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Genetics

Gregor Mendel (1822-1884) wasthe first to explain that certain'traits' were inherited in plantsfrom one generation to the next.These would later become knownas genes. Frederich Miescher in1869 analyzed a substance fromthe nucleus of cells, which hetherefore called nuclein. Furtherstudy of nuclein revealed that itcontained elements like hydrogen,oxygen, nitrogen and phosphorous,with a specific ratio of nitrogen tophosphorous. Then in 1878Albrecht Kossel determined thatnuclein contained nucleic acid, fromwhich he isolated five nucleobases(nitrogen compounds now referredto by the letters C, G, A, T, Urepresenting cytosine, guanine,adenine, thymine, and uracil). Itwas also discovered that ribose, asugar was present in the nucleincompound. What Miescher hadisolated from the cell nucleus wasactually what would latter beidentified as DNA (Deoxy-ribo-Nucleic-Acid).

In 1888 the term chromosome wasfirst suggested by von Waldeyer(1836-1921) to describe thecarriers of these traits located inthe nuclein. The name refers to theway they were identified using

dyes, combining the Greek wordschrome (color) and soma (body).Then in 1909 Wilhelm Johannsencoined the term 'gene' to refer tothese traits. He also distinguishedwhat he called the genotype todescribe the genetic constitution ofan organism, and the phenotype todescribe the rest of the organism.Phoebus Levene in 1919 identifiedthe nucleobase, sugar and phosphatethat made up a unit called anucleotide, which later X-raydiffraction patterns showed wereregularly occurring in the strand ofDNA.

Linus Pauling (1901 – 1994) proposedthat the DNA structure was a triplehelix in 1952, but this proved to beelectrostatically unstable. The nextyear in 1953, James Watson (1928 -present) and Francis Crick (1916 –2004) made their case for a doublestranded DNA, following the discoveryof Rosalind Franklin (1920 -1958).This is the model we use today.

While this chemical and structuralanalysis of genes proved to be ofgreat importance in the study of theconstituents of organisms, it missedthe even more important role playedby the living condition from whichthey were abstracted. The attempt tointerpret only the molecularconstituents of an organism, and the

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July 2014

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Bhakti Madhava Puri, Ph.D.

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Sripad Bhakti Madhava Puri, Ph.D.

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Bhakti Niskama Shanta, Ph.D.

Bhakti Vijnana Muni, Ph.D.

Syamasundar Das, BA (Hons) Arch.

Jadu Krishna Das, BS Chem. Engr.

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chemical reactions associated with them isinsufficient for describing the living or in vivoactivity that actually occurs in a thrivingorganism. Take away the life of an organism andall the chemical reactions that weresystematically occurring stop, despite all thesame chemicals being present. In other words,it is not just a matter of chemical reactionsproducing life.

The hypothetical DNA theory, established by thehistorical study of DNA isolated and crystallizedfrom an organism's nucleus, only gives us achemical picture of what is going on in anorganism. The actuality of the living organism'sfunctionality is vastly underdetermined by suchchemical descriptions. In order to determinehow genes are functioning in their livingenvironment, selected mutations by x-radiationor other means is used to establish what aparticular gene is doing or not doing. Theconception of genes established by this type ofinvestigation was summarized in a paper by L.J.. Stadler in 1954, in which he gave what isappropriately called the operational definition ofa gene [1].

Stadler writes:

[O]perationally, the gene can bedefined only as the smallestsegment of the gene-string thatcan be shown to be consistentlyassociated with the occurrence ofa specific genetic effect.

(1) It cannot be defined as asingle molecule, because we haveno experimental operations thatcan be applied in actual cases todetermine whether or not a givengene is a single molecule”; (2) “itcannot be defined as an indivisibleunit, because, although ourdefinition provides that we willrecognize as separate genes anydeterminers actually separated bycrossing over or translocation,there is no experimental operationthat can prove that furtherseparation is impossible”; and (3)for similar reasons, it cannot bedefined as the unit of reproductionor the unit of action of the gene-string, nor can it be shown to bedelimited from neighboring genesby definite boundaries.

The operational definitionmerely represents theproperties of the actual gene,so far as they may beestablished from experimentalevidence by present methods.The inferences from thisevidence provide a tentativemodel of the hypothetical gene,a model that will be somewhatdifferent in the minds ofdifferent students of theproblem and will be furthermodified in the light of furtherinvestigation.

Further investigation came with the molecularstructure of DNA being established along witha host of other discoveries brought about bymolecular biologists. The complexities of thebasic function of protein formation so vital toa cell was as much increased by such analysis,as simplified or made clearer forunderstanding. There are billions and trillionsof atoms in a cell, all working together to keepit alive. Such a well organized system is notmaintained by chemical reactions alone. R. A.Jorgenson writes [2]:

"In modern terms, knowing thecomplete sequence of achromosome does not allow usto precisely determine all of themany interdependent elementsof a gene, including all thoseelements in cis that arenecessary for the normaloperation of a given gene thatis associated with a specificgenetic effect."

Epigenetics – between genotype and

phenotype

C. H. Waddington (1905 - 1975) firstproposed the term “epigenetics” in 1942 todescribe the region between the gene and thewhole organism (phenotype) [3]. Today, whatis called the epigenome refers to all thechromosomal modifications, DNAmodifications, chromatin protein modificationsand their complexes. It is the epigenome thatdetermines both the expression of the genesand their inheritance. R. A. Jorgenson reports[4], "Many of these modifications appear tobe “programmable” and to be “read out” to

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influence chromosomal functions." Nobellaureate Barbara McClintock stated thisrevolutionary proposal more clearly in herNobel lecture [5], “to determine the extent ofknowledge the cell has of itself, and how itutilizes this knowledge in a ‘thoughtful’ mannerwhen challenged.”

The difference between chromatin and chromosome. [6]

Paragenetics

In 1960 R. A. Brinks suggested thatchromosomes possess a paragenetic functionin addition to their genetic function [7]. Thephysical nature of the paragenetic function ischaracterized by the variety of forms or statesof chromatin that can reside at any geneticlocus. While the genetic function is stable, theparagenetic function is labile andprogrammable in ontogeny. It is this latterfunction that allows organisms to transferinformational macromolecules (RNA andproteins) in a systematic and regulated mannerover what is known as the “RNA informationsuperhighway.” Given this capacity, organismsmay be able to store information at numerousgenetic loci in the form of parageneticchromatin states, which can be reprogrammedduring ontogeny or environmental stress [8].This reprogrammable system could operateover the whole organism as a storage device,

,

allowing it to make informed ‘decisions' during

growth and development, or in response to the

environment. Such processing capacity could be

considered a form of ‘intelligence,' which also could

be passed on to future generations.

The study of the flow of information within and

between cells and organisms represents the cutting

edge of modern biological research. While physical

correlates of cognitive behavior in living organisms

are being discovered, it does not spell reduction to

such correlates. The electronic activity within the

physical components of a radio, for example, may

be minutely determined, but ultimately it is not

merely the electrical activity that produces the

intelligent speech that is heard. Only the intelligent

person whose voice is being broadcast through the

radio can explain that. Without the broadcaster,

the radio would sit silently even though fully

functional. An organism without its living agency

also appears to be devoid of metabolic activity

although all the chemical components are fully

present.

How to connect life to matter will be the ultimate

challenge that has to be met. This will prove to be

a philosophical problem we hope to address in the

near future.

References

1. Stadler, L. J. (1954). The gene. Science 120, 811–819.

2. Jorgensen, R. A. (2010). Of genes and genomes:

challenges for the twenty-first century. Front. Plant

Sci. 1:1. doi: 10.3389/fpls.2010.00001

3. Waddington, C. H. (1942). The epigenotype.

Endeavour 1, 18–20.

4. Jorgensen, R. A. (2004). Restructuring the genome in

response to adaptive challenge: McClintock’s bold

conjecture revisited. Cold Spring Harb. Symp. Quant.

Biol. 69, 349–354.

5. McClintock, B. (1978). Mechanisms that rapidly

reorganize the genome. Stadler Genet. Symp. 10, 25.

6. http://www.diffen.com/difference/Chromatin_vs_

Chromosome

7. Brinks, R.A. (1960). Paramutation and chromosome

organization. Rev. Biol. 35: 120.

8. Jorgenson, R. A., et. al., (2006) A Paragenetic

Perspective on Integration of RNA Silencing into the

Epigenome and Its Role in the Biology of Higher

Plants. Cold Spring Harb. Symp. Quant. Biol. 2006 71:

481-485.

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became an important critic of recapitulationtheory [4].

As evolutionary biologists did not find any scopefor demonstrating recapitulation of phylogeny theonly option was to pursue the theory that perhapsontogeny could somehow lead to evolution. Thisbecame one of the dominant themes of the workof many embryologists who somehow tried toexplain their findings through the ModernSynthesis. This included Garstang, Sir GavinRylands de Beer and Balfour [5]. De Beer cameup with the idea of heterochrony (developmentalchanges in the timing of events, leading tochanges in size and shape) as providing a centralrole for evolution. Heterochrony had threedimensions: (i) Pre-displacement and post-displacement, (ii) neoteny (the change in timingof developmental events: slower) and, (iii)hypermorphosis (the change in timing ofdevelopmental events: further). This was basedupon the idea of rate genes, which is a Mendeliangene that controls the speed of a particulardevelopmental process. For him novelties couldoccur at any stage of development. He criticizedthe Haeckelian idea that evolutionarymodifications could occur only among adultcharacters as terminal additions to an ontogenicsequence. A different set of concepts were beingborn in the beginning of 20th century due to arealization of the importance of epigenesis [6].

Homology: One of the big problems to

Evolution

De Beer understood that homology was a bigproblem for evolution. Spemann (Fig.1) had alsorejected Haeckel’s recapitulation theory as well asGegenbaur’s evolutionary morphology and

Introduction

Evolutionary Developmental biology seeks to searchout the causal factors behind evolution andontogeny. Modern biology recognizes that populationgenetics is not sufficient to explain species diversity.In addition, due to a failure in understanding theorigin of structural novelties and body plans frommere genetics, a deeper approach that includes asystematic organic concept is necessary to realize areasonable explanation of species diversity. Moderndevelopmental biology faces questions well beyondboth Darwin’s idea of evolutionary mechanisms andthe Modern Synthesis. Even developmental biologyhas become one of the strongest proofs againstevolution of body plans.

Embryology: The strongest proof against

evolution

Darwin had considered embryology to be one of thestrongest proofs for evolution. He wrote,“Embryology is to me by far strongest single classof facts in favour of (evolutionary) change of form[1],” and, “Embryology in Chapter VIII is one of mystrongest points I think [2].” Darwin got supportfrom Weismann, Haeckel, Roux, etc. but by around1900 ontogeny and evolution became separated dueto a series of setbacks. The experiments of Drieschhad disproved preformism and Roux’s theory ofEntwicklungsmechanik or developmental mechanics.Driesch became a vitalist and proposed the conceptof entelechy. In this way Roux and Drieschrepresented two poles in developmental biology, viz.preformationism and epigenesis at the beginning ofthe 20th century.

Darwinian evolutionary embryology was primarilybased upon the then prevailing concept of shareddevelopmentally conserved stages, universality ofthe germ layers etc. which used the criterion ofhomology. The concept of embryological archetypeshad dominated zoology after Darwin. But biologistslike Francis Maitland Balfour and Walter Garstangcame to think of Haeckel’s interpretation asexcessive by the beginning of 20th century [3].Embryology had not revealed any ancestral patternswhich could be used for the extrapolation fromontogeny to phylogeny. Balfour became aware ofthe features in the early ontogeny of secondaryadaptations but he could not find there any proof ofinheritance of ancestral characters. Garstang also

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Bhakti Vijnana Muni, Ph.D.

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phylogenetic trees. He rejected the genetic conceptof homology as highly speculative. He took theexample of regeneration of experimentallyremoved lenses in the eyes of amphibians. Eventhough the regenerated lens in the eye is lesshomologous than the older lens, it had developedfrom a different source than the original one. Dueto having a separate origin it could not count ashomologous based on the genetic definition ofhomology. An adult structure could be traced backto a developmental precursor but it has nocorrespondence to any structure in the egg. Thusit exists only potentially in the egg leading to aconclusion that the structure of the offspring isrelated to parental structure only ideally [7].

In this way experimental embryology revealed thathomology was not so straightforward. De Beeraccepted that developmental biology offered asubstantial challenge to our understanding of thenature of homology [8]. For example, homologousstructures need not develop from the same part ofthe egg or embryo. Further, they may not generatefrom the same germ layers. They need not beinduced by the same organizers or inductionprocesses. Homologous structures could arise bymeans of quite different developmental processes.It showed that early developmental stages ofdifferent species contained substantial differences.Development in the later stages, i.e. during theadult stages, reflected these differences in theearly stages of development. The earlydifferentiation was compatible with thedifferentiation of structures found in the adultstages. De Beer understood that it was futile to tryto map sameness of structures by the samenessof a limited and particular set of genes. It is nowunderstood that phenotypic structures that arecontrolled by identical genes can be non-homologous, homologous characters can becontrolled by non-identical genes. De Beer said,“It is now clear that the pride with which it wasassumed that the inheritance of homologousstructures from a common ancestor explainedhomology was misplaced; for such inheritancecannot be ascribed to the identity of genes. [9]”He further said, “But if it is true that through thegenetic code, genes code for enzymes thatsynthesize proteins which are responsible for thedifferentiation of the various parts in their normalmanner, what mechanism can it be that results inthe production of homologous organs, the same‘patterns’, in spite of their not being controlled bythe same genes? I asked this question in 1938,and it has not been answered. [10]”

Hourglass model is highly controversial

Experimental confirmation of the incorrectnessof Haeckel’s idea of the recapitulation theory hasbeen reported abundantly. This idea wasoriginally given by von Baer in 1828 as a guidingprinciple of comparative embryology and is wellknown as his third law [11]. It was an intuitivespeculation of Darwin that animal morphologywill be more conserved in the early stages ofembryology and less in the adult forms. Hethought this was the most reasonable and themost compelling evidence in favor of commondescent. In that line of thinking natural selectionwill have the greatest opportunity to effectevolution in the adult stages and the least duringthe early embryological stages. In the earlierstages the adaptive possibilities would be lessas they should be more pruned as a result ofancestral evolution or differentiation. Earlierembryological forms would represent the morenecessary features and would afford lesseropportunities to diverge. Adult structureshowever should have more signs of speciesspecific adaptations. However studies ofmorphological development did not confirmDarwin and von Baer. Studies show remarkabledivergence between related species within thesame phylum. This divergence can be seen bothin the early and as well as in the later stages indevelopment. These have very little apparentinfluence on adult morphology. This has been asaga that is completely against any Darwinianidea.

Modern developmental biology however coineda term called the ‘pharyngula stage’ or the‘phylotypic period’ for the morphology thatoccurs in mid-embryogenesis in an attempt torevive evolutionary developmental biology in theera of post Haeckelian debacle. This is thehourglass model (Fig. 2) proposed by Denis

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Duboule and Rudolf Raff in the 1990’s. Thehourglass model suggested that in thephylotypic period there is a relative conservationamong different species of the same phyladuring mid-embryogenesis. This meant thateven though the morphological studies doindicate extensive divergence both in the earlyas well as the later stage, mid-embryogenesiscoincides with a period of maximal similaritybetween all the species within each animalphylum.

This led evolutionary biologists towards evenmore speculative theories about gene-development nexus. One theory considered thatas in the phylotypic stage there is substantialincrease in the interactions between gene anddevelopmental processes, any resultingevolutionary modification will be highlydeleterious as a result of extensive anddamaging side-effects. Another theoryconsidered that as a result of increase in thehighly coordinated and precise activitynecessary for the growth and patterning duringthe phylotypic period, there would necessarilybe a relatively conserved stage among thedifferent species of the same phyla. The genomicorganization of the Hox genes became a focalpoint for establishing these theories. Hox genesare an abbreviation of the term homeobox andare a group of related genes that control thebody plan of an embryo along the anterior-posterior axis. These genes are necessary indetermining the type of segment structures likelegs, antennae and wings in fruit flies and alsothe number and structure of vertebrate ribs inhumans that will form on a given segment afterthe embryonic segments have been formed.

The hourglass model is a kind of heterochronousconcept which is concerned with the timing ofembryological processes. Although support forthe hourglass model was found in some studiesfrom morphology as well as genetic sequencestudies it has remained a controversial subject.Some studies claim the exact opposite, thatthere is a peaking of divergence at thephylotypic period and there is no temporalpattern of phenotypic conservation. E.g.Richardson et. al. wrote a paper entitled [12],“There is no highly conserved embryonic stagein the vertebrates: implications for currenttheories of evolution and development”. Theyexplain there that, “In view of the currentwidespread interest in evolutionarydevelopmental biology, and especially in theconservation of developmental mechanisms,

re-examination of the extent of variation invertebrate embryos is long overdue. We findthat embryos at the tailbud stage — thought tocorrespond to a conserved stage — showvariations in form due to allometry,heterochrony, and differences in body plan andsomite number. These variations foreshadowimportant differences in adult body form.Contrary to recent claims that all vertebrateembryos pass through a stage when they arethe same size, we find a greater than 10-foldvariation in greatest length at the tailbud stage.Our survey seriously undermines the credibilityof Haeckel's drawings ... The wide variation inmorphology among vertebrate embryos isdifficult to reconcile with the idea of a phylo-genetically-conserved tailbud stage, andsuggests that at least some developmentalmechanisms are not highly constrained by thezootype. Our study also highlights the dangersof drawing general conclusions about vertebratedevelopment from studies of gene expressionin a small number of laboratory species.”

Further Beninda Olaf et. al. report, “Thephylotypic stage has never been preciselydefined, or conclusively supported or disprovedby comparative quantitative data. We testedthe predictions of the ‘developmental hourglass’definition of the phylotypic stage quantitativelyby looking at the pattern of developmentaltiming variation across vertebrates as a wholeand within mammals. For both datasets, theresults using two different metrics were counterto the predictions of the definition: phenotypicvariation between species was highest in themiddle of the developmental sequence. Thissurprising degree of developmental characterindependence argues against the existence ofa phylotypic stage in vertebrates. Instead, wehypothesize that numerous tightly delimiteddevelopmental modules exist during the mid–embryonic period… The onus is now clearly onproponents of the phylotypic stage to presentboth a clear definition of it and quantitative datasupporting its existence [13].”

Hox genes, Developmental Biology and

Evolution

Hox regulatory genes are also genes and thismakes them a candidate for the sameMendelian rules as any other gene clusters.Some experiments also have been performedto demonstrate their Mendelian nature. Forexample the Rx homeobox gene of miceactivates the process essential to the formation

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of the eye and its bony orbit [14]. The debateproduced by the Cambrian fossil record has givenimpetus to find mechanisms that can show thatevolution could be a rapid process of organismalreorganization. This has produced a debatewhether one define a species on the basis ofgenes, morphology, geography or reproductiveisolation [15]. As Hox genes have an importantrole in the development of body plans, they areproviding an appealing starting point for suchstudies in understanding the causal role in theregionalization of the body plans of all bilaterallysymmetric animals. The speculation is rife thatthey may provide a new way to understandevolution in a redefined way. In this way it isspeculated that it may come to the rescue ofevolution by covering the lost ground for Modernsynthesis which failed to integrate withdevelopmental biology during the last century.

As Hox genes play an important role indevelopmental biology they seem to link thedevelopmental processes with evolutionarymechanisms governed by genetic changes bybringing them closer to epigenesis. In spite of allsuch claims the speculations are more heuristicthan factual. Genetic research does not reallyaim at the study of development as such, buthas rather aimed strictly to the study of their roleset against a constant developmentalbackground [16]. The Hox genes are sometimescalled ‘master genes’ or master controllers. Thisis meant to portray their crucial role asdevelopmental switches. They trigger largenumbers of downstream genes in the generationof complex structures like the eye. But suchapproaches are criticized for too much hedging.Epigenesis is the antithesis of preformationism.Waddington had tried to produce a non-mysticaland non-vitalistic account of development bycombining epigenesis with genetics, an accountwhich he called epigenetics. Although generegulation is important to development, it is atthe same time not all that important. This factbegan to become clear after the experiments ofDriesch (Fig. 1). Due to these considerations(failure to integrate epigenesis with genetics)Hox genes became a good candidate to explainthe genetic basis of developmental biology. Ithas been found however that the experimentalmanipulation of these genes only produces somegrotesque or monstrous features. E.g. inDrosophila the antennae were converted intolegs, or it effectively transformed the thirdthoracic segment into another second thoracicsegment, or produced a second set of wingsinstead of halteres. Because of these the idea ofHox genes as master controllers gained some

air. But it has subsequently been understoodupon reflection that they are not so muchmaster controllers but act more like efficientmicromanagers. Hox genes are themselvessubject to regulation as all other genes bycellular processes like cell-cell signaling. Eventhe so called ability of Hox genes to producelarge scale rearrangements of body plans ismore context dependent. E.g. Akam says,“When it comes to the downstream targets ofthe Hox genes, context is everything, inparticular, which other transcription factors arepresent in the same cell will be a key factordetermining the outcome of Hox gene action.”[17]

This made the Hox gene’s epithet of beingmaster controller an overestimation andresulted in the overselling of Hox genes indevelopment. This also indicates its limitationsin effecting any evolutionary changes. E.g. Buddproposes along the lines of the concept of thegenetic assimilation of Waddington thathomeobox genes are used post hoc tostreamline developmental processes oncegradual morphological change has occurred. Hecalls this model ‘homeotic takeover’ which maybe more amenable to the concept of naturalselection [18]. It significantly downgrades theestimated capacities of Hox genes and bringsthe whole question of evolution significantlycloser to same parameters which the Mendeliangenes have already been subjected to.

Mueller points out that the origin of novelty andits role in the evolution of phenotypic complexityrepresents an evolutionary problem that hadbeen sidelined by the Modern Synthesis due toits focus on variation and population dynamics.Major theoretical consequences of the evo-devoconjecture depend on the properties ofdevelopmental systems. An understanding ofthe problems faced by evolutionary biology hasled to the proposal that organismal evolutionprogressed from a pre-Mendelian world to theMendelian one that we study today [19]. Modernorganisms are Mendelian in the sense thatgenotype and phenotype are inherited in a closecorrelation, and development is under program-like genetic control. The developmentalmechanists pin their hopes on the existence ofa hypothetical pre-Mendelian world where amuch looser connection between genotype andphenotype would have prevailed. This couldhave permitted the generation of multiple formsfrom single genotypes depending onenvironmental influences [20]. Thesespeculations are examples of typical tendency

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of reverting to excessive hedging. More hedgingis seen when they try to justify that the genericphysical properties of cells, cell aggregates andtissues would have been the decisivedeterminants of biological form before the adventof genetic programs which would have frozen theforms only later. This significantly complicatesliving processes placing them in an unknownterritory of which there is no evidence of existence.

Limitation of Genetics in explaining evolution

Many scientists like J. A. Shapiro, McClintock,Zent-Györgyi, George Wald and Anthony Flewovercame any linear, mechanical and digitalconcept of cell based on the concept of gene thatarose within post Mendelian biology. The conceptof gene had gained a realist interpretation interms of segments within the DNA molecule inthe 20th century. But Ruth Hubbard wrote a booknamed, ‘Exploding the Gene Myth’ [21] whereshe explained, “The myth of the all-powerful geneis based on flawed science that discounts theenvironmental context in which we and our genesexist.” Shapiro has compared the attempts of thegeneticist in trying to explain life in terms ofgenes with that of a man searching for the keysunder a lamppost [22]. McClintock clearly sawthat the genome was a member of the cellularapparatus which was itself subject to cellularcontrol [23]. As the concept of “gene” has evolvedinto a more dynamic and inclusive conception,any oversimplified understanding of livingorganisms in terms of only discrete interactingmolecules does not have any actual explanatorysignificance. Living organisms are dynamicallycomplex functional entities which are irreducibleto simple mechanical-chemical descriptions [24,25]. This means that all our evolutionary viewshave become flawed as randomness andnecessity will never be able to explain evolution.The growing realization of the sentient conceptof the cellular phenomenon is squarely bringingthe question of evolution into the domain ofcognitive control. McClintock for example cameto consider organisms as subjective beings fromher research [26]. The major realization withinpost-Mendelian biology is that Mendel’sexperiments managed to bring to light only somepartial truth in terms of genes but the whole truthis proving to be an organic-systematic sentientconcept.

Conclusions

The problem of organismal form is an ancientdispute among different kinds of philosophers andscientists. Aristotle explained that the soul is thefirst principle of living organisms and

distinguished them from non-living objects likerocks which have no soul [27]. The disputebetween pre-formationism and epigenesis, forinstance in Roux and Driesch, represent the twopoles of the developmental argument whichdemand all our attention even now. Due to thetheoretical analysis of experimental resultsscientific understanding has already led biologiststo undertake a deeper level of theoretical andontological underpinning. No mechanization likethe evo-devo and developmental systems theoryhas any realistic solution. With the growingrealization of the limitations of these approachesthe time is now ripe for the biological sciences toexplore a more cognitive role in geneticassimilation and developmental integration.According to Vedanta there is no evolution beyonda species. This is confirmed in the fossil recordswhich show sudden appearance of forms andstasis. The Vedantic idea is that there isconservation of species identity in Nature.Essentially Nature is living or biocentric and is afar cry from the chemical understanding of 20thcentury. The sensory capacities of organismsprovide the basis for a very important newparadigm for biology. Organisms are regarded asintelligent and sentient. Our hope is that scientistspursuing the 21st century evolutionary biology willbecome conversant with these principles of life andwill be able to see biology from that new and freshlight.

Finally the author would like to express his deepindebtedness and gratefulness towards his sikshagurudev Sripad Bhakti Madhava Puri Maharaja,Ph.D. for the detailed discussions and guidanceimparted to him in bringing out this article as anoffering of humble service.

References

1. Darwin, C. R., (1860). Letter to Gray, A.,

Sept. 10,

www.darwinproject.ac.uk/letter/entry-2910

2. Darwin, C. R., (1859). Letter to Lyell, Sept.,

25,

www.literaturepost.com/chapter/7741.html

3. Hall, B. K., (1998a). Germ layers and the

germ-layer theory revisited: Primary and

secondary germ layers, neural crest as a

fourth germ layer, homology, demise of the

germ-layer theory. Evol. Biol. 30: 121–186.

4. Hall, B. K., Wake, M. H., (1999).

Introduction: Larval development, evolution

8

and ecology. The origin and evolution of

larval forms (Academic Press, San Diego),

pp. 1–19.

5. Hall, B.K., (2000). Balfour, Garstang and de

Beer: The First Century of Evolutionary

Embryology, Amer. Zool., 40:718–728.

6. Ibid., 5.

7. Brigandt, I. (2006). Homology and

Heterochrony: The Evolutionary

Embryologist Gavin Rylands de Beer

(1899–1972). Jour. Exp. Zool., pp. 317–

328.

8. de Beer, G. (1971). Homology: An

Unsolved Problem (Oxford University

Press), pp. 16.

9. Ibid., 8

10. Ibid., 8.

11. von Baer, K. E., (1828). Uber

Entwickelungsgeschichte der Thiere:

Beobachtung und Reflektion (Koenigsberg).

12. Richardson, M.K., Hanken, J., Gooneratne,

M.L., Pieau, C., Raynaud, A., Selwood, L.,

Wright, G.M., (1997). There is no highly

conserved embryonic stage in the

vertebrates: implications for current

theories of evolution and development.

Anat. Embryol. (Berl), 196(2), pp. 91-106.

13. Bininda-Emonds Olaf, R. P., Jeffery, J., E.,

Richardson, M.K., (2003). Inverting the

hourglass: quantitative evidence against

the phylotypic stage in vertebrate

development. Proc. R. Soc. Lond. B, 270,

1513, pp. 341-346.

14. Mathers, P., Grinberg, A., Mahon, K.,

Jamrich, M., (1997). The Rx homeobox

gene is essential for vertebrate eye

development. Nature, 387, pp.604–607.

15. Schwartz, J.H., (1999). Homeobox Genes,

Fossils, and the Origin of Species. The

Anat. Nat. Rec., 257, pp. 15–31.

16. van derWeele, C. (1999). Images of

Development: Environmental Causes in

Ontogeny (Albany: State University of

New York Press).

17. Akam, M., (1998). Hox genes, homeosis

and the evolution of segment identity: No

need for hopeless monsters. Int. Jour.

Dev. Biol., 42, pp. 445–451.

18. Budd, G., (1999). Does evolution in body

patterning drive morphological change –

or vice versa? BioEssays, 21, pp. 326–

332.

19. Newman, S.A., (2005). The pre-

Mendelian, pre-Darwinian world: Shifting

relations between genetic and epigenetic

mechanisms in early multicellular

evolution. Jour. Bio., 30, pp. 75–85.

20. Ibid., 19.

21. Hubbard, R., Wald, E., (1999). Exploding

the Gene Myth: How Genetic Information

Is Produced and Manipulated by Scientists,

Physicians, Employers, Insurance

Companies, Educators, and Law Enforcers

(Beacon Press).

22. Shapiro, J. A., (2011). Evolution: A View

from the 21st Century (FT Press Science),

pp. 3.

23. Harmann, H., (2002). Macrorvolution,

Catastrophe and Horizontal Transfer, In

Horizontal Gene Transfer (Ed. Syvanen,

M., Kado, C.I., Academic Press), pp. 424.

24. Puri, B.M., (2012). The Science of Spiritual

Biology. The Harmonizer, Nov., pp. 1.

25. Gerstein, M.B., Bruce, C., Rozowsky, J.S.,

Zheng, D., Du, J., Korbel, J.O.,

Emanuelsson, O., Zhang, Z.D., Weismann,

S., Snyder, M., (2007). What is a gene,

post-ENCODE? History and updated

definition. Genome Res., 17, pp., 669-681.

26. Keller, E.F., (1983). A Feeling for the

Organism, 10th Anniversary Edition: The

Life and Work of Barbara McClintock

(Freeman, San Fransisco), pp. 200.

27. Aristotle, (2006). On The Soul (trans. J.

A. Smith, Digireads).

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sum of its parts” and the claims of Immanuel Kant[4]:

“there will never be a Newton ofthe blade of grass, because human

science will never be able to

explain how a living being canoriginate from inanimate matter”

Glitch of Reductionism in Immunology

Biologists believe that biological systems arecomposed exclusively of atoms and molecules(without consciousness and soul) and it is feasibleto explicate life by physicochemical properties oftheir individual constituents, down to the atomiclevel. Francis Crick stated, “The ultimate aim of themodern movement in biology is to explain allbiology in terms of physics and chemistry” [5] andfor more than half century this mindset guided theresearch in molecular biology. However, in thismindset biologists misconceive biological systems,which are complex, functional wholes. The dynamicintegrated relationship of biological systems cannotbe understood by study of their individualconstituent parts. The complex nature of afunctional whole also cannot be realized orpredicted from the properties of the individual,isolated components. [6]

In biology textbooks cells and organelles areexplained in the form of their constituents.Physiology and psychology are explained as anoutcome of biochemistry and neurophysiology,respectively. Similarly, immunology is alsodescribed in terms of molecular properties ofantibodies, T-cell receptors, majorhistocompatibility complex molecules, cytokinesand proteasomes. Studying these narrations,students get the impression that living organismsare mere physicochemical systems. However,

advancement inbiology confirmsthat such anapproach has ad e t r i m e n t a linfluence onb i o m e d i c a lresearch, andespecially ondrug discoveryand vaccinedevelopment. In

this approach there is an intentional predominance

Biology is Spurning Reductionism

To understand how life works, scientists must relyupon simplification (idealized models anddeterministic concepts), both in terms of analysisand explanation. René Descartes introducedreductionism by explaining that the world can beconsidered to be a clockwork mechanism. Accordingto Descartes, to understand a whole we have tostudy the parts and with that knowledge of parts wecan reassemble each component to recreate thewhole. Descartes’ ‘clockwork universe’ is thefoundation of the Newtonian mechanistic approachand scientists, including biologists, use this approachto understand reality. Following this approach,scientists are looking for an objective representation(by reducing the whole to its simplest components)of an extremely complex reality.

Influenced by this guiding vision biologists try toexplain life in terms of physical and chemicalproperties of individual components of the body of aliving organism. Reductionism can be classified inthree categories: (1) ontological reductionism (everysystem is composed of certain fundamentalelements), (2) epistemological reductionism (lawsand theories of a complex system can be obtainedfrom laws and theories of a lower level system), and(3) methodological reductionism (knowledge ofcomplex systems can be grasped by studying theirindividual constituents). Reductionism is commonlypracticed as an analytical methodology to exploremolecular and cellular processes in biology. Themethod of dissecting biological systems into theirconstituent parts has been successful in developinga catalog of the chemical constituents of numerousliving processes. However, this reductionism isreaching its limits and such approach cannot addressthe complexity of either a smallest functional cell [1]or a complex human brain [2]. An increasing numberof scientists argue that biological systems cannot beconceived by Descartes’ clockwork model. Biologicalsystems cannot be grasped either by thedeterminism of Newtonian mechanics or by randomsystems analysis of statistical mechanics [3]. Theproperties of a protein are not equal to the sum ofthe properties of each amino acid. In a living cellproteins can distinctively catalyze a chemical reactionor identify an antigen not only because their aminoacids are arranged in a particular manner, but alsobecause their three-dimensional structure andfunction are controlled by sentient living cell. Theempirical evidence in 21st century biology confirmsAristotle’s statement, “The whole is more than the

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Bhakti Niskama Shanta, Ph.D.

Immanuel Kant

of physical explanation over biological explanation[7] and it is presumed that the complete natureof a higher level can be understood form theproperties of a lower level.

Nagel [8] explained that reductionism tries toelucidate the details of a higher level theorythrough the theory of lower levels, and itpresumes that axioms and laws of the higher levelcan be inferred from the theory of lower levels.Therefore, reductionism is completely dependenton the feasibility of interlinking the terms of lowerlevel and higher level theories, and on theviability of rationally obtaining laws from thelower level theory that are valid for the higherlevel theory. [9] The reductionist approach ofdissecting the immune system into its partsbreaks the dynamic integrated relationship of theparts and in the process the vital irreduciblecharacteristics of the immune system as a wholeare destroyed. It is an attempt to understand theimmune system by examining its constituents inisolation and without interference from theenvironment. Although this type of simplisticapproach is useful for immunologists to gain someknowledge of different mechanisms at work inindividual parts of the immune system, but byfollowing this approach immunologists cannotachieve a sufficient rational explanation for thefunctioning of the complex immune system as awhole. The dynamic integrated relationshipbetween the constituents of a biological systemcannot be realized by totaling the characteristicsof its isolated parts. [6] Several aspects ofimmunogenicity depend upon biological potential(like, immunoglobulin gene repertoire, self-tolerance, the production of cytokines, andvarious cellular and regulatory processes) of hostorganism, but we cannot find that when the partsare examined discretely. Moreover, areductionistic approach cannot explain how theseaspects of the immune system are controlled ina host organism to produce neutralizingantibodies. [10] Antibodies also work in anintegrative manner and the neutralizing synergybetween various antibodies cannot be reduced tothe straightforward addition of effects ofconstituent molecules in isolation. [11] Themethods based on a reductionistic approachcannot plausibly have power over the immunesystem and hence are inefficient for developmentof vaccines.

Naive Reductionism in Vaccine Development

A vaccine which can imitate the natural immuneresponse towards an infectious pathogen andpermanently safeguard against infection by thesame pathogen is considered a good vaccine. [12]

In vaccine development research, scientists try todevelop synthetic vaccines using the molecular dataobtained from the reductionistic knowledge ofimmunology. Such studies presume anoversimplified reality and hence are insufficient tomimic dynamic integrated biological phenomena oran organic whole. To know what causes protectionagainst a particular disease in the immune systemreductionists try to deactivate antibodies orcytotoxic T-cell responses. To find a physico-chemical explanation for the specific bindingreactions they dissect antigenic sites and cellularreceptors. To unravel the mechanism for how anindividual neutralizing antibody manages to attachto the target antigen they study the antigen-antibody complexes using X-ray crystallography.Such approaches are useful for amassing significantdata and information for structural links of differentinteractions during infectivity neutralization.However, using the same data and informationimmunologists cannot explain: (1) how immunesystem as a whole puts an end to the capability ofpathogen to infect its host, and (2) how vaccinationcan produce the necessary neutralizing antibodies.[13]

Due to a growing familiarity with molecularstructure of antigenic sites recognized by antibodiesand T-cell receptors, immunologists believe that itis possible to discover vaccines using the moleculardesign strategies found in structure-based drugdesign. [14] In that approach they overlook theuniqueness of the relationship between a drug andits receptor or target molecule. In a procedurecalled ‘rational design’ they make an attempt tomodify the structure of the drug slightly to achievean improvement in its biological function. Thissimplistic mechanistic view in abiology imposes anunjustifiable attention on a single cause tounderstand the functioning of an intricate biologicalsystem. The commonly practiced linear causalityexplanations in physics and chemistry areinsufficient to address the network and circularcausality of an organic whole. The immenselycomplex organic whole does not allow abiology tounravel all the causal relations of a functionaldynamic integrated biological phenomenon. [15]Due to a misunderstanding, reductionists falselybelieve that causality is a relationship between twochemicals/objects or between a structure and afunction. In reality, causality is a relationshipbetween successive events and abiology cannotestablish a unique causal relationship between thestructure and the function of a biomolecule in anorganism. In living organisms a single chemicalstructure of a biomolecule can execute manydifferent functions and also one function can beproduced by several different chemical structures.[16] Abiology can at best hunt for correlations and

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not causal relationships between a structure anda biological function. [17] A naive ‘rational design’of biomolecules in vaccine development researchcannot establish a relationship between‘neutralization of an infectious agent’ (biologicalfunction) and the structure of an antibodymolecule. High-throughput screening,combinatorial chemistry, genomics, proteomics,bioinformatics and so on are based onunmitigated reductionism and therefore havefailed to live up to the expectations in terms ofproduction of the new drugs. [18] Drug discoveryis driven by only a belief that in vitro cell culturesand computer models can help us understand lifeand therefore ignores the fact that in such an

a p p r o a c hthere is nocongruencebetween invitro assaysand the in

vivo systems.Moreover, amonotonous

application of animal models as a substitute forclinical studies in human disease has alsocontinually proven derisory. [19] Hence, suchoversimplified reductionistic approachesunderestimate the patients and life in general.[20]

Evolutionary Biology Imposes an Extreme

Reductionistic View

Evolutionary biology proclaims that during thecourse of evolutionary history natural selectioncan select a particular molecular structure that isresponsible for a specific function with survivaladvantage. [21] In an organism differentmechanisms with several different genes andgene products may be responsible for theappearance of the same function and vice versa.For example, using genome data scientists foundthat two enzyme functions are associated withseven different folds each [22] and severalbiochemical functions can be carried out byproteins with the same fold (even by membersof a single homologous family). [23] In suchsituations natural selection (only looking for afunction with survival advantage) has no meansto distinguish between different molecularstructures. Therefore, instead of structuralexplanation, this abiology attempts to provide afunctional explanation for the present biologicalstructures on the basis of survival advantages inthe past. Like a man looking-for-keys-under-the-lamppost evolutionists try to analyze DNAsequences with the belief that a linear causalsuccession connects the sequence of a gene to

the biological function of the product of that gene.This simplistic stance overlooks the role of cellularand extra-cellular environment, and of regulatorygenes when its claim that gene sequence isexclusively the cause of the manifestation of aco-linear protein sequence. Ignoring the role of thesentient cell, this view further believes that thethree-dimensional structure of the protein is solelydetermined by the protein sequence only. Immunesystem crystallographic studies of several antigen-antibody complexes show that a considerableamount of induced mutual adaptation of the twopartners takes place at the time of the bindingprocess. Some oversimplified reductionisticanalyses try to represent the binding site imagesas two-dimensional flat areas at the surface ofproteins, or even one-dimensional linear sequencesforming continuous epitopes without anyconformational characteristics. In reality, antigenicspecificity cannot be explained even by three-dimensional structures, because, in such bindingprocesses, time (the fourth dimension) also playsa crucial role. [24] It is now well established thateven at a cellular level all biological functions arewell regulated from within by a sentient cell. [25]The three-dimensional structure of an epitope isonly a time slice image of processes within anintegrated dynamic whole, and therefore, thestructure and function of a binding site cannot bestudied separately. Hence, the protein tertiarystructure cannot be predicted from sequenceinformation alone. [26]

Charles Darwin in his evolution theory advocatedan extreme reductionistic view that the humanability to form and hold beliefs had evolved frompurposeless chemicals and the lower animals.However, Darwin was concerned about the selfdefeating nature of his own theory: “With me thehorrid doubt always arises whether the convictionsof man’s mind, which has been developed from themind of the lower animals, are of any value or atall trustworthy. Would any one trust in theconvictions of a monkey’s mind, if there are anyconvictions in such a mind?” [27] In due course oftime Darwin’s abiology also produced a generalconsensus among scientists for an extremereductionistic view that in a future based on geneanalysis science can understand and control all thefunctions of living entities including psychologicalbehavior. However, in reality what to talk aboutpsychological behavior, even the simplestphysiological functions like muscle contractioncannot be understood by simplistic reductionisticbiochemical explanations such as the interactionbetween actin and myosin. [28] Biochemicalpathways do not precede physiological functionsand in reality they both take place at the sametime. Therefore, biochemical explanation cannot

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provide a causal rationalization for thephysiological event. [21] Evolutionary biology alsocannot provide functional explanations for whyantibodies exist, how antibodies meet therequirements to shield host organism againstinfection and how the antibodies with such anability to neutralize the infectivity of a pathogenare produced. [29] Evolutionary biologydogmatically believes that the majority of humandiseases are caused by the interaction of severalgene products. It is impossible for reductioniststo identify all the gene products that areresponsible for a specific biological function andmoreover, genetic information of one gene is alsodependent on other genes. The environment andboth cellular and extracellular conditions also playa vital role in deciding the way the geneticinformation can be expressed. Genes in isolationcannot do anything including self-replication,because biological functions are carried out withina sentient organic whole and those complexfunctions are inimitable in isolation. Ignoring this,experiments based on ‘single gene deletion’ arecontinually conducted in abiology to comprehendcomplex genetic networks. To understand the tasko f

individual genes reductionists perform knockoutexperiments in mice by inactivating or removinga particular gene. It is observed in the studiesthat: (1) in many of these experiments knockouthas no significant effect at all [30], (2) in somecases knockout has a completely unforeseen effect[31], and (3) disruption of the same gene canhave diverse effects in different strains of mice.[32] Such diverse observations and a naiveextrapolation of data from mice to other speciesonly prove the impracticality of this approach. [19]Only an insignificant number of new drug targetsare discovered based on human genome sequencedata. [33] Gene therapy, stem-cell research,antisense technology and cancer vaccines failedto deliver results as per expectation [18] andmoreover, they involve dangerous risks along withharmful side effects. [34]

Conclusion

In a living organism several events occur in whichone object is hidden by another object that passes

between it and the observer. For example, theantibody character of an immunoglobulin moleculecan be sensed only when its corresponding antigenis known. Similarly, the epitope character of a setof amino acids in a protein can be ascertained onlyby recognizing an immunoglobulin that can bind toit. [35] Due to this several biological functionscannot be described by a structure identifiablebefore the interactions. Cell sentience plays a vitalrole at antigenic sites in a protein and antibodycombining sites. Antibody specificity hassignificance only when cell’s sentient faculty allowsthe antibody to discriminate and react differentlywith two or more epitopes. Therefore, the simplisticreductionistic models are too far from reality to beable to understand and predict the antigenicspecificity. Sentience is essential in all biologicalfunctions and by dissecting a biological structureinto its atomic constituents it is impossible tounderstand the organic whole. Vaccinationcompletely depends on our immunologicalknowledge of sentient organisms. Inaccurateassumptions in simplistic models in reductionismcan cause autoimmune disease by altering abeneficial immune reaction into a harmful one.

Several studies in molecular biology do notrepresent genuine biology. Present drug discoveryresearch is also a purely protein chemistry becauseit is only concerned with molecular and atomicforces. It is misleading to include such studiesunder the field of immunology. In immunochemicalresearch scientists only study the chemistry ofinteraction between a protein antigen and anantibody molecule (also a protein). Therefore itcannot represent a genuine biology. In thisabiology immunologists are only making futileattempts to reduce biology to chemistry. Thebiological realm is driven by sentience and withoutthat we cannot have functions like pathogenidentification and elimination or the ability todiscriminate self from non-self. Frontier biologyacknowledges that even the smallest cells aresentient beings [36] and therefore advocates achange in the dogmatic reductionist stand of muchof the old biological research. In the field ofpsycho-neuro-immunology scientists are studyinghow immunity is affected by the cognitivephenomenon of depression, stressors, and severalother psychosocial aspects. The level of T-cells andresponses to mitogens were found lower instudents during the exam period. [37] People witha happy mood are found to have higher capabilityto fight off the cold when given a squirt of therhinovirus. [38] Reductionistic theories produce aloss of faith in religion, which has a great influenceon our health. Therefore, immunologists must heedthe lesson from the conclusions of the Encyclopediaof Medicine [39]:

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•“The recent trend towards integration of religionand medicine has been stirred primarily by

medical research demonstrating intimate and

often complex relationships between religion and

health… Over one hundred studies have nowdocumented the high prevalence of religious

coping among persons with a variety of diseases

ranging from diabetes, kidney disease, heartdisease, cancer, arthritis, and cystic fibrosis, to

more general conditions such as chronic pain…

Nearly 850 studies have now examined these

associations, with between two-thirds and three-quarters of these finding that the religious person

tends to be healthier and better able to cope with

illness.”

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