consequence of this product on the nearby tissues is that it actually promotes the growth of new blood vessels to form as new supply lines. 

Imagine an army on a battle-field, the main concerns with advances into enemy-lines is the ability to maintain the supply chain. Lots of resources are committed to that prospect. The loss of supply leads inevitably to failure and possible eradication of the advancing infantry battalion.

Consequently a lot of strategies are developed to disrupt the supply-chains by either warring factions. And equally so, lot of time and energies are devoted to confusing the enemy (for the cancer the host patient is the enemy and vice versa) on where and how the supplies are being transported.
The effects of the VEGF expressed from cancer cells

Cancer needs the supply-chain to be constantly revamped and enhanced to feed its growing mass of tumor cells. 

The VEGF released in the surrounding area gives birth to new unstable blood vessels which arborize to create a large network that can be seen on angiograms as a blush 
The Tumor Blush

(due to the amount of blood supply) and on PET scans as a glow
PET Scans

 (due to the rapid utilization of glucose by the cancer cells brought to it through the blood vessels). Sometimes in rapidly growing cancers outstrip even their own manufactured blood supply with the result that the central part of the cancer undergoes “necrosis” (Cell death).

Cancers on X-Rays will sometimes show a central echo (darkness) which indicates necrosis and is verified by pathological determination. Once the cancer cells have turned on the volume so to speak, their survival tactics change to the anaerobic method where they produce larger quantities of HIF-1 (Hypoxia Inducible Factor -1) to continue their growth patterns in face of reduced blood supply and lowered oxygen.
Gompertzian Curve

If you plot the growth pattern of the cancer cells they inevitably show a Gompertzian Growth Curve similar to population dynamics as pointed out by Laird in 1964. The Gompertzian function is defined by:

The initial phase is slow when the cancer cells are acquiring new blood supply, followed by a steep and rapid ascent which indicates a rapid doubling of tumor cell volume and that is followed by a slower rate of growth. This last phase has multivariate reasons for slowing down: the growth based on low or no oxygen, the growth limited by the pressures from adjoining tissues and central loss (necrosis) equaling the peripheral gain (new growth).

Q: So what has science done on the heals of Judah Folkman’s discovery?

A: Several compounds have been developed to thwart the VEGF released by the cancer cells.By far the most prominent of them is a compound called Avastin (Roche). Several studies have been undertaken to evaluate this drug. 

Let’s look at the benefits and risks of this particular medication Avastin (Bevacizumab):

Avastin is approved for treatment of stage IV metastatic colo-rectal cancer, metastatic or recurrent unresectable non-squamous cell cancer of the lung and kidney (renal cell) cancer.

Metastatic Colo-Rectal Carcinoma (mCRC):

Based on the pooled data from large studies the average survival for good prognostic patients with mCRC is about 17-18 months. In randomized trials comparing Avastin+IFL chemotherapeutic regimen vs. the IFL regimen alone there is an improvement of 7-9 months (26-27 months).  In patients previously treated with chemotherapy however, the benefits with Avastin were a modest 2.2 months when compared with equivalent chemotherapeutic regimen (FULFOX-4). The indications here are of some significance since the overall survival did increase lending to the veracity of the trial data. When overall survival increases in a given trial to the benefit of the drug under study, provided there has been no observer bias by front-loading of better performance patients versus those with poor physical states, younger patients compared to older patients, or some other confabulating circumstance then the trial data should be taken seriously. That is why the studies have to be considered in their entirety rather then just their conclusion.

However given the benefits one then has to look at the side effects related to the addition of the drug that potentially raises the survival time. Avastin is known to cause some side effects that occurred between 2-20% of the patient population with about an equal number  (8.4-21%) of patients declining further treatment due to the complications.

These facts in cold hard currency of understanding suggest that a 7-9 month survival is associated with a 20% risk of complications that are severe and potentially life threatening. The foregoing clist is not complete but the most harsh ones are listed and are present irrespective of the organ site being treated. In other words whether it is colon or lung or kidney the treatment itself can induce such complications.

1. Gastrointestinal perforations and fistula formation. (Stomach or intestinal rupture followed by in cases with communication with other organs or other parts of the intestine and vagina, cervix, urinary bladder etc.
2. Delayed healing of surgical wounds.
3. Severe bleeding from the colon, lung, vagina nose or even in the brain.
4. Severe Hypertension associates with Heart damage and strokes.
5. Kidney failure.
6. Blood clots inside veins (partly also due to the cancer itself).

All of the afore mentioned complications can be monitored judiciously by the treating physician and successfully abrogated.

Non-Squamous Non-Small Cell Lung Cancer:

The E4599 trial showed both a (PFS) Progression Free Survival and (ORR) Overall Response Rate and modest (OS) Overall Survival improvement:

In (non-squamous) (NSCLC) Lung Cancer the benefits were even modest to a 2.3 month advance in overall survival when compared with standard chemotherapy of Taxol and Carboplatinum. 

The squamous Cell Lung Cancers had a higher incidence of life-threatening pulmonary bleeding, hence patients with such diagnosis are excluded from anti VEGF therapy.

The cavitating effect secondary to necrosis due to therapy.

Kidney Cancer (Renal Cell Carcinoma):

In Kidney Cancer there was a significant progression free survival of 10.2 months compared with 5.4 months in patients treated with Interleukin-2 alone. However the overall survival was improved by 2 months only from 21 months for IL-2 alone to 23 months for IL-2+(A)vastin.

Breast Cancer:

The much discussed indication of Avastin against Breast Cancer came to a boil in December 2010 when the FDA Panel reversed itself and rejected offering Avastin to metastatic breast cancer patients citing “no advantage in survival but with significant side effects.” It appears based on the large studies, which support that contention. There was and still is a hue and cry about this rejection from both patient advocacy groups and certain physicians, yet on its own merit the argument appears sound and justified.  The issue raised is one of Quality of Life Improvement in patients treated with Avastin versus the dangers of life-threatening Side Effects. Here the benefits clearly flatten the curve, so to speak and since there is no benefit in overall survival, the real truth based on data points available, show that Avastin in Breast cancer is a non-event.

Roche (+Genentech) is now seeking the use of Avastin in Ovarian Cancer as a first-line therapy advantage, claiming a delayed progression free survival and improved quality of life. 

The data are to be presented soon from the OCEANS Trial  which will set the stage for potential FDA approval. The preceding trials including ICON-7 seemed to suggest some PFS (Progression Free Survival) improvement but did not elaborate on OS (Overall Survival). 

The E-2100 study (above data) that preceded the OCEANS trial (accrual completed, results are pending).
Again the FDA approval will lie heavily on the potential for increasing the overall survival and not on a statistical marmalade. Progression Free survival without overall survival is in the minds of some, equivalent to better supportive care. The impetus must be on OS rather than on response rate, PFS (Progression Free Survival) or DFS (Disease Free Survival) to win the approval of US Regulatory body concerned with costs.  Roche’s pharma head Pascal Soriot said recently, "In Europe ... we are pretty confident because typically in Europe you can gain approval on the basis of good progression-free survival data. In the U.S., we still have to wait until the data are fully mature to see what the overall survival data look like and get a good sense for the FDA's response, but I have to say that what we have seen so far ... is making us relatively optimistic that we have a good chance in the U.S. as well.”  
Notice I did not include Quality of Life in this circumstance and that is where some issues remain. After all what is the benefit of a quality of life improvement without improving the overall survival? Therein lies an expensive question with an equally expensive answer in monetary terms. And that begs the question, after all, what is life worth?

Completed and some Ongoing Trials:

Trial ID
Trial acronym
Advanced ovarian cancer
Medical Research Council
Newly diagnosed ovarian cancer
Platinum-sensitive recurrent ovarian cancer

Speaking of costs a typical year-long therapy with Avastin costs around $100,000. There must be some bang for that expensive buck especially when vying for the public dollar.

So where do we stand or for that matter go? Is Avastin the Holy Grail that Judah Folkman once opined about? Or is it another expensive drug with marginal benefit? These questions at the outset when asked of the regulators and bean-counters seem to be answered in the negative but to that patient where the additional survival or quality of life survival is considered they are a life-saver. Emotions and arguments will sway public opinion both ways and ultimately the regulating body cognizant of the money issue will win as it always does. Anti VEGF therapy has proven Judah Folkman's dream. It is a "single" in baseball terms and four of those constitute a Home Run!


Laird, A ,K,  Brit J. of Cancer ,18(1964)490-50

Napoleone Ferrara, Robert S. Kerbel. Angiogenesis as a therapeutic target. Nature 438, 967-974 (15 December 2005)

Alberto Sobrero, Paolo Bruzzi. Bevacizumab Plus Fluorouracil: The Value of Being Part of a Developing Story. Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3660-3662.

Kohne CH, Cunningham D, Di Costanzo F et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol, 2002, 13, 308-317.

Kabbinavar F, Zurlo A, Irl C and Hurwitz H. Bevacizumab improves outcomes of patients with mCRC treated with IFL with or without bevacizumab independent of baseline risk. Proc ASCO, 24, 2006, Abstr. 3539

Sandler A, et al. A randomized phase II/III trial of paclitaxel plus carboplatin with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer.N Engl J Med. 2006 Dec 14;355(24):2542-50 E4599:

I. Rini, S. Halabi, JE. Rosenberg… Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206B. - Journal of Clinical Oncology, Vol 26, No 33 (November 20), 2008: pp. 5422-5428

GOG: ICON7 - A randomised, two arm, multi-centre Gynaecologic Cancer InterGroup phase III trial of adding bevacizumab to standard chemotherapy (carboplatin and paclitaxel) in first line treatment of patients with epithelial ovarian cancer

Wednesday, May 25, 2011

The Elephant Man

"I have deceived even your very eyes: what your wisdoms could not discover, these shallow fools have brought to light,--" William Shakespeare

Outside the ticket office a man dressed in red striped large bell-bottoms and blue striped cotton jacket is busy cajoling the customers to buy more tickets and add entry into various tents to see what surprises lie within the folds. People scurry along carrying their little ones on their shoulders while the loudspeaker playing loud music interspersed with the Ringmaster’s baritone calls to come and watch the “Greatest Show on Earth.”

A little child walking aside his father holding on to him by his hand pulls him towards the tent of the “Human Freaks.”  “No, Johnny, you don’t want to see that do you? There are much more exciting things out there. Look at the lion tamer and those people on the trapeze.” As he points to the giant billboards advertising the events. Besides entry into the Elephant Man tent requires another few dollars.
“But dad, I want to see the elephant-man.” Little Johnny protests.
“I am telling you Johnny, you wont like what you see.” The father gently tries to dissuade the child.
“Okay. We’ll go see him after the trapeze and the high-wire act that is starting now.” The father relents.
“Okay.” Johnny answers dejected in the procrastination of his demands but excited that he will be able to see the elephant-man.

A lone announcer dressed in a green striped jacket down to his knees and standing on three-foot stilts, with his head covered by a joker's hat, gestures towards the tent. Adorning the entrance of a vertically black and white lined tent are the words, “Human Freaks- The Elephant Man” emblazoned in gold. Johnny tugs at his father’s hand, without success.

Both walk into the main cavernous tent where the crowd is brimming with excitement and parades of animals, players in joker-type loud colored costumes and bright red shining noses walk the circular enclave, each person walking a different animal and all in lockstep to the drumbeat marching to the hypnotic music from the overhead loudspeakers.

“Ladies and Gentlemen. Please direct your attention to the silver coated wire above you…” And the act begins. A drama in very corner within the tent, interspersed with flame-throwers and large Python-carrying snake charmers. It is gluttony of spectacles and soon Johnny is enmeshed in the theatrics of it all.
As they exit the tent, Johnny remembers the elephant man briefly to make a meek protest, “But dad…”
“Lets go get that cotton candy, the white one that I promised you and then we can look at the animals in the cages, Okay?”
“Okay!” Johnny cries. His thoughts now firmly fixated on the spun-fluff of the cotton candy.

As they walk across to the food section a six-foot life sized poster of the face of the elephant man stares down at them with the caption. Johnny looks at the poster and quickly averts his eyes. “See Johnny, I told you that is not what you want to see. I mean who wants to see some ugly scary man.”
“But dad, I just wanted to see…” Johnny’s voice loses its fervor, “we all talk about him in school...” The poster still intrigues the sense of desire. The image is enough to turn Johnny’s stomach. But to see him in person, now that would be something and he can tell all his friends too. Johnny is lost momentarily in his thought, but just until the view of the cotton candy appears and dissipates all other thoughts.

Reaching the stall the father pays for the sugary delight and a happy son and father walk along the gaiety of the circus, oblivious to the sight of the elephant man, his grotesque features and his misshapen body. All left unseen. The father feels that the delicate senses must not be affronted by this reality. All of the elephant man and his deficiencies and nature’s ugliness should be left to the land of imagination. So it is with imagination that it makes monsters with time.
Father and son leave the circus happy in the circumstance of their recent endeavor, both regaling in the joy and sensations of perfection. Father animatedly talking to his son about all that they have seen to keep the sense of excitement from getting stale while the son walks besides him wondering at the empty feeling inside of him and wondering why.
Joseph Merrick "Elephant Man"

Johnny’s desire to see the elephant man and society’s look at medicine from a distance is one and the same. Medicine and the curiosity of the Elephant Man, both have been rendered, the ugly and grotesque and made into invisible monsters. 

Medicine has been discussed as the lone cause of what ails the society. The comparison to the grotesque by its very nature has made its practitioners garner the same repute. At first with tiny little cuts from outside it has been weakened to a state of malaise. As certainly as the Elephant Man’s much-discussed persona is debated, his tumors continue to grow. No one wants to see and seek a solution.
Joseph Merrick's handwritten letter

Tis true my form is something odd, 

But blaming me is blaming God;
Could I create myself anew
I would not fail in pleasing you.
If I could reach from pole to pole
Or grasp the ocean with a span,
I would be measured by the soul;
The mind's the standard of the man."
- Joseph Merrick. (The Elephant Man)

Joseph Merrick as a sideline died at the age of 27. He is purported to have a combination of "neurofibromatosis type I and Proteus Syndrome affecting Chromosomes 10 and possibly 18. He died of asphyxiation due to tracheal obstruction at a London Hospital in 1890.

Many medical practitioners and their business partners alike assigned to the lofty chairs of visibility have thrown their lot into the appeasement society. They have rendered themselves blind to the travails of what ails medicine. They sit and foster papers in journals about what their “feelings” are and how it would be a disparaging affair should this or that not be done to make medicine better. The reality is not one of those ivory tower maestros know what happens in the trenches of medicine where the real battles of life and death are fought. They are like the father who dissuades his son from seeing the real Elephant Man by distracting him with high-wire acts and a pleasure of cotton candy. No one wants to rattle the cage, or at least in some cases know where the cage is. No one wants to enter the tent where the elephant man sits. They all know he is there, they talk about him but fear that when viewed would send a pungent aroma into their rarified perfumed presence. They build images in their minds but none want to actually see. No, this view is not worth the price of the ticket. Let “him” sit in his secluded tent and we can discuss what needs to be done –ad-nauseum. And so the circus goes on. 

All the glitter and glitz of the fire-breathing drama of visual delights overtake the senses while the agony of the lone elephant man lingers within the chapels of his mind.

Stabbed by a thousand little cuts, medicine lies bleeding at the doorstep of sanity. The world is awash with ideas and mechanisms to fix it. Cries of foul play are heard and aspersions cast at it in the daily tribunes, times, posts and blogs. Nothing is done save for a few more statements, articles and oohs and aahs. Medicine is like the elephant man- warts and all, who sits in his tent waiting for the crowd to understand his dilemma and see who he really is, a person and not a monster, that he is worth understanding, learning and saving and not merely an afternoon of literary exposition. That, curing his problem will help the future. 

But the circus goes on and the elephant man sits quietly wondering how he will rid himself of the growing "carbuncles" that doom his existence.

One foot in sea and one on shore,

To one thing constant never."
- Much Ado About Nothing, William Shakespeare.

Friday, May 20, 2011


Oh Woe is me, T’have seen what I have seen, see what I see! ~ William Shakespeare

Where does reality end and fiction starts? Or is it a continuum of spectral shades? How can one tell the difference? Is there a dividing line somewhere?

Let me take you back to a time when things were not as complicated, a time when ease of understanding was based on the limited but growing food of knowledge. I call it food, for the simple reason that knowledge like food is what makes us grow. So then the subject, is too much knowledge, bad? The answer is the same as for food. In moderation and the right kind will keep us healthy and wise.
Berkley, Gloucestershire

It is 1796 and you are in the bucolic countryside of Berkley, Gloucestershire. The stories of people dying of this vicious disease have spread far and wide. The Variola vaccination practice imported from the Ottoman Empire in early 1700s by Lady Mary Wortley Montagu to Europe to help prevent the scourge of smallpox. Unfortunately the practice had far-reaching and damaging results with 20% of the 60% vaccinated with Variola ended up dying of smallpox. People now do not venture out of their houses much for fear of falling victim to the disease.
Edward Jenner

A country doctor named Edward Jenner has heard stories about milkmaids becoming immune to the disease and also about a farmer named Benjamin Jesty who has used the cowpox pustules to infect his wife and children rendering them immune to smallpox. Dr. Jenner is curious. He remembers the advice of William Harvey, “don’t think, try” and he is cautiously patient but scientifically anxious to see the results. His gardener brings his child named James Phipps, an 8-year old boy, to him to protect him from the scourge. Edward Jenner now fully convinced of the potential from all the anecdotes he has heard tries his method on a consenting parent's child. 

He takes the pus from the cowpox pustules off the udders of a cow (subsequently named Blossom) and with a piece of sharp-edged wood scratches the pus on to the child’s skin and then waits. He watches over the child recording all the pertinent findings of fever, malaise and sweats that the child expresses. The child recovers completely without any sequelae. So far so good, he thinks. He is concerned for the more difficult and potentially lethal part of his experiment, to use Variola specimen from a small pox victim and deliberately infect the child. He does that on two successive occasions and both times the child demonstrates immunity to smallpox. Dr. Jenner has thus for the first time in history successfully demonstrated the cause and effect of an experiment. Dr. Jenner goes on to demonstrate on thirteen more individuals and sends a one-page paper to the Royal Society of Medicine in London. The paper is rejected initially for want of more detail and substance.
Edward Jenner's dissertation regarding Cowpox vaccination

This then is the sequence of a thorough understanding of the question posed by Dr. Jenner to himself. Does Cowpox, as everyone seems to claim, protect against smallpox? His answer in the form of the experiments done initially on 13 and subsequently on 23 patients demonstrate that the scientific premise is correct. Going into the experiment with James Phipps, Edward Jenner had copious doubts and a kernel of hope for success. The dogged and clear scientific proof of immunity obtained from the cowpox vaccination that rendered the 23 people immune to smallpox was the glorious success obtained with rigorous scientific proof. The British Government ordered mandatory vaccination to the population and subsequently all over the world to the result that in 1976, smallpox was considered eradicated from the planet.

Here was a distinguished scientist operating on an assumption of benefit for his patient and with apprehension and careful follow up he determined the benefits of the treatment. Except for the Variola vaccination that had become commonplace and deadly no other knowledge was available save for the anecdotes. This then was the sunrise onto the hinterlands of medical science. A cause and effect had been proven to the benefit of the entire world. No wonder they call Edward Jenner the father of immunity.

Watson and Crick

Now let us venture into another successful scientific discovery that has revolutionized the current thinking and from which we will be reaping benefits for the foreseeable future.
It is April of 1953, James Watson and Francis Crick have just published a scientific paper that makes the following famous understatement,  "This structure has novel features which are of considerable biological interest."  The duo had been interested in the DNA molecule for some time. The race is on, in the scientific community, to be the first to decipher it. Linus Pauling Nobel Laureate in Chemistry had proposed a trihelical structure for the DNA. 
Rosalind Franklin

It was not until Watson and Crick had heard a lecture given by Rosalind Franklin and Maurice Wilkins where the latter showed an x-ray diffraction image of the DNA that Watson and Crick were convinced about their lingering impression that the DNA was a double helix and based on preexisting information, contained 30% adenine and Thymine and 20% Cytosine and Guanine. 
X-Ray Crystallography of DNA

Based on the stick-figure Watson and Crick used as their model the phosphate sugars would be the outside backbone of the DNA and the nucleic acids would be bound together by weak hydroxyl links. Unfortunately Rosalind Franklin died in 1958 and therefore was not nominated for the Nobel Priize in medicine that was subsequently shared by Watson, Crick and Wilkins.
The DNA Proposed Model

 This is a story of a relentless dedication based on axioms and hypothesis and fragmented knowledge that were painstakingly pieced together by scientists through hard work and imagination. "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material,” wrote Watson and Crick in the scientific paper that was published in Nature, April 25, 1953. It didn’t escape the rest of the world either!

One more story of import hails back to the 1970s and 80s. It concerns a determined soul who spent 20 out of 24 hours a day feeding himself the knowledge of genetic damage as a causative agent for cancer. His name is Robert Weinberg. He pioneered the research of oncogenes and tumor suppressor genes in his Whitehead Institute
He gathered the brightest individuals from all over the world and gave them a clean slate with few signposts of the known and potential unknown.  He identified and characterized both the first oncogene and the first tumor suppressor gene and demonstrated how certain gene regulators, or transcription factors, contribute to cancer metastasis. These are far reaching discoveries in the field of cancer medicine. The fruits of his labor have enabled oncologists to question genetic traits leading to cancer and how tumor suppressor genes are equally as important as the promoter genes in the story of cancer.

Robert Weinberg is a jovial hearty kind of a guy who exemplifies the team spirit. It is his obsession to get to the root of the disease called cancer. His research is one of painstaking slow and methodical rigor with many failures that sometime come in like driving rain. There are no shortcuts. No trolling the scientific papers and creating a new paper by modifying a few sentences and paragraphs. His and his colleagues’ version of trutht finding is the real science. The science that creates value and is remembered long after the scientist is gone. As all scientists are, he is not one to shy away from controversy and he is not one to slink away from issues. He approaches them head on and is determined to be at the forefront of new discovery. It is simple for him, all rests on hard work and dedication.

Fast-forward to today where there is a plethora of journals and the scientific community is awash in scientific publications. Everyday the mail seems to bring in a bag full of journals and each has at least 12-18 or more “peer-reviewed” articles of "importance". Every day there is a new discovery that such and such medicine causes such and such result. If this could all be true we would be discarding cancer and some other diseases to the heap of “has-been” pile.

So what gives? Why are we inundated with literature about new discoveries and latest bonanzas of scientific acumen and yet life remains stunted by the same diseases as it has for quite a while. Oh, I am not saying that progress has not been made. Yes it has from 1940s to the present the life span of men and women have scaled up significantly. Now in relation to cancer almost 52-56% of all-comers with cancer live out their full lives. So yes we have cured malignancies and yet the pace is slower then the burgeoning libraries of scientific papers.

Could it be that the data that is being culled is a rehashing of material? Or could it be that we are using statistics in meaningful ways to promote a point of view through the arbitrariness of mathematics and statistics? How can Vitamin D one day be preventative for most solid cancers including Colon cancer and the next day it is not? How can drinking one glass of wine give you health one day and the next day half a glass of wine three-days-a-week is the maximum recommendation for women because it can cause breast cancer (lobular carcinoma variety)? How is it that the Cholesterol lowering agents Statins were suspected of increasing the risk of cancer and then later decreasing the same risk? And how about this one that Selenium reduces the risk of prostate cancer and recently it has been determined that it does not. How come smoking… No! No! I don’t think anyone would touch that one, not even Philip Morris and company. Anyway there is a large number of how comes out there and they pose a question that needs to be answered. What makes a “landmark” scientific study reverse its own conclusions?
Is it possible that the dependence on ancillary scientific techniques of probabilities with vague multivariate reference points through the wizardry of mathematics can transform a quasi scientific findings into a virtual etched-in-stone “evidence” that someone else the next day by juggling the same numbers, vilify? 

There is disruption in the medical care that patients receive as a result of such gimmickry.

Another method of how some of the “ivory-tower” gifted scientists use their magic is by analyzing multiple studies under the guise of “meta-analysis.” This method suffers from similar lack of fastidiousness as the epidemiological probability experiments. While the former rely on previous information by authors-other than the one writing, the latter relies on a small number of variables ignoring others that might have an impact on the outcome. The data obtained is tainted by the original author’s bias and opinion and the meta-analytical author is approaching at it with his own determined  bias. Meanwhile no new information is obtained only new “nuance” is gleaned. The prevalence of meta-analysis studies is alarmingly huge and growing and yet nothing new comes out of it most of the time except 15 minutes of fame. The reason this is accepted is because a new study requires enormous resources and consumes large costs for patient accrual, time and money. Why not try to manipulate old material into a newly transformed data. And then we go about using that data in other studies. “A lie told often enough becomes the truth.”

Pseudoscience comes in many shades of grey. It is labeled junk, if the data used is obscure and has little factual truths in it. Another form in this spectrum of pseudoscience is Defective Science where the authors hungry for celebrity allow a confirmation bias to cloud their sense of right and true.
Martin Fleischmann

Stanley Pons

Martin Fleischmann and Stanley Pons of Cold Fusion fame 

failed to procure their name in history and in the scientific community with a failed concept under bright lights of the media in 1989. And then there is fraudulent science and misconduct purely for ideological or personal reasons where reputable scientists succumb to the pressures of potential fame and fortune and make up data to suit the premise they wish to explore.

And there are legitimate scientists who have done significant work to great personal peril to prove a theoretical argument and base it on excellent science and these individuals have won scorn and ridicule from their peers for many years before finally finding the reputation they deserved. A well-entrenched thought is difficult to dislodge and garners a ton of support in its defense. The three names that come to mind are Barbara McClintock and her Transposons or "jumping genes", Barry Marshall and his discovery of Helicobacter Pylori as the cause of peptic ulcer disease (He had to drink water teeming with Helicobacter Pylori and get peptic ulcer for his scientific proof, since much of the gastroenterology establishment was mired in the multibillion dollar antacid industry and Lynn Margulis and her hard fought scientific battle to prove endosymbiosis and evolution took an equivalent amount of whips and scorn before finding her rightful place in history.

Unfortunately for the lay person who succumbs to the 10 second fragments of television  news where studies are bandied about as the gospel. Too many people believe in the hoaxes sponsored by various companies that are out to prove their point of view and call it scientific study. While the spokesperson uses phraseology that makes him or her look authentic, he or she doles out percentages and statistics to confuse and obfuscate reality. The premise of pseudoscience invokes a visceral response from the public where with crafty words and nuances of fully exploited rationalization traps are offered as evidence via a celebrity mouthing the paid words. Pseudoscience is like a sociopath gaining empathy with false words. Once the trap has been set the public will follow the lead until another roar of a new idea kindles their imagination. Humans have a desire to believe and pseudoscience has the false words to convince.

It has and should be said that sometime being first out of the gate even with pseudoscience wins the initial battle of money war since real science is time consuming and diligent and by then the looters have looted the kitty.

It might seem childish to say, “hey what about the truth?” And in a world revved up and strung tighter then an unplucked mandolin anything goes is the reality. The majesty of the reward lies at the other end of the lies. It is for us to know and understand and comprehend the nature and virtue of the written word.

Science is allowing itself to incorporate pseudoscience in its matter. The nucleus of such a deplorable apparition is one step away from the transduced signal of a fully depressed gas pedal of a runaway car like the cancer cell.  We are allowing such badly used information and calling it scientific rigor. The value of science is looking down the abyss and is tethered only to the single thread of truth holding it back. If too often science contradicts itself, the believability will suffer. We cannot allow the Galileo’s of the world to be hampered by the Ptolemy’s “The Almagest.” Rigorous science requires verifiable truth and not some shades in between. Scientists should be weary of methodologies, statistics and conclusions derived in the studies. Even arguments based on probabilities are like imposters strutting stuff built on ethereal foundation.

I started with food and so I shall finish with that concept. Excessive food is bad for health. Excessive pseudoscientific literature is equally bad for progress especially in medicine, where the patient and his physician get bloated with a sense of airy, unnatural view of the world that mitigates the harsh reality into a false sense of comfort ending in calamitous ruin. The Journals and their editorials should pay heed to what is said, how it is said and what is the premise behind the words before putting it to print. Sadly if they don’t do their job well they will eventually have no job at all. Printing journals for the sake of filling pages with nonsense is irresponsible to all science.

No profit grows where is no pleasure ta’en;

In brief, sir, study what you most affect.
Tranio, scene I Taming of the Shrew ~ William Shakespeare


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