Logic of Failure and Failure of Logic: Mathematical Models

“If the butterfly flaps its wings…” so goes the chaos theory of dynamical systems where the sensitive and not extreme dependence on the initial condition determines the disorder of the system as a whole.

So one might then consider that living in an extremely complex world that is governed by multivariate conditions, transposing each condition onto  a theoretically based model would requires zillion terabytes to compute - which we don’t have yet, creates a problem for such enterprises. So herein lies the premise of this undertaking that only the brilliant mind of Edward Lorenz could have named the “Butterfly Effect.”

                                           Edward Lorenz's Strange Attractor

Each piece of the whole exerts influence on the whole in ways that we cannot completely comprehend. Our understanding continues to evolve and the Eureka moments, encompassing as they may be, are also expositions of the limitations of the dynamical system that we do not fully comprehend. Nothing is in isolation and nothing changes without some effect from something else. For instance the human population explosion over the past century is associated with consequences, such as pressures for survival with corresponding extinction of some species as well as artificial preservation of others for our own needs (horses and dogs for instance). So to say we live in a dynamic system is an understatement of our own existence. It is a dynamic system that is constantly in flux. A plastic mold constantly being remolded.

Progress for humanity is littered with the refuse of failure. It seems to mimic life where 1.5 billion species have gone extinct based on fossil data. Our failures maybe not as dramatic as that but they are indicative of our limits.

Our failure is based on limits of understanding, the initial and subsequent conditions that are the prerequisite in a dynamic system and the perceived outcome. There lies the tail of this tale.

Mathematical Modeling:

To understand nature humans have used the art of reductio ad absurdum. To reduce something to its most basic elements so that we can see how that something ticks. This philosophy has given birth to multiple industries that have used nature as a template. Aerospace, Medical, Engineering and Nuclear to name a few. Having mastered the art of seeing things flayed open for all pieces to be visible has also inculcated in us the art of modeling that would help newer design predictable function, performance and even the future.

Mathematical Modeling is a full-blown tool used in all sciences and disciplines. Do we understand it is the question?

Ah! there is the rub. Mathematical Modeling is a philosophical construct that has with time become the process du jour of scientific thought. It has been used successfully many times and many times it has come short. As much as the former is true, it is the latter that gives us pause. From our failures comes the light of knowledge. This then is the fruit derived from dashed hopes that leads to advancing the language of mathematical perfection. Something we seek but may never realize.

The fundamental question is whether it is possible to predict response of some process after various numerical inputs have been used to determine the outcome with a high degree of reliability.

The first order here is the initial thought also called “the concept.” The concept is based on several inputs that include materials, mechanics, interacting parts, procedures etc. This minimalistic list is left to the “judgment and experience of the mathematical analysts.” Any increase in the number of variables such as interacting and changing external dynamic factors requires a complex series of undertakings that involve probabilities and mathematics steps in.

So mathematical models vary by what the desired study is, variables involved, materials  used, and the intensity of the computational analysis. For instance a model based on the aeronautical dynamics of a composite material will require information on the deformation patterns, tensile strength and elasticity of the material under study.

Carbon fiber Composite material

All such comparisons would be based on aluminum (the gold standard) that has been in use for decades. Additional information regarding its tolerance to fatigue (recall the Aloha Airlines disaster) and its resistance to fire (Use of Nomex fibers in composites and as this relates to the strength or weakness of the material) will be brought to bear on the new concept to be exploited.

Aloha Airlines with decompression due to metal fatigue

After the initial conceptualization process has been completed, the concept then has to be validated by the rigor of predicting component/subcomponent and/or system failures. This is done via simulated experiments. At this point all subcomponents, components, subassemblies and the total assembly of the product under consideration are forced through known “stressors.” A successful prediction based on inducing failures under different external variables gives validation to the concept. The errors that creep in could relate to the initial conceptualized model, numerical approximation (recall Edward Lorenz’s error), the simulated experiment, or the statistical variables employed. Since most of the modeling is based on predictable axioms, they are axioms nevertheless and as such suffer the wrath of nature’s whims.

Rotors on Blackhawk Helicopter

Remembering that a mathematical model is an order of reference within the hierarchy of a larger model, must give the analyst pause and concern at every level, for instance an analyst performing a validation experiment of a rigid machine exposed to large degrees of vibration has to have “Harmonic analysis” in mind as one of the parameters. An example here could be the rotor blade subjected to the supersonic speeds has to undergo deformation, linear and rotational stresses and place significant centrifugal forces at the rotor disc level. Fatigue damage in homogenous material is especially dangerous because they are unpredictable, giving no prior notification of the imminent failure, they occur suddenly

and show no exterior plastic deformations. Advanced composite materials exhibit gradual damage accumulation to failure. Typically, matrix cracking, delamination occur early in the rotor life, while fiber-fracture and fiber-matrix debonds initiate during the beginning of the life and accumulate rapidly towards the end, leading to the final failure.  Thus actual experimentation shows that composite rotor blades become better predictors of failure then homogenous ones. This was borne out of actual experimentation. The mathematical modeling did not reveal the anomalous behavior of different material used in the simulated outcome. In a calm wind environment this would have different dynamics compared in conditions of strong wind shear where performance, function and integrity may be challenged. After several years of research and development Boeing has designed the 787 aircraft with 50% composite material for its light weight to improve efficiency and overall fuselage strength.

Boeing 787

A mathematical model estimating the population by using the “Birth Rate” and “Death rate” does not really tell us the real story. Changing the parameter to “Per Capita Birth Rate,” and “Per Capita Death Rate” signifies the population being tested thus it gives a better record. Using the right parameter in the methodology makes a difference in the computed outcome and desired result.

Robert Thomas Malthus

History teaches us that the Malthusian Model of population expansion and resource comparison was woefully inadequate since there were no inputs for catastrophes. It was a steady-state model, which as we know is not how humans and nature behave and neither does it incorporate externalities like the Influenza epidemic of 1918 that decimated a quarter of the world population. His modeling was simplistic in the steady-state growth of the population outstripping the food supply proclaiming the incipient crises.
Adding a single variable can yield an unexpected result. View the Spring loaded pendulum or a double pendulum effects on the chaotic movement of the pendulum itself as calculated in the Wolfram Mathematica Program.

Spring loaded Pendulum

  Double Pendulum

So what is this mathematical modeling genie and how do we use it and benefit from it?

Mathematical Modeling streamlines some processes:

Conceptualizes a thought.

Thoughts are placed through a simulated rigor.

The thought is subjected to various externalities.

Modifications of the model can test different scenarios on the same hypothesis.

The problems that are inherent in Mathematical Modeling include:

The concept may not be proven

The concept is insensitive to the variables

It is too simple in its characteristics.

It is too complex requiring unavailable computing power.

The model cannot lend itself to a mathematical solution.                                

                                                                                                                         

Uninspiring as it may be there are small order magnitude variables that are rarely incorporated in the validation process and these include:

Symmetry or x=y then y=x and

Transivity or if x=y and y=z then x=z

Thus only using Reflexivity of x=x limits the useful load on the experiment.

Validation Processes include the content, context and criterion: Content refers to the materials and information available, Context is in reference to the externalities and criterion is based on specific environment use. All three validations have to be undertaken in the simulated experimental model to achieve a high degree of confidence of its reliability. After all the predictability of the validation process is based on repeatability. The Monte Carlo model of repeat computer simulations to draw inference of the viability, repeatability and validation of the outcome of the experiment is another mathematical model used in various scenarios.

Mathematical Model foundationally is a philosophical and logical construct. Although philosophy is a nuance of an understanding and logic is based on the variable parametric value, both constructs are highly subject to perceptions, understanding, resource limits and bias. Thus the Logic of Failure can be a failure of logic.

Logic of Failure:

A model that did not consider the strange attractors:

Challenger Liftoff

The Challenger Disaster: On January 28^th in 1986 after a cold spell in Florida the Challenger lifted off to a highly publicized event.

Unbeknownst to the occupants in the Space Shuttle Cockpit was that the O-Rings or the “Toric joints” had become brittle due to exposure below the glass transition temperatures of 40 degrees Fahrenheit overnight. They failed 73 seconds into flight. The failure of the O-Ring resulted in high temperature gasses expulsion onto the external fuel tank leading to a catastrophic “System Anomaly!”

System Anomaly

The Risk analysis done prior to the Challenger flight and based on previous such space flight was calculated at 1 in 100,000. But later analysis showed it was realistically at 1 in 100. Given that the Challenger mission was the tenth mission and no previous failure data was available to asses the real risk of failure which actually would have been 1 in 10 (Since this was the tenth such flight). The O-Ring issue had not been previously addressed but had been in consideration for the Launch parameters. These parameters were set at 50 degrees Fahrenheit.  The overnight lower temperatures however were not considered into the equation.

Richard Feynman (Nobel Laureate)

The noted Richard Feynman made the dramatic announcement of the etiology of the failure before a nation in mourning.

Xray of the O-Rings

H1N1 Epidemic: In the Spring of 2009 the CDC (Center for Disease Control made a bold and provocative declaration that the estimated numbers of the H1N1 cases in the country were “upwards of 100,000.

H1N1 virus

At that point and time only 7415 had been confirmed. These lofty projections were based on a mathematical modeling done by two supercomputers. Both computers fed similar data drew the same conclusion. The “Rubbish in rubbish out” motto is self-explanatory. The model was projected on the basis of an exponential rise in cases based on previously drawn comparators of the Influenza Epidemic of 1918. The World Health Organization predicted dire outcomes of a worldwide pandemic and issued orders for quarantine of suspected individuals. Fortunately that proved to be untrue but in the process the world panicked. Conjecture and axioms have a way of loading up and ganging on the unsuspecting scientists and lay people alike. Airline traffic declined hotels lost booking, conferences were cancelled with unanticipated huge economic losses. Those forced to travel wore unwieldy masks to protect themselves furthering fear. This was not a case of “red-face” or “black-eye.” It was a debacle promulgated by a scientific folly.

HIV viral load and the CD4 levels

HIV Progression: Two high profile science papers in the prestigious journal Nature were published in 1995 related to HIV and AIDS. During the media buzz of the coming Armageddon (HIV) stated large population decimation as a result of this infectious virus.  Human existence was at stake. The premise was to treat all patients infected with HIV even if they were asymptomatic. The two studies by Drs David Ho and George Shaw called the Ho/Shaw predictive model used the “viral load and the quantitative value of the CD4 T cells (Immune Cells) as their parameters for their therapeutic assertions. The rise of the viral load was one parameter and the fall of the CD4 cells was the other. There was a reciprocal relationship between the two and thus the model predicted that in order to prevent an asymptomatic carrier from full blown AIDS they should be “hit hard and hit early” with a protease inhibitor. There was no Control Group used for either of the studies done separately by the doctors. Large numbers of patients were treated using the model. Eventually data gleaned from these treatments showed that the initial drop in the viral load was associated with a rise in CD4 cells but over a prolonged period of close observation the reverse happened and the viral load increased. So there was no validation of the conceptual design that had not been rendered through a properly designed scientific study with a control group to determine real efficacy. The unintended consequence of this undertaking of treating asymptomatic patients was that it created in short order multiple mutations in the virus that became resistant to the protease inhibitor. Now those with the disease would not get help. After many years and unnecessary treatment this treatment method was abandoned.

The message in this modeling was based on only two parameters without a control group. A preexisting opinion (bias) became a forced finding of fact. The model generated with the two parameters, in isolation of the true knowledge of the various players of immunity, was at best self-delusional and at worse unnecessarily forced therapy upon countless asymptomatic patients with resultant viral mutation showing resistance to the drug in use.

The Failure of Logic:

A model that considered strange attractors:

Economic Black Swan Effect: One can trace the history of the 2007-2008 Market meltdown and the fall of Wall Street giants like Lehman Brothers,

Bear Sterns and

 Washington Mutual, to two Nobel prize winners Robert Merton and Myron Scholes with Fischer Black propounded the theory of the Black-Scholes Option-pricing model. The model assumed that the price of heavily traded assets follow a geometric Brownian motion with constant drift and limited volatility. In relation to stock option, the model incorporates the constant price variation of the stock, the time value of money, the option's strike price and the time to the option's expiry. The Black-Scholes option theory became the darling of Wall Street. It created derivatives and the CBOE (Chicago Board of Option Exchange) enjoyed a tremendous rise in contracts and therefore revenues. In 1973 the Exchange traded 911 contracts and in 2007 the volume of contracts reached one trillion.

Myron Scholes (Nobel Laureate)

Messers. Scholes and Merton started the now infamous LTCM (Long Term Capital Management) Hedge fund The fund was based on absolute-return trading strategies that included fixed income arbitrage using convergence trades exploiting asymmetries of the US, Japanese and European government bond prices, combined with high leverage. The latter strategy exposed the fund management to a 25 to 1 debt to equity ratio in its later stages. The meteoric monetary gains of 40% in 12 months using this exploitation lasted until the East Asian Financial Crises of 1997 followed by the Salomon Brothers withdrawal from arbitrage and the Russian Financial Crises in 1998 sealed the insolvency of the mathematically modeled LTCM Hedge Fund. Investors ran from the Japanese and European Bonds to the US Treasuries for safety and in so doing erased and reversed the asymmetries against the proposed models used by the LTCM managers leading to huge losses in less than 4 months.

Keeping things in context, the Black-Scholes model was a simplified model using laws of thermodynamics to equate to the changes in the price of shares. The gentle trending above and below the mean was the premise of the stock movement rather than the violent seesaw effect that happens in the real world. The concept of slow movements of share prices in short term trading strategies was given credence to within the model rather then the real world events that can whipsaw and rubberneck in a trending market. The computers with buying and selling software programs that can hit the market at record speed can create havoc with the share prices and are predetermined by programs created by the quantitative financial analysts or quants. The market is a living, breathing mechanism based on the desires expressed singly by individuals or in large packets by the computing devices and governed ultimately by humans. This was not parameter used in the Black-Scholes model.

In keeping with the economic modeling methods the quants then decided to use the derivatives market to develop products like the CDOs or Collateralized Debt Obligation notes, the CDSs or Credit Default Swaps bundled securities.

The rapid increase of CDOs

The concept was simple, take a large number of mortgages of different risks, package them together and securitize them. The large bundled mortgages would be rated by an agency that was paid by the CDO creators and everyone would be content; the investor, comforted by the rating, the loan originator by the diversity of the portfolio and the seller by the pricing power of the product. The mortgage payments were allocated to the triple “A” investors first and then the rest. The equity investor in cases of default was left holding the useless IOU. These large caches of securitized mortgages made the banks and lending agencies hustle more lending to individuals that they would not have touched in prior years due to financial risk, now were welcomed. These were also the people who could not afford to pay the mortgages or held any assets as collateral to the loans.

Housing prices

In their paper published in August 2010 The Failure of Models that Predict Failure: Distance, Incentives and Defaults, Authors: Uday Rajan, Amit Seru, Vikrant Vig, state, 

“As the level of securitization increases, lenders have an incentive to originate loans that rate high based on characteristics that are reported to investors, even if other unreported variables imply a lower borrower quality…To illustrate this effect, we show that a statistical default model estimated in a low securitization period breaks down in a high securitization period in a systematic manner: it under-predicts defaults among borrowers for whom soft information is more valuable. Regulations that rely on such models to assess default risk may therefore be undermined by the actions of market participants” 

Bank Leverages

The house of cards fell, swallowed a country and plunged the world into a fiscal abyss.

The banks and Mortgage lending agencies, looking for a quick profit and unaware individuals looking for a picket fenced home, all participated in the “perfect storm.” The credit default market took advantage of desire and at one point was estimated at $55 trillion!

Using mathematical modeling has its benefits of dealing with an idea, however in a complex world where the variables are in the millions if not billions the chance of creating a model to satisfy all potential adversities is zero. In economics especially, real life and mathematic modeling are decoupled. Benoit Mandelbrot calculated that IF the Dow Jones Average followed a normal distribution it would have moved 3.4% on 58 days between 1916 and 2003. In fact it moved 1001 times. He also calculated that should have moved 4.5% on six days however in reality it moved 366 times. It should have moved 7% once in 300,000 years. The reality is in the 20^th century it moved 48 times. In all the market had 25-standard-deviations several days in a row. The market sometimes moves in the extreme tail of its normal distribution curve. A perfect example of the tail wagging the dog!

So are Mathematical Models cursed to eventually fail? The simple answer is no. They work well in design details of the components, assemblage and when environs are taken into account. However when large-scale “real world” scenarios are attempted without relevant information, the asymmetries that remain unaccounted for in the modeling concept cannot be validated until the “real world” tests the product in its own environment.

Human Diversity (in the Genes)

Staring at my mailbox, I found enormous amounts of spam mail. Most if not all was nonsense. There was an occasional one that piqued my curiosity, but not enough to open them for fear of the worms and viruses. It got me thinking about the genetic system that we have within us that drives us from birth to death. Similar in scope and behavior as it relates to information gathering and dissemination.

The inner universe that controls the function of the visible one is a basket of deceit, overthrow, control, incarceration, submission and acceptance. The Human Genome Project determined that human DNA, in its Watson-Crick double helical mode, breathes life through 23 (22 + sex pairs) pairs of chromosomes. Although the break up of the DNA into chromatin material and further subdivide into chromosomes is for the purpose of division so that the two ends of the “daughter-cells” can pull the equal numbers via tubules on each side in a dividing non-germinal cell. Once separated and enclosed in the newly divided cell the DNA resumes its original shape.

The progeny of two (such) sister cells are not alike with respect to the types of gene alteration that will occur. Differential mitoses also produce the alterations that allow particular genes to be reactive. Other genes, although present, may remain inactive. This inactivity or suppression is considered to occur because the genes are ‘covered' by other non-genic chromatin materials. Gene activity may be possible only when a physical change in this covering material allows the reactive components of the gene to be ‘exposed' and thus capable of functioning." -- Barbara McClintock

The amazing thing is that it is the DNA and its programming that forms, modulates, modifies and renders senescent the vessel (the body) it is carried in by a set of 25,000-30,000 genes (Based on the Sanger Institute’s human genome information in the VEGA database, these remain as estimates). Genome is not a stationary entity, but rather it is subject to alteration and rearrangement.  Even more fascinating is that the DNA at its basic level is composed of four, count four nucleic acids; (A) Adenine, (T) Thymine, (C) Cytosine and (G) Guanine. These four are locked in predetermined set of twos in a permanent state of dance. The A always mates with T and G always with C.  So from this simplicity arises the most complex of life forms that exist on our planet.

Manifest within the genes is the code that makes us and every other living breathing being around us. These genes code for the color of the flowers, the blade of grass, and the fur on the poodle that sits at your feet and its eyes that look at you longingly and the wet nose that sniffs for discovery. The control and color and grandeur of the world’s inhabitants are predicated by the genetic expressions. 

So the question can be asked what makes a small number of genes create such diversity? What makes the subtle or dramatic changes just looking at each other’s faces, to recognize the difference amongst us? Therein lies the beauty and majesty of the genetic workshop.

At it’s most basic Mendelian level (Gregory Mendel - July 20, 1822 – January 6, 1884) the genes from two parents are paired together each carrying its own sets of programmable codes. When the merger takes place the dominant genes will overshadow the recessive ones and express their abilities into the character. That was the widespread thought in the past. The present has unfolded the napkin of the genetic nuance and there is a whole lot of mischief going on within the folds.  

In 1952 a geneticist named Barbara McClintock (awarded the Nobel Prize in 1983) discovered that there were genetic transpositions occurring through the genomic material of maize. She termed these transgressions as “Jumping Genes.” The technical name was “Transposons.”  It turns out that the genetic material does prefer a sense of variety. As the saying goes “Variety is the spice of life,” genes take that to heart. Within the genomic system is a silent but busy mechanism that is in full perennial blossom.

Transposons are genetic materials that move or transpose from one part of the DNA to another. They comprise of at least two main groups, the DNA Transposons and the Retrotransposons (RNA Transposons)

1. DNA Transposons
2. LTR or Long Tandem Repeats
3. LINEs or Long Interspersed Nuclear elements
4. SINEs or Short Interspersed Nuclear Elements.

The DNA Transposons encode the protein transposase, which they require for insertion and excision of the DNA material/fragment that are clipped from within the linear DNA material of the entire genome and inserted into another part of the genome. It is a “cut-and-paste” biological technology at work. The question is why? Why does the DNA partake in this promiscuity? The answer for this and all the other transpositional mechanistic fragments is for “Diversity.” The “jump” of a gene from one part to another favors diversity and as Charles Darwin maintained evolution favors “survival of the fittest.” There is an evolutionary programming within the DNA to maintain itself through adversity. It therefore tries to continue the evolutionary experiment to make itself robust against extinction based on the “Soma Theory.” (The Soma or body has to be maintained for propagation of the genome and once replicated, the Some or body can be disposed of).

So what happens with each transpositioned genetic material? Interestingly when a material transposes itself to another site it would by necessity, depending on its new location -especially if it happens to be near a functional gene, cause it to either over-function or under-function or just stop functioning.

The fact that transposable elements do not always excise perfectly and can take genomic sequences along for the ride has also resulted in a phenomenon scientists call exon  shuffling. Exon shuffling results in the juxtaposition of two previously unrelated exons, usually by transposase, thereby potentially creating novel gene products (Moran et al., 1999).

Lets look at few examples of inter-genetic mischief:

                   1. Deletion, 2. Duplication and 3. Translocation (Above)

1. 9:22 (BCR or Break Point Cluster region attaches to the Abelson gene) Translocation leads to Chronic Myeloid Leukemia.
2. 11:14 Translocation leads to Malignant Lymphoma.
3. 15:17 Translocation leads to Acute Promyelocytic Leukemia.
4. 9p21 Polymorphism leads to heart disease.
5. Insertions of L1 into the factor VIII gene caused hemophilia (Kazazian et al., 1988).
6. Researchers found L1 in the APC genes in colon cancer cells but not in the APC genes in healthy cells in the same individuals. This confirms that L1 transposes in somatic cells in mammals, and that this element might play a causal role in disease development (Miki et al., 1992).

              1. Gene Translocation and 2. Gene Transfer (Right)

Transposons have been labeled as "spam" by some and rightly so. Most of the time spam is relegated to spam archives and does not interfere with workings of the computer, but some times it can insert a "computer virus" or "worm" in it's hidden code, "crash" the computer system and infrequently it may provide valid information. The Transposons work mostly as promoters and when this promoter effect gets juxtaposed to a functional gene that codes for proliferation of a particular cell type, malignancy ensues. Fortunately just like the Antiviral Software that exists for computer also exists in the human body. If the Transposons cause an adverse event it can be deselected or rendered inactive. Question is how?

The genetic "antiviral software" is called the siRNA (small interfering RNA) or RNAi (RNA interference). These RNA fragments are snippets of the messenger RNA that derives its information from the DNA. These snippets can lay themselves on  
the Transposons and neutralize them by a methylation process or simply by suppressing the gene function. It is the body's own defense mechanism to fight internal revolt. Even though the Transposon material are perfectly intact and capable of moving, yet they are kept inactive by epigenetic defense mechanisms such as DNA methylation, chromatin remodeling, and miRNAs.

                                                                    RNA and DNA

Consider the issue of a quiescent gene used specifically for proliferation of cells in organ (liver, lung, kidney etc.) growth during in-utero phase, which is then mutated during adult life as for instance the gene that codes for pluripotential cells that liberate CEA (Carcinoma Embryonic Antigen) or AFP (Alpha Feto Protein)  between the 12-28 weeks of life. That mutation in later life would lead to unrestricted cell growth and cancer formation with liberation of these proteins CEA (found in gastrointestinal malignancies) and AFP (hepatocellular carcinoma or liver cancer). These serum proteins become guides for disease monitoring and response to therapy by an oncologist. The switch that gets turned on later in life was not supposed to happen, but it happens when the specific gene goes awry. The gene mutation may occur due to many causes both environmental genetic stressors to these mischievous Transposons.

The RNA Transposons work differently. They are also known as retrotransposons. In other words, retrotransposons do not encode transposase; rather, they produce RNA transcripts and then rely upon reverse transcriptase enzymes to reverse transcribe the RNA sequences back into DNA, which is then inserted into the target site. (They therefore have codes for proteins that cleave specific portions of the RNA, and then via other enzymatic protein that they have co-opted or part of their own framework, entice the reverse transcriptase to get attached to the DNA. So in essence (the RNA) the messenger becomes (the DNA) the message creator).

The two main types are the LINEs and SINEs.

SINEs constitute 10.4% of the human genome. LINEs constitute 17% of the genome.  Of the 17% of the LINE transposons only a 100 remain active in the human genome. 47% are LTRs (Long Terminal Repeats) and the DNA Transposons “cut-and-paste” only constitute 2-4% of the genome. 50% of the entire human genome is composed of these transposons.

Therefore not surprisingly this DNA/RNA Transposons behavior has been in vogue for millennia. Similar Transposons copies have been found in various primates such as the Alu (also present in humans) and in a large segment of common Transposons in animals that includes the whales, which helps better understand the mammalian evolutionary branch in the Tree of life.

Large segments of the human DNA contain various genetic materials from viruses that have inserted their own genetic materials. Most of this lies dormant as "junk DNA." some have gained respect as " proto-oncogenes" that can via various mechanisms convert to "oncogenes" and start the cancer process. These genes include the c-myc gene, src gene etc. Other primates and animals, indicating non-species specific manifestation, also share these viral genetic insertions.

Another interesting fact is our body's ability to generate a large diversity of immunological antibodies against various viral, bacterial, fungal agents. This diversity is believed to arise as a result of the Rag protein that smuggled it's way onto being reverse-coded onto our DNA millions of years ago. It survives and is functionally propagated because of its utility and benefit of its host! The robust human immune surveillance with its enormous diversity to generate disease specific antibodies is a magnificent example of the benefit of evolutionary “Jumps,”

References:

1. McClintock, B. (June 1950). "The origin and behavior of mutable loci in maize". Proc Natl Acad Sci U S A. 36 (6): 344–55

2. Wei-Jen Chung,Katsutomo Okamura,Raquel Martin, Eric C. Lai (3 June 2008). "Endogenous RNA Interference Provides a Somatic Defense against Drosophila Transposons". Current Biology 18 (11): 795–802

3. Yang, N., & Kazazian, H. H. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nature Structural and Molecular Biology 13, 763–771 (2006

4. Kazazian, H. H. Mobile elements: Drivers of genome evolution. Science 303, 1626–1632 (2004) doi:10.1126/science.1089670

5. Kazazian, H. H., et al. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332, 164–166 (1988)

6. Kazazian, H. H., & Moran, J. V. The impact of L1 retrotransposons on the human genome. Nature Genetics 19, 19–24 (1998)

7. Moran, J. V., et al. Exon shuffling by L1 retrotransposition. Science 283, 1530–1534 (1999)

8. Miki, Y., et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in colon cancer. Cancer Research 52, 643–645 (1992)

Wither, the primary care physician.

The spiraling dynamics of medical care:

Patient care is transforming daily. It no longer is the “physician” who came via horse and buggy to be greeted at the door of an infirmed patient’s home. Things evolved from that to doctor offices, and hospitals. And as surely the process morphs into another, the doctors became employed by the hospitals for services that only the hospitals could provide and the process moved along.

Just when equilibrium had been restored between the providers of health care, the sting of  change was in the air. The knowledge of medicine increased voluminously, to the point that specialties arose and within them subspecialties blossomed. Times had changed again chaos reigned supreme. The Internist and the Family Medicine practitioner once the gatekeeper of the health of the community was n the crosshairs and found it difficult to make ends meet, since the patients who used to go to him/her for blood pressure now preferred Cardiologist or a Nephrologist and the blood sugar monitoring was being handled by the Endocrinologist. The specialists started to provide additional limited care to the patients by practicing a little bit of internal medical care since patients did not desire to frequent many physicians. The conflict soon arose between the “gatekeeper” internist/family medicine physicians and the specialist. Noting this irony the insurance companies hopped in to reap some rewards keeping more of the premiums as year-end profits and encouraged patient care to be meted out at the primary care level with the additive incentive for the physician receiving bundled payments. They deemed that if the transfer to specialty care were required then there would be some severance or partial payment at the end of the fiscal year. Their (Insurers) cost benefit spreadsheets showed that specialty care was more expensive then primary care for a similar patient. The complex formulae employed forced many primary care physicians to limit the referrals outside their practice. Unfortunately that limitation was associated with the legal side weighing in with their cries of inadequate care.

The floodgates of crying foul and dashed interpersonal relationships between physicians became the hallmark of medical society. Trust became an empty shell that echoed only the words that were yelled into it. The trade organizations were busy collecting dues as the society was witnessing a turmoil with far-reaching consequences.

As happens with change many physicians not willing to lose the war decided to throw in the towel and if they were in they’re 50s decided to retire from medicine. Their knowledge and experience lost to the multitudes of would-be patients. Those that were younger joined the forces of hospitalists where they were bereft of the tumult of daily practice and the 9-5 job or its equivalent was all they cared about. Do your job, get the paycheck and call it a day.

What then? Well as all things have unintended consequences so does this theme. The hospitals under the scrutiny of the third party payers when squeezed for money ruled in favor of solvency over the contracted doctor. And as surely as this ink dries there are hospitals reducing salaries of the hospitalists or outright canceling their services just to keep their doors open.

Another consequence of greater import is that the independent thinking by the private practitioner has become relegated to the “guidelines” created by the hospitals to streamline their revenue stream for “cost-effective” medical care. Invoking the scout’s honor the hospitalists are dutifully saluting to the demands in order to keep their jobs. When you take the nobility out, all that remains is business. The check is still in the mail at the end of the day and that is all that matters.

A once noble profession is being thrashed on the brutal rocks of economics. And if this wasn’t enough, the depleting supply of those tried and true stalwarts of medicine, the primary care physicians, is rapidly dwindling due to cuts in their practice from attrition of patients and in their professional fees.

Meanwhile the boys in the ivory tower, now have another brilliant idea: Lets get the nurses to start practicing medicine! Now if that isn’t the most illogical form of thinking, I don’t know what is? Why not let the nurses who wish to practice medicine go to medical school. Why not encourage the needs of medical education to those busy science and art majors. Why not make medicine attractive and noble again. Why not have the old strange attractor called desire due to societal influence imbued with nobility be the flag that makes for new converts. Why not call the doctors, “doctors” instead of “providers.” Why not?  Why not resurface the pothole-riddled roads of understanding with fresh thoughts from the physicians in the trenches rather then those opining from their lofty environs? Why keep slipping on the slippery slope to mediocrity and oblivion? There are too many whys and why-nots.

We have entered the realm of unintended consequences due to a few professorial types that entered the hierarchy of medicine and its governance a while ago and as “ivory tower intelligentsia” is wont to do, they have ceded to the pressures of their egotism by creating verbiage and an environment that has slowly disintegrated the nobility and care in medicine.

To that I say, “Leave medicine to its rightful trustee: the physician!”

Hypothesis and Evidence

It was a Sunday afternoon or was it evening? Not quite sure of the time element but I do recall the dent on the rear fender of the car. It was a small indentation, something that I thought might have been the outcome of a parking lot minor mishap. But it gnawed at me for a while and so I decided to investigate it. That little journey took me into the realm of “evidence,” as proof began to reveal itself. Slowly in stepladder fashion, I climbed my way to a new understanding. The hypothesis of the mishap was correct but when and where?

So what is evidence really? Is it a thing, an object, a thought or an imagined corollary without permanence of form in material? Interesting wouldn’t you say? It does have that mind-jangling, asymptotic, confusing ring to it.

Philosophy of Evidence:

Evidence, it appears, is a philosophical construct. Now lets not get too far ahead and collapse this argument by closing our minds. Seriously, stay with me on this one. Evidence can be a bloody knife, a set of fingerprints, a historical construct based on previously accepted principles, a color of an object, a sound wave, a mentioned reasoning in a book, the smell of a plant or a golf glove. You see all these so-called evidences can be used in science, law, biology, medicine, engineering and related fields. So “evidence” by definition has no limitations on the type of construct. It is an informational piece of relevance that is reasoned to agree or disagree with a hypothesis.

So it becomes clear that evidence, is a secondary phenomenon, required to prove a hypothesis. Without one of these you cannot prove one of those. But to generate a hypothesis one has to have a thought construct based on some relevant information that allows you to undertake such an enterprise, doesn’t it?

So evidence can be gained prior to the hypothesis being developed but here in lies the poverty in all scientific disciplines. If one finds certain data and develops a hypothesis to fit the data then one has committed the act of “observer bias.” For, there the question remains, was the hypothesis just a ruse based on the data accidentally at hand and thus a conjecture made and arrived at by forcing a square peg in a round hole, or in some cases a round peg into a round hole. Or is it simply like shaking a tree and the apples fall down thus making us declare that it is an apple tree? There hides a lot of intent in these revelations.

Let us test a hypothesis then to clarify the subject; Man can fly. We both know that is impossible. Yet given the evidence that exists today with thousands of aircraft flights man does indeed hurtle through space albeit in an aircraft designed for such purpose. Yet he himself cannot fly. So the evidence seems to prove the hypothesis that man can fly, yet it does not quite prove that. Does it? Another corollary would be if someone postulated that clouds occur as a result of rain. Well here the reverse is true but the premise postulated is obviously in peril since our observations hold that clouds occur without rain all the time.

Similarly in a criminal case a bloody knife found near the victim does not convict the perpetrator of the crime, unless his fingerprints are found on the knife. Even then the evidence is limited since the context of the fingerprints’ presence on the knife has to be taken into account; the real perpetrator may have stolen someone else’s knife. And on and on the lawyers pick through the haystack to get at the needle.

Evidence supporting a hypothesis is usually static in time. It is the governing principle of that day, week, month, year, decade or even sometimes a century. Today’s evidence may not be relevant for tomorrow and the hypothesis from today may not carry weight the next month let alone the next hour given new evidentiary information. Thus a true proof of a hypothesis is the epistemological data from the past and present as it relates to the truths, beliefs and justifications.

In evidentiary proof of a given hypothesis, rational explanations or justifications are not a guarantee of being correct. It may be rational to think that “reason to believe” and “evidence” are synonymous although the former is a mental construct and the latter may reference material substance. Thus “evidence” which justifies belief may be rational but not proof for a given hypothesis. Similarly being mistaken and doggedly representing reasoned rationality does not determine qualified proof. In the book “Proofiness,” Charles Seife mentions, “Hamlet Evaluation System” utilized by the U.S. Military to justify the purported sham victory in Vietnam that later became labeled as the “Five-o’clock Follies” for their misrepresentation of the actual events.

The term used for judicious and careful thinking and scrupulously obtaining evidence is “Cognitive Prosperity” which implies the holding of large number of true beliefs and relatively few false beliefs is used for individuals who use tedious and time-labored endeavors in uncovering the proofs for a given hypotheses.

“I thought we should require physical determinations, and not abstract integrations. As pernicious taste begins to infiltrate, from which real science will suffer far more than it will progress, and it would be often better for the true physics if there were no mathematics in the world.”- Daniel Bernoulli.

Mathematical Hypotheses:

The use of the Probability calculus as the key to all evidence is glazed over by the sweet syrup of statistical nuances whereby manipulation of the numbers can relate proof to some hypothesis. Looking at the Probability of Confidence Intervals in a Gaussian distribution suggests that a 95% probability indicates a defacto proof for any proposed hypothesis, especially in medicine and that the remaining 5% (2.5+2,5) on either side of this normal distribution can be considered outlier and therefore not representative of the factual evidence. Not only this thinking obscures the truth, it also misrepresents the entire evidence. The real truth in mathematical modeling comes from the “law of large numbers” where the “Normal Distribution” will give a 99.7% confidence interval at the 3^rd standard deviation, which one might argue is still not 100% and therefore not the real “truth.” In other words the larger the “x” in N=(x) the better the evidence to convict the hypothesis.

The rampant use of Bayesian rules holds that it is reasonable for one to believe that the evidence to which one is exposed is related to one’s prior probability distribution. So in fact that if one has had previous encounters, the relatedness to those encounters and the probability derived from them can lay the foundation for the future evidentiary proofs for hypotheses. Now any reasonable, thinking and fair-minded person would vociferously object to that line of reasoning. Yet it is in use today and accepted widely.

“What is Creditable… is not the mere belief in this or that, but the having arrived at it by a process which, had the evidence been different, would have carried one with equal readiness to a contrary belief.” – Blanshard, Reason and Belief.

Proving a hypothesis thus must avail of all evidentiary information both pro and con before being labeled as fact. “Evidence thus must become a neutral arbiter of all proposed theoretical commitments including axioms and hypotheses”.

The objectivity of science is secured by the shared relevant evidence conceived, discovered or brought forth in the discovery process prior to rendering a hypothesis as a fact.

Astronomical Hypotheses:

The Geocentric theory espoused by the Greek Astronomers for centuries and explained by Claudius Ptolemy (c90-148AD) was rendered moot by Galileo Galilei (1564-1642AD), who proposed the Heliocentric theory, championing the Copernicunism of the day, that still survives today, based on a telescopic evidence of the movement of the    planets and the stationary status      of the sun. The Ptolemaic arguments were based on a complex mathematical modeling derived from visual evidence only. Of course the heliocentrism is now in slumber mode since the knowledge that the solar system revolves around the galactic center and the galaxies roar by at light speed to the far edges of space in an ever-expanding universe ever increasing in distance from their neighbors. This expansion has been in progress since the Big Bang.

                 Cosmic Microwave Background Radiation from the Big Bang

The serendipitous discovery of the (CMB) Cosmic Microwave Background Radiation by Arno Penzias and Robert Wilson in 1964 at Princeton, NJ was the first evidentiary proof of the Big Bang. 

              Arno Penzias and Robert Wilson in front of Radiotelescope Princeton, NJ

When all possible reasons for the cosmic microwave chatter received via the radio telescope including “bird-droppings” had been considered and rejected, only then the hypothesis was generated and this information rendered as proof since the CMB was universal in its presence. So the Big Bang did happen based on the CMB.

Medical Hypotheses:

Ignaz Philipp Semmelweis (1818-1865) a Hungarian physician described as the “savior of mothers” imposed strict hand-washing disinfection with chlorinated lime in obstetrical clinics to prevent “puerperal fevers.” He did not have proof of the germs but intuitively knew that “something” was causing the fever that could be prevented with this simple solution. Preventing maternal death, it did!

Edward Anthony Jenner (1749-1823) inoculated an 8 year-old child named James Phipps in 1796 with Cowpox blister material to successfully vaccinate him against Smallpox. There are sketchy references that other non-physicians had utilized this vaccinating procedure before him. The hypothesis therefore existed and Edward Jenner was the first to lay the scientific proof as the foundation of vaccination against smallpox and earning the endearing term, “father of vaccination.”

                                           Edward Jenner

Barry James Marshall (September 1951-) from University of Western Australia proved that Helicobacter Pylori was the causative agent for peptic ulcers. Hitherto the reasoning had been that stress, spicy foods and excess acidity were the leading causes. However he proved his premise after a monumental struggle against the established rigidity of embedded medical reasoning, by drinking water teeming with H.Pylori followed by an endoscopic evaluation that showed the development of ulceration in his stomach and then treated it with an antibiotic to cure the illness without repercussions all without the aid of antacids. Dr. Marshall received a Nobel Prize in Medicine for his efforts.

                          Barry James Marshall

Marie Sklodowska Curie (1867-1934) the first recipient of two Nobel Prizes in Physics and Chemistry discovered radioactivity from Radon. She, based on her inspiration established the use of radiation therapy for cancers. The premise of radioactivity and its potential use to benefit humans was her hypothesis and when the therapeutic use was undertaken, it showed success in patients, proving the hypothesis with proof.

Germ Theory:

In spite of greats like Girolamo Fracastoro, Agostino Bassi, Anton van-Leeuwenhoek and Ignaz Semmelweis, the first individual to formulate that germs were the cause of illness was John Snow. He discovered that Cholera outbreak in Soho London in 1854. Filtering and boiling it to prevent further spread of the illness proved the hypothesis of dirty water, but it did not get proven until Koch’s Postulate was established that Vibrio Cholerae, the organism was the proximate cause of the illness.

The incredible diligence in the yesteryears towards the etiology of disease has slowly disintegrated into mathematical probability events. Where once absolute proof was a requirement now probability suffices. Cases in point are the various “Epidemiological proofs” that are arrived at with incongruous data. For instance there were initial studies that maintained that carbohydrate diets were heart healthy, finding that a high carbohydrate diet leads to high triglycerides led to mathematical modeling to suggest increased protein was better, except if one’s kidneys cannot process the nitrogen from the proteins, and now we find ourselves with the old commonsensical grandma’s tenet that less is better and fruits and vegetables are extremely important for health. There are further proofs that ingestion and retention of excess fat (obesity), smoking and alcohol usage are deleterious to human health. The changeable thinking shows the gravitas placed on cigarettes, when in 1893, smoking was actually promoted as a treatment for bronchitis. Now we know that it is a curse of/on civilization. We laugh at that original therapeutic premise, yet it was a practical suggestion based on faulty reasoning then. Smoking temporarily suppressed the coughing induced by bronchitis, therefore it was hailed as a panacea.

Genetics:

It was once postulated not to distant in the past when the human genome project was completed that disease especially cancer would be cured since discovery of the 25,000 active genes allowed us to peer into the machinations of what makes humans tick. The one-gene-one-disease concept, since has been discarded as information regarding epi-genetics and inter-genetic workings of the DNA helix has come to light. Genes work through varying degrees of modulation under the governing of other molecules like the interference RNA (miRNA). 

These agents can over-express, or suppress a gene’s function. Not only does the human DNA play musical chairs to Barbara McClintock’s “Jumping Genes” or "Transposons"

                            Transposons (jumping genes) that cause the striped colored corn

 it also can through the various SNPs (Single Nucleotide Polymorphisms) that occur randomly allow the process of evolution for survival through making us “fitter.” 

These changes have unintended consequences. Sure we have the DNA mismatch repair mechanisms to protect ourselves, but if inundated with errors, some can pass through and wreak havoc on the body. This relative change on the gene makeup can shut off the protein production that gene produces  conversely it can allow production in excess amounts. The varying degrees of function thus changes the growth potential of the cell in which this corrupted influences is being waged. A wayward cell with a renegade genetic mechanism is the hallmark of cancer. The hypothesis that knowing the genetic makeup will yield cure for cancer remains unfulfilled. More evidentiary information is needed. And more is to come.

Unintended Consequences:

The rampant use of antibiotics is creating a dangerous scenario that finds the pharmaceutical industry on its heels to find newer and newer generations of medicines. This ambitious project is governed by both the desire to have saleable product and also because the organisms are evolutionally quite expedient in their mutational edict to escape the death threat imposed by such agents. This broad and generous use of antibiotics has caused the emergence of newer strains of bacteria eg. MRSA (Methicillin Resistant Staphylococcus Aureus), VRE (Vancomycin Resistant Enterococcus), Resistant strains of TB (Tuberculosis) and AZT resistant strains of HIV. Additionally the constantly mutating and evolving Hepatitis B virus ten years ago had 4 sub genotypes now the HBV has evolved into eight, due to selection pressures imposed upon it by vaccination. More importantly a new mutant Poliovirus was recently discovered in Africa that has caused over 450 deaths in children.

Our understanding of the germ theory has taken on a whole different premise. Having fought the battle against the germs with products that allow humanity to survive has brought consequences of a new emergence of evolutionally mutated agents with newer tools to fight against us. The population of the viruses is in the trillions and humanity is in the billions. Victory in any battle belongs to the agile, constantly evolving and deceptive force.

Evidence based Medicine:

“Evidence based Medicine” is a terminology that has found a haven in medical circles. The intent in the statement is to provide proof for all the guidelines and dicta invoked in the premise of “how-to and what-to” in practicing the art of medicine. Those guides and dicta become concrete with the use of the term “evidence based medicine” and when used in that manner, no questions may be asked. It is a method by some to stifle scientific thought and therefore progress. Medicine is constantly changing because the environment changes too. To place a burden on the practice of medicine with past tense information is deliberately preventing the use of newer methodologies for the betterment of human health. The failure of this logic is in evidence throughout history. Agility and changeable thinking with newer hypotheses and newer proofs will lead to a better outcome. Today is in flux due to the understanding of the past and the unknowns of a hypothetical future.

… Oh, and not forgetting the minor mishap that started this whole thinking, the evidence of a bluish color present in the dented fender matched with a child’s blue colored metal tricycle. Faced with irrefutable evidence of matched colors between the dent and the bike Junior had nowhere to hide. QED.

References:

1. Kelly, Thomas, "Evidence", The Stanford Encyclopedia of Philosophy (Fall 2008 Edition), Edward N. Zalta (ed.)

2. Blanshard, Brand (1974). Reason and Belief. (London: Allen and Unwin).

3. Carnap, Rudolf (1950). Logical Foundations of Probability (Chicago: University of Chicago Press).

4. Carnap, Rudolf (1966). An Introduction to the Philosophy of Science. Edited by Martin Gardner. (New York: Dover).

5. Fisher, R.A. (1930). ‘Inverse Probability’, Proceedings of the Cambridge Philosophical Society 26(4): 528-535.

6. Goldman, Alvin (1979). ‘What Is Justified Belief?’ in George Pappas (ed.). Justification and Knowledge (Dordrecht: Reidel Publishing Company): 1-23.

7. Horwich, Paul (1982). Probability and Evidence (Cambridge: Cambridge University Press).

8. Silins, Nico (2005). ‘Deception and Evidence’, in Philosophical Perspective, vol.19: Epistemology (Malden, MA: Blackwell Publishers)

9. Williamson, Timothy (2000). Knowledge and Its Limits. (Oxford: Oxford University Press).

10. Seife, Charles Proofiness, The dark art of Mathematical Deception,  pub Viking Press 2010.