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CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Author and Curator: Larry H Bernstein, MD, FCAP

 

The previous Part II: Cracking the Code of Human Life,

Part II  From Molecular Biology to Translational Medicine:How Far Have We Come, and Where Does It Lead Us? Is broken into a three part series.

Part II A. “CRACKING THE CODE OF HUMAN LIFE: Milestones along the Way” reviews the Human Genome Project and the decade beyond.

Part IIB. “CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics” lays the manifold multivariate systems analytical tools that has moved the science forward to a groung that ensures clinical application.

Part IIC. “CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease “ extends the discussion to advances in the management of patients as well as providing a roadmap for pharmaceutical drug targeting.

Part III concludes with Ubiquitin, it’s role in Signaling and Regulatory Control.

This article is a continuation of a previous discussion on the role of genomics in discovery of therapeutic targets titled, Directions for Genomics in Personalized Medicine, which focused on: key drivers of cellular proliferation, stepwise mutational changes coinciding with cancer progression, and potential therapeutic targets for reversal of the process. And it is a direct extension of Cracking the Code of Human Life (Part I): “the initiation phase of molecular biology”.

These articles review a web-like connectivity between inter-connected scientific discoveries, as significant findings have led to novel hypotheses and many expectations over the last 75 years. This largely post WWII revolution has driven our understanding of biological and medical processes at an exponential pace owing to successive discoveries of chemical structure,

  • the basic building blocks of DNA  and proteins,
  • of nucleotide and protein-protein interactions,
  • protein folding, allostericity,
  • genomic structure,
  • DNA replication,
  • nuclear polyribosome interaction, and
  • metabolic control.

In addition, the emergence of methods

  • for copying,
  • removal and
  • insertion, and
  1. improvements in structural analysis as well as
  2. developments in applied mathematics have transformed the research framework.

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics Computational Genomics I. Three-Dimensional Folding and Functional Organization Principles of The Drosophila Genome Sexton T, Yaffe E, Kenigeberg E, Bantignies F,…Cavalli G. Institute de Genetique Humaine, Montpelliere GenomiX, and Weissman Institute, France and Israel. Cell 2012; 148(3): 458-472. http://dx.doi.org/10.1016/j.cell.2012.01.010/

Chromosomes are the physical realization of genetic information and thus

  • form the basis for its readout and propagation.

Here we present a high-resolution chromosomal contact map derived from

  • a modified genome-wide chromosome conformation capture approach
  • applied to Drosophila embryonic nuclei.

the entire genome is linearly partitioned into

  • well-demarcated physical domains that
  • overlap extensively with
  • active and repressive epigenetic marks.

Chromosomal contacts are hierarchically organized between domains.

Global modeling of contact density and clustering of domains show

  • that inactive domains are condensed and
  • confined to their chromosomal territories, whereas
  • active domains reach out of the territory to form
  • remote intra- and interchromosomal contacts.

Moreover, we systematically identify specific

  • long-range intrachromosomal contacts between
  • Polycomb-repressed domains.

Together, these observations allow for

  • quantitative prediction of the Drosophila chromosomal contact map,
  • laying the foundation for detailed studies of
  • chromosome structure and function in
  • a genetically tractable system.

Insert pictures

profiles validate the Hi-C Genome wide map

profiles validate the Hi-C Genome wide map

IIC. “Mr. President; The Genome is Fractal !” Eric Lander

(Science Adviser to the President and Director of Broad Institute) et al.
delivered the message on Science Magazine cover (Oct. 9, 2009) and
generated interest in this by the International HoloGenomics Society at
a Sept meeting.

  • First, it may seem to be trivial to rectify the statement in “About cover”
    of Science Magazine by AAAS. The statement “the Hilbert curve is a
    one-dimensional fractal trajectory” needs mathematical clarification.

While the paper itself does not make this statement, the new Editorship
of the AAAS Magazine might be even more advanced if the previous
Editorship did not reject (without review) a Manuscript by 20+ Founders
of (formerly) International PostGenetics Society in December, 2006.

  • Second, it may not be sufficiently clear for the reader that the
    reasonable requirement for the DNA polymerase to crawl along
    a “knot-free” (or “low knot”) structure does not need fractals. A
    “knot-free” structure could be spooled by an ordinary “knitting globule”
    (such that the DNA polymerase does not bump into a “knot” when
    duplicating the strand; just like someone knitting can go through
    the entire thread without encountering an annoying knot): Just to
    be “knot-free” you don’t need fractals.

Note, however, that the “strand” can be accessed only at its beginning –
it is impossible to e.g.

  • to pluck a segment from deep inside the “globulus”.

This is where certain fractals provide a major advantage – that could be

  • the “Eureka” moment for many readers.

For instance, the mentioned Hilbert-curve is not only “knot free” – but

  • provides an easy access to “linearly remote” segments of the strand.

If the Hilbert curve starts from the lower right corner and ends at the lower left corner,

  • for instance the path shows the very easy access of what would be the mid-point
  • if the Hilbert-curve is measured by
  • the Euclidean distance along the zig-zagged path.

Likewise, even the path from the beginning of the Hilbert-curve is about equally easy to access –

  • easier than to reach from the origin a point that is about 2/3 down the path.

The Hilbert-curve provides an easy access between two points

  • within the “spooled thread”;

from a point that is about 1/5 of the overall length

  • to about 3/5 is also in a “close neighborhood”.

This may be the “Eureka-moment” for some readers, to realize that

  • the strand of “the Double Helix” requires quite a finess to fold into
  • the densest possible globuli (the chromosomes) in a clever way
  • that various segments can be easily accessed.

Moreover, in a way that distances

  • between various segments are minimized.

This marvelous fractal structure

  • is illustrated by the 3D rendering of the Hilbert-curve.

Once you observe such fractal structure, you’ll never again think of

  • a chromosome as a “brillo mess”, would you?

It will dawn on you that the genome is orders of magnitudes more

  • finessed than we ever thought so.

Insert picture

profiles validate the Hi-C Genome wide map

profiles validate the Hi-C Genome wide map

Those embarking at a somewhat complex review of some

  • historical aspects of the power of fractals may wish to consult
  • the ouvre of Mandelbrot (also, to celebrate his 85th birthday).

For the more sophisticated readers, even the fairly simple

Hilbert-curve (a representative of the Peano-class) becomes

  • even more stunningly brilliant than just some “see through density”.

Those who are familiar with the classic “Traveling Salesman Problem”

  • know that “the shortest path along which every given n locations can
  • be visited once, and only once” requires fairly sophisticated algorithms
  • (and tremendous amount of computation if n>10 (or much more).

Some readers will be amazed, therefore, that for n=9 the underlying Hilbert-curve

Briefly, the significance of the above realization, that the (recursive)

  1. Fractal Hilbert Curve is intimately connected to the
  2. (recursive) solution of TravelingSalesman Problem,
  3. a core-concept of Artificial Neural Networks summarized below.

Accomplished physicist John Hopfield aroused great excitement in 1982
(already a member of the National Academy of Science)

with his (recursive) design of artificial neural networks and learning algorithms

which were able to find reasonable solutions to combinatorial problems

such as the Traveling SalesmanProblem.
(Book review Clark Jeffries, 1991;  1. J. Anderson, R. Rosenfeld, and
A. Pellionisz (eds.), Neurocomputing 2: Directions for research, MIT
Press, Cambridge, MA, 1990):

“Perceptions were modeled chiefly with neural connections in a

  • “forward” direction: A -> B -* C — D.

The analysis of networks with strong

  • backward coupling proved intractable.

All our interesting results arise as consequences of the strong

  • back-coupling” (Hopfield, 1982).

The Principle of Recursive Genome Function surpassed obsolete

  • axioms that blocked, for half a Century,
  • entry of recursive algorithms to interpretation
  • of the structure-and function of (Holo)Genome.

This breakthrough, by uniting the two largely separate fields of

  • Neural Networks and Genome Informatics,

is particularly important for those who focused on

  • Biological (actually occurring) Neural Networks
  • (rather than abstract algorithms that may not, or
  • because of their core-axioms, simply could not
  • represent neural networks under the governance of DNA information).

IIIA. The FractoGene Decade from Inception in 2002 to Proofs of Concept and
Impending Clinical Applications by 2012

  1. Junk DNA Revisited (SF Gate, 2002)
  2. The Future of Life, 50th Anniversary of DNA (Monterey, 2003)
  3. Mandelbrot and Pellionisz (Stanford, 2004)
  4. Morphogenesis, Physiology and Biophysics (Simons, Pellionisz 2005)
  5. PostGenetics; Genetics beyond Genes (Budapest, 2006)
  6. ENCODE-conclusion (Collins, 2007)
  7. The Principle of Recursive Genome Function (paper, YouTube, 2008)
  8. You Tube Cold Spring Harbor presentation of FractoGene (Cold Spring Harbor, 2009)
  9. Mr. President, the Genome is Fractal! (2009)
  10. HolGenTech, Inc. Founded (2010)
  11. Pellionisz on the Board of Advisers in the USA and India (2011)
  12. ENCODE – final admission (2012)
  13. Recursive Genome Function is Clogged by Fractal Defects in Hilbert-Curve (2012)
  14. Geometric Unification of Neuroscience and Genomics (2012)
  15. US Patent Office issues FractoGene 8,280,641 to Pellionisz (2012)

file:///C|/Documents_and_Settings/Andras/Desktop/The_FractoGene_Decade_cover_page.htm  2012.12.16. 12:36:55

When the human genome was first sequenced in June 2000, there were two pretty big surprises.

The first was that humans have only about 30,000-40,000 identifiable genes,

  • not the 100,000 or more many researchers were expecting.

The lower –and more humbling — number

  • means humans have just one-third
  • more genes than a common species of worm.

The second stunner was how much human genetic material — more than 90 percent —

  • is made up of what scientists were calling “junk DNA.”

The term was coined to describe similar but

  • not completely identical repetitive sequences of amino acids
    (the same substances that make genes),
  • which appeared to have no function or purpose.

The main theory at the time was that these apparently

  • non-working sections of DNA were
  • just evolutionary leftovers, much like our earlobes.

If biophysicist Andras Pellionisz is correct, genetic science

  • may be on the verge of yielding its third — and
  • by far biggest — surprise.

With a doctorate in physics, Pellionisz is the holder of Ph.D.’s

  • in computer sciences and experimental biology from the
    prestigious Budapest Technical University and
    the Hungarian National Academy of Sciences.

A biophysicist by training, the 59-year-old is a former research

  1. associate professor of physiology and biophysics at New York University,
  2. author of numerous papers in respected scientific journals and textbooks,
  3. a past winner of the prestigious Humboldt Prize for scientific research,
  4. a former consultant to NASA and
  5. holder of a patent on the world’s first artificial cerebellum,
    a technology that has already been integrated into research
    on advanced avionics systems.

Because of his background, the Hungarian-born brain researcher might

  • also become one of the first people to successfully launch a new company
  • by using the Internet to gather momentum for a novel scientific idea.

The genes we know about today, Pellionisz says, can be thought of as something

  • similar to machines that make bricks (proteins, in the case of genes), with certain
  • junk-DNA sections providing a blueprint for the
  • different ways those proteins are assembled.

The notion that at least certain parts of junk DNA might have a purpose for example,

  • many researchers now refer to
  • with a far less derogatory term: introns.

Insert picture

3-d-genome-map

3-d-genome-map

In a provisional patent application filed July 31, Pellionisz claims to have

  • unlocked a key to the hidden role junk DNA plays in growth — and in life itself.

His patent application covers all attempts to

  • count,
  • measure and
  • compare

the fractal properties of introns

  • for diagnostic and therapeutic purposes.

IIIB. The Hidden Fractal Language of Intron DNA

To fully understand Pellionisz’ idea,

  • one must first know what a fractal is.

Fractals are a way that nature organizes matter.

Fractal patterns can be found

  • in anything that has a nonsmooth surface (unlike a billiard ball),
  1. such as coastal seashores,
  2. the branches of a tree or
  3. the contours of a neuron (a nerve cell in the brain).

Some, but not all, fractals are self-similar and

  • stop repeating their patterns at some stage

the branches of a tree, for example,

  • can get only so small.

Because they are geometric, meaning they have a shape,

  • fractals can be described in mathematical terms.

It’s similar to the way a circle can be described

  • by using a number to represent its radius
    (the distance from its center to its outer edge).

When that number is known, it’s possible to draw the circle it represents

  • without ever having seen it before.

Although the math is much more complicated,

  • the same is true of fractals.

If one has the formula for a given fractal,

  • it’s possible to use that formula to construct, or reconstruct,
  • an image of whatever structure it represents,
  • no matter how complicated.

The mysteriously repetitive but not identical strands of genetic material

  • are in reality building instructions organized in
  • a special type of pattern known as a fractal.

It’s this pattern of fractal instructions, he says, that tells genes what they

  • must do in order to form living tissue,
  • everything from the wings of a fly to the entire body of a full-grown human.

In a move sure to alienate some scientists,

  • Pellionisz has chosen the unorthodox route of
  • making his initial disclosures online on his own Web site.

He picked that strategy, he says, because

  1. it is the fastest way he can document his claims
  2. and find scientific collaborators and investors.

Most mainstream scientists usually blanch at such approaches,

  • preferring more traditionally credible methods, such as
  • publishing articles in peer-reviewed journals.

Basically, Pellionisz’ idea is that

  • a fractal set of building instructions in the DNA
  • plays a similar role in organizing life itself.

Decode the way that language works, he says, and

  • in theory it could be reverse engineered.

Just as knowing the radius of a circle lets one create that circle,

  • the more complicated fractal-based formula
  • would allow us to understand how nature creates a heart or
  • simpler structures, such as disease-fighting antibodies.

At a minimum, we’d get a far better understanding of

  • how nature gets that job done.

The complicated quality of the idea is helping encourage

  • new collaborations across the boundaries that sometimes
  • separate the increasingly intertwined disciplines of
  • biology, mathematics and computer sciences.

Hal Plotkin, Special to SF Gate. Thursday, November 21, 2002.

http://www.junkdna.com/plotkin.htm

(1 of 10)2012.12.13. 12:11:58/ Hal Plotkin, Special to SF Gate.
Thursday, November 21, 2002

insert pictures

Hilbert3d

Hilbert3d

Hilbert512

Hilbert512

Fractal Defects in the genome, repeat structural variants withtheir largest example of Copy Number Variants

Fractal Defects in the genome, repeat structural variants with their largest example of Copy Number Variants

Golden_ratio  Fractal chaos Holographic neural network

Golden_ratio Fractal chaos Holographic neural network

IIIC. multifractal analysis

The human genome: a multifractal analysis.
Moreno PA, Vélez PE, Martínez E, et al. BMC Genomics 2011, 12:506.

http://www.biomedcentral.com/1471-2164/12/506

Background: Several studies have shown that genomes

  • can be studied via a multifractal formalism.

Recently, we used a multifractal approach to study the

  • genetic information content of the Caenorhabditis elegans genome.

Here we investigate the possibility that the human genome shows a

  • similar behavior to that observed in the nematode.

Results: We report here multifractality in the human genome sequence.

This behavior correlates strongly on the presence of

  1. Alu elements and to a lesser extent on
  2. CpG islands and (G+C) content.

In contrast, no or low relationship was found for

  • LINE, MIR, MER, LTRs elements and DNA regions
  • poor in genetic information.

Gene function, cluster of orthologous genes, metabolic pathways, and exons

  1. tended to increase their frequencies with ranges of multifractality
  2. and large gene families were located in genomic regions with varied multifractality.

Additionally, a multifractal map and classification for human chromosomes are proposed.

Conclusions: we propose a descriptive non-linear model

for the structure of the human genome,

This model reveals a multifractal regionalization where

many regions coexist that are far from equilibrium and

this non-linear organization has significant molecular and medical genetic implications

  • for understanding the role of Alu elements in genome stability
  • and structure of the human genome.

Given the role of Alu sequences in

  1. adaptation and
  2. human genetic diversity,
  3. genetic diseases,
  4. gene regulation,
  5. phylogenetic analyses,

these quantifications are especially useful.

MiIP:The Monomer Identification and Isolation Program

Bun C, Ziccardi W, Doering J and Putonti C.
Evolutionary Bioinformatics 2012:8 293-300.
http://dx.doi.org:/10.4137/EBO.S9248

Repetitive elements within genomic DNA are

  • both functionally and evolutionarilly informative.

Discovering these sequences ab initio

  • is computationally challenging,
  • compounded by the fact that sequence identity
  • between repetitive elements can vary significantly.

Here we present a new application,

  • the Monomer Identification and Isolation Program (MiIP),
  • which provides functionality to both
  1. search for a particular repeat
  2. as well as discover repetitive elements within a larger genomic sequence.

To compare MiIP’s performance with other repeat detection tools,

  • analysis was conducted for synthetic sequences as well as
  • several a21-II clones and HC21 BAC sequences.

The primary benefit of MiIP is the fact that

  1. it is a single tool capable of searching for both known monomeric sequences
  2. as well as discovering the occurrence of repeats ab initio,
  3. per the user’s required sensitivity of the search

Triplex DNA A. A third strand for DNA

The DNA double helix can under certain conditions

  • accommodate a third strand in its major groove.

Researchers in the UK have now presented a complete set of

  • four variant nucleotides that makes it possible to use this phenomenon
  • in gene regulation and mutagenesis.

Natural DNA only forms a triplex

  • if the targeted strand is rich in purines – guanine (G) and adenine (A) –
  • which in addition to the bonds of the Watson-Crick base pairing
  • can form two further hydrogen bonds, and the ‘third strand’ oligonucleotide
  • has the matching sequence of pyrimidines – cytosine (C) and thymine (T).

Any Cs or Ts in the target strand of the duplex will only bind very weakly,

  • as they contribute just one hydrogen bond.

Moreover, the recognition of G requires

  • the C in the probe strand to be protonated,
  • so triplex formation will only work at low pH.

To overcome all these problems, the groups of Tom Brown and Keith Fox
at the University of Southampton

  • have developed modified building blocks, and have now
  • completed a set of four new nucleotides, each of which will bind to one
  • DNA nucleotide from the major groove of the double helix.1

They tested the binding of a 19-mer of these designer nucleotides

  • to a double helix target sequence in comparison with the corresponding
  • triplex-forming oligonucleotide made from natural DNA bases.

Using fluorescence-monitored thermal melting and DNase I footprinting,

  • the researchers showed that their construct
  • forms stable triplex even at neutral pH.

Tests with mutated versions of the target sequence showed that

  1. three of the novel nucleotides are highly selective for their target base pair,
  2. while the ‘S’ nucleotide, designed to bind to T, also tolerates C.

In principle, triplex formation has already been demonstrated as

  • a way of inducing mutations in cell cultures and animal experiments.2

Michael Gross

References

1 DA Rusling et al, Nucleic Acids Res. 2005, 33, 3025

http://NucleicAcidsRes.com/Rusling_DA

2 KM Vasquez et al, Science 2000, 290, 530

http://Science.org/Vazquez_KM

B. Triplex DNA Structures.

Triplex DNA Structures. Frank-Kamenetskii, Mirkin SM. Annual Rev Biochem 1995; 64:69-95./ www.annualreviews.org/aronline

Since the pioneering work of Felsenfeld, Davies, & Rich (1),

  • double-stranded polynucleotides containing purines in one strand
  • and pydmidines in the other strand
    [such as poly(A)/poly(U), poly(dA)/poly(dT), or poly(dAG)/poly(dCT)]
  • have been known to be able to undergo a
  • stoichiometric transition forming a triple-stranded structure containing
  • one polypurine and two polypyrimidine strands.

Early on, it was assumed that the third strand was located in the major groove

  • and associated with the duplex via non-Watson-Crick interactions
  • now known as Hoogsteen pairing.

Insert pictures

triplex DNA

triplex DNA

Triple helices consisting of one pyrimidine and

  • two purine strands were also proposed.

However, notwithstanding the fact that single-base triads

  1. in tRNAs tructures were well-documented,
  2. triple-helical DNA escaped wide attention before the mid-1980s.

The considerable modern interest in DNA triplexes arose

  • due to two partially independent developments.

First, homopurine-homopyrimidine stretches in supercoiled plasmids

  • were found to adopt an unusual DNA structure, called H-DNA which
  • includes a triplex as the major structural element.

Secondly, several groups demonstrated that homopyrimidine and

  • some purine-rich oligonucleotides
  • can form stable and sequence-specific complexes
  • with corresponding homopurine-homopyrimidine sites on duplex DNA.

These complexes were shown to be triplex structures rather than D-loops,

  • where the oligonucleotide invades the double helix
  • and displaces one strand.

A characteristic feature of all these triplexes is that the two chemically

  • homologous strands (both pyrimidine or both purine) are antiparallel.

These findings led explosive growth in triplex studies. One can easily imagine

  • numerous “geometrical” ways to form a triplex, and
  • those that have been studied experimentally.

The canonical intermolecular triplex consists of either

  1. three independent oligonucleotide chains or of
  2. a long DNA duplex carrying homopurine-homopyrimidine insert
  • and the corresponding oligonucleotide.

Triplex formation strongly depends on the oligonucleotide(s) concentration.

A single DNA chain may also fold into a triplex connected by two loops.

To comply with the sequence and polarity requirements for triplex formation,

  • such a DNA strand must have a peculiar sequence:

It contains a mirror repeat
(homopyrimidine for YR*Y triplexes and homopurine for YR*R triplexes)

  • flanked by a sequence complementary to
  • one half of this repeat.

Such DNA sequences fold into

  • triplex configuration much more readily than do
  • the corresponding intermolecular triplexes, because
  • all triplex forming segments are brought together within the same molecule.

Insert pictures

It has become clear recently, however, that

  • both sequence requirements and chain polarity rules for triplex formation
  • can be met by DNA target sequences
  • built of clusters of purines and pyrimidines.

The third strand consists of adjacent homopurine and homopyrimidine blocks

  • forming Hoogsteen hydrogen bonds with purines
  • on alternate strands of the target duplex, andthis strand switch
  • preserves the proper chain polarity.

These structures, called alternate-strand triplexes,

  • have been experimentally observed as both intra- and intermolecular triplexes.

These results increase the number of

  • potential targets for triplex formation in natural DNAs
  • somewhat by adding sequences composed of purine and pyrimidine clusters,
  • although arbitrary sequences are still not targetable
  • because strand switching is energetically unfavorable.

References:

Lyamichev VI, Mirkin SM, Frank-Kamenetskii MD.

J. Biomol. Stract. Dyn. 1986; 3:667-69.

http://JbiomolStractDyn.com/Lyamichev_VI/

Mirkin SM, Lyamichev VI, Drushlyak KN, Dobrynin VN0 Filippov SA, Frank-Kamenetskii MD.

Nature 1987; 330:495-97.

http://Nature.com/

Demidov V, Frank-Kamenetskii MD, Egholm M, Buchardt O, Nielsen PE.

Nucleic Acids Res. 1993; 21:2103-7.

http://NucleicAcidsResearch.com/

Mirkin SMo Frank-Kamenetskii MD.

Anna. Rev. Biophys. Biomol. Struct. 1994; 23:541-76.

http://AnnRevBiophysBiomolecStructure.com/

Hoogsteen K.

Acta Crystallogr. 1963; 16:907-16

http://ActaCrystallogr.com/

Malkov VA, Voloshin ON, Veselkov AG, Rostapshov VM, Jansen I, et al.

Nucleic Acids Res. 1993; 21:105-11.

http://NucleicAidsResearch.com/

Malkov VA, Voloshin ON, Soyfer VN, Frank-Kamenetskii MD.

Nucleic Acids Res. 1993; 21:585-91

Chemy DY, Belotserkovskii BP,Frank-Kamenetskii MD,
Egholm M, Buchardt O, et al.

Proc. Natl. Acad. Sci. USA 1993; 90:1667-70

http://PNAS.org/

C.Triplex forming oligonucleotides

Triplex forming oligonucleotides: sequence-specific tools for genetic targeting.

Knauert MP, Glazer PM. Human Molec Genetics 2001; 10(20):2243-2251. http://HumanMolecGenetics.com/Triplex_forming_oligonucleotides:
sequence-specific_tools_for _genetic_targeting.

Triplex forming oligonucleotides (TFOs) bind in the major groove of duplex DNA

  • with a high specificity and affinity.

Because of these characteristics,

  • TFOs have been proposed as homing devices
  • for genetic manipulation in vivo.

These investigators review work demonstrating the ability of TFOs and

  • related molecules to alter gene expression and
  • mediate gene modification in mammalian cells.

TFOs can mediate targeted gene knock out in mice,

  • providing a foundation for potential application
  • of these molecules in human gene therapy.

D. Novagon DNA

John Allen Berger, founder of Novagon DNA and

  • The Triplex Genetic Code Over the past 12+ years,

Novagon DNA has amassed a vast array of empirical findings

  • which challenge the “validity” of the “central dogma theory”,
  • especially the current five nucleotide Watson-Crick DNA and
  • RNA genetic codes. DNA = A1T1G1C1, RNA =A2U1G2C2.

We propose that our new Novagon DNA 6 nucleotide Triplex Genetic Code

  • has more validity than the existing 5 nucleotide (A1T1U1G1C1)
  • Watson-Crick genetic codes.

Our goal is to conduct a “world class” validation study

  • to replicate and extend our findings.

Methods for Examining Genomic and Proteomic Interactions

A. An Integrated Statistical Approach to Compare
Transcriptomics Data Across Experiments:

A Case Study on the Identification of Candidate Target Genes
of the Transcription Factor PPARα

Ullah MO, Müller M and Hooiveld GJEJ.

Bioinformatics and Biology Insights 2012:6 145–154.

binding-of-a-ppar-ligand-to-the-ppar-ligand-binding-domain

binding-of-a-ppar-ligand-to-the-ppar-ligand-binding-domain

http://bionformaticsandBiologyInsights.com/An_Integrated_Statistical_Approach_to_Compare_ transcriptomic_Data_Across_Experiments-A-Case_Study_on_the_Identification_ of_Candidate_Target_Genes_of_the Transcription_Factor_PPARα/

Corresponding author email: guido.hooiveld@wur.nl

An effective strategy to elucidate the signal transduction cascades

  • activated by a transcription factor is to compare the transcriptional profiles
  • of wild type and transcription factor knockout models.

Many statistical tests have been proposed for analyzing gene expression data,

  • but most tests are based on pair-wise comparisons.

Since the analysis of micro-arrays involves the testing of

  • multiple hypotheses within one study, it is generally accepted that one should
  • control for false positives by the false discovery rate (FDR).

However, it has been reported that

  • this may be an inappropriate metric for
  • comparing data across different experiments.

Here we propose an approach that addresses the above mentioned problem

  • by the simultaneous testing and integration of the three hypotheses (contrasts)
  • using the cell means ANOVA model.

These three contrasts test for the effect of a treatment in

  • wild type,
  • gene knockout, and
  • globally over all experimental groups.

We illustrate our approach on microarray experiments that focused

  • on the identification of candidate target genes and biological processes
  • governed by the fatty acid sensing transcription factor PPARα in liver.

Compared to the often applied FDR based across experiment comparison,

  • our approach identified a conservative
  • but less noisy set of candidate genes
  • with same sensitivity and specificity.

However, our method had the advantage of properly adjusting for

  • multiple testing while integrating data from two experiments,
  • and was driven by biological inference.

We present a simple, yet efficient strategy to compare

  • differential expression of genes across experiments
  • while controlling for multiple hypothesis testing.

B. Managing biological complexity across orthologs with a visual knowledge-base
of documented biomolecular interactions Vincent VanBuren & Hailin Chen
Scientific Reports 2, Article number: 1011
http://dx.doi.org:/10.1038/srep01011
Received 02 October 2012 Accepted 04 December 2012

The complexity of biomolecular interactions and influences

  • is a major obstacle to their comprehension and elucidation.

Visualizing knowledge of biomolecular interactions

  • increases comprehension and
  • facilitates the development of new hypotheses.

The rapidly changing landscape of high-content experimental results

  • also presents a challenge for the maintenance of comprehensive knowledgebases.

Distributing the responsibility for maintenance of a knowledgebase

  • to a community of subject matter experts is an effective strategy
  • for large, complex and rapidly changing knowledgebases.

Cognoscente serves these needs by building visualizations for queries

  • of biomolecular interactions on demand,
  • by managing the complexity of those visualizations, and by
  • crowdsourcing to promote the incorporation of current knowledge
  • from the literature.

Imputing functional associations between

  • biomolecules and imputing directionality of regulation for those predictions
  • each require a corpus of existing knowledge as a framework to build upon.

Comprehension of the complexity of this corpus of knowledge

  • will be facilitated by effective visualizations of
  • the corresponding biomolecular interaction networks.

Cognoscente (http://vanburenlab.medicine.tamhsc.edu/cognoscente.html)

  1. was designed and implemented to serve these roles as a knowledgebase
  2. and as an effective visualization tool for systems biology research and education.

Cognoscente currently contains over 413,000 documented interactions,

  • with coverage across multiple species.

Perl, HTML, GraphViz1, and a MySQL database were used in the development of Cognoscente.

Cognoscente was motivated by the need to update the knowledgebase

  • of biomolecular interactions at the user level, and
  • flexibly visualize multi-molecule query results for
  • heterogeneous interaction types across different orthologs.

Satisfying these needs provides a strong foundation for

  • developing new hypotheses about regulatory and metabolic pathway topologies.

Several existing tools provide functions that are similar to Cognoscente, so we selected several popular alternatives to assess how their feature sets compare with Cognoscente ( Table 1 ). All databases assessed had easily traceable documentation for each interaction, and included protein-protein interactions in the database.

Most databases, with the exception of BIND, provide an open-access database that can be downloaded as a whole.

Most databases, with the exceptions of EcoCyc and HPRD, provide

  • support for multiple organisms.

Most databases support web services for

  • interacting with the database contents programmatically,
  • whereas this is a planned feature for Cognoscente.

INT, STRING, IntAct, EcoCyc, DIP and Cognoscente provide built-in

  • visualizations of query results, which we consider
  • among the most important features for facilitating comprehension of query results.

BIND supports visualizations via Cytoscape.

Cognoscente is among a few other tools that support

  • multiple organisms in the same query,
  • protein->DNA interactions, and
  • multi-molecule queries.

Cognoscente has planned support for

  • small molecule interactants (i.e. pharmacological agents).

MINT, STRING, and IntAct provide a prediction (i.e. score)

  • of functional associations, whereas
  • Cognoscente does not currently support this.

Cognoscente provides support for multiple edge encodings

  • to visualize different types of interactions in the same display,
  • a crowdsourcing web portal that allows users to submit
  • interactions that are then automatically incorporated in the knowledgebase,
  • and displays orthologs as compound nodes
  • to provide clues about potential orthologous interactions.

The main strengths of Cognoscente are that it provides a combined feature set that is superior to any existing database, it provides a unique visualization feature for orthologous molecules, and relatively unique support for multiple edge encodings, crowdsourcing, and connectivity parameterization. The current weaknesses of Cognoscente relative to these other tools are that it does not fully support web service interactions with the database, it does not fully support small molecule interactants, and it does not score interactions to predict functional associations. Web services and support for small molecule interactants are currently under development.

Related references from Leaders in Pharmaceutical Intelligence:

Big Data in Genomic Medicine larryhbern
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Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com)
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Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com
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Sohan Modak

Sohan

Sohan Modak

Owner, Open vision Inc.

Top Contributor

Larry, in a series of papers, Fertil, Deschavannes and colleagues have done beautiful analyses of fractal diagrams of Genome sequences in a series of papers.[Deschavanne PJ, Giron A, Vilain J, Fagot G, Fertil B (1999) Mol Biol Evol 16: 1391-1399; Fertil B, Massin M, Lespinats S, Devic C, Dumee P, Giron A (2005) GENSTYLE: exploration and analysis of DNA sequences with genomic signature. Nucleic Acids Res 33(Web Server issue):W512-5]. Clearly this gives an extraordinary insight in the specificity of positional sequence clusters. While fractals work well with octanucleotide clusters, longer the oligonucleotide tracks, higher the resolution. I feel that high resolution fractal maps of fentanucleotide sequences will provide something truely different and may be used as a tool to compare normal cellular DNA sequences to those from cancer cell lines and provide an operational window for manipulations.

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Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin

Curator: Aviva Lev-Ari, PhD. RN

As a new edition of The Double Helix hits bookshelves, Boing-Boing‘s Maggie Koerth-Baker takes the opportunity to interview James Watson about his characterization of Rosalind Franklin, who, Koerth-Baker says, “is unfairly maligned in the book as a haggy, naggy, old maid caricature” and referred to throughout as “Rosy,” even though that was not a nickname she used.

Reconsideration of Rosalind Franklin by James Watson

As a new edition of The Double Helix hits bookshelves, Boing-Boing’s Maggie Koerth-Baker takes the opportunity to interview James Watson about his characterization of Rosalind Franklin, who, Koerth-Baker says, “is unfairly maligned in the book as a haggy, naggy, old maid caricature” and referred to throughout as “Rosy,” even though that was not a nickname she used.

Answering questions by email, Watson admits that his perception of Franklin was “colored” by his friendship with Maurice Wilkins, who was openly hostile toward her.

As the new edition of the book illustrates, the friction between Franklin and Wilkins was largely due to miscommunication. While Wilkins believed Franklin was hired to be his assistant, a letter from their department head, John Randall, published in the new edition indicates that she was actually hired to lead the DNA project.

“Reading Watson’s perspective alongside the letter and a footnote explaining how Wilkins saw the situation, it becomes clear that one of the most famous conflicts in the history of science started because the department head wasn’t communicating very well with either Franklin or Wilkins,” Koerth-Baker says.

Watson tells her that the Randall letter “makes me think even more what a tragic situation Wilkins and Franklin found themselves in. Wilkins had begun the DNA work at King’s and had it taken away from him and given to Franklin, without understanding why — that Randall had made the arrangements described in this letter. The situation would have been intolerable for anyone, let alone two such incompatible characters as Wilkins and Franklin.”

Would Watson portray Franklin any differently if he were to write the book today?

“I am not an historian and wouldn’t want to write the book you describe,” he tells Koerth-Baker. “But if I were to do so, I would, of course, refer to the Randall letter and show how it set up the misunderstanding. I would write more sympathetically about the plight of both Wilkins and Franklin.”

In addition, he says, “I would also be able to write about her views of life at King’s College, including her dislike of her colleagues, in particular Maurice,” which is “made vivid” in another letter reproduced in the book.

SOURCE:

The Turn of the Screw: James Watson on The Double Helix and his changing view of Rosalind Franklin

 at 7:57 am Thu, Nov 8

The Double Helix is a famous book. It’s also an infamous one. Written by James Watson in 1968, it tells the story of how he and Francis Crick figured out the structure of DNA. The catch is that Watson chose to write that story in what was, at the time, a damn-near unprecedented way. He didn’t write a history. He didn’t exactly write an autobiography, either. Instead, The Double Helix is a bookabout history, told in story form, where everything is seen through the eyes of a single narrator — the 25-year-old James Watson.

He is not the world’s most likable narrator. Nor the most reliable one. I mean that in the sense of the “unreliable narrator” from fiction. We see this world through young Watson’s eyes, and his perspective isn’t always accurate. The story is shaped by his prejudices and his personality, and it can’t really be read as THE account of what actually happened. That’s a good thing, because the choice of style allowed Watson to really capture the back-room conflict (and cooperation), and the sense of urgency, that drives scientific discovery. It’s a bad thing because it’s far too easy to forget that The Double Helix has more in common with Truman Capote’s In Cold Blood than, say, The Decline and Fall of the Roman Empire. It’s not a scholarly history. It’s more like memoir crossed with narrative non-fiction. You can’t walk away from it thinking that Watson’s narration represents some kind of objective truth.

The new, annotated and illustrated edition of The Double Helix — published this month by Simon and Schuster — makes that fact abundantly clear. Full of photographs, letters, handwritten notes, and commentary from other people involved in the history of DNA, this edition gives you glimpses of other perspectives — of a story much bigger than the one told in The Double Helix, itself.

It also made me wonder about James Watson’s reaction to documents that completely upend the story as he told it — especially documents relating to Rosalind Franklin, a scientist whose work was instrumental in deciphering DNA’s structure and who is unfairly maligned in the book as a haggy, naggy, old maid caricature.

So I asked him about it.

I should clarify that I wasn’t able to talk to James Watson by phone. This interview was done via email, and that’s not my favorite way to work. With email (and you’ll see this) it’s far too easy to end up with one-sentence answers to complicated questions. Worse, there’s no opportunity for follow-ups. But I do appreciate the Watson took the time to write some good answers to my questions about Franklin, and I wanted to share those with you.

First, though, a little background. Rosalind Franklin was a biophysicist who worked primarily with x-ray crystallography, a method of determining the shape and structure of things that we can’t see with our own eyes. Imagine that you have captured Wonder Woman’s invisible airplane. You can’t see it. But you know it’s there because when you throw a rubber ball at the space, the ball bounces back to you. If you could throw enough rubber balls, from all different sides, and measure their trajectory and speed as they bounced back, you could probably get a pretty good idea of the shape of the plane.

That’s basically what x-ray crystallography does. You shoot x-rays at a crystalline structure, like a molecule of DNA. Those beams hit the molecule and bounce off and you use the patterns of diffraction to learn something about the molecule’s shape.

In the early 1950s, James Watson and Francis Crick were attempting to figure out the structure of DNA, but they weren’t the only ones. In fact, Crick had avoided getting involved with DNA for several years because his friend, Maurice Wilkins, was also studying it. This is where Franklin comes in.

In 1950, the head of Wilkins department hired Rosalind Franklin. Wilkins — and his friends Crick and Watson — were under the impression that Franklin was supposed to be Wilkins’ assistant. But she didn’t act like his assistant. She acted like his colleague or, perhaps, his competitor. And that disconnect between who Wilkins thought Franklin was supposed to be and who she thought she was created a really shitty working environment. Wilkins was angry at Franklin, and his anger seems to have rubbed off on how his friends perceived her. Mix that with a little sexism and you get some of The Double Helix‘s most controversial parts. Here’s an excerpt from James Watson’s initial description of Franklin:

I suspect that in the beginning Maurice hoped that Rosy would calm down. Yet mere inspection suggested that she would not easily bend. By choice she did not emphasize her feminine qualities. Though her features were strong, she was not unattractive and might have been quite stunning had she taken even a mild interest in clothes. This she did not. There was never lipstick to contrast with her straight black hair, while at the age of thirty-one her dresses showed all the imagination of English blue-stocking adolescents. So it was quite easy to imagine her the product of an unsatisfied mother who unduly stressed the desirability of professional careers that could save bright girls from marriages to dull men.

It goes without saying that Watson was not particularly concerned with the fashion choices of his male colleagues. Likewise, the nickname “Rosy” isn’t one that Franklin ever used. It was bestowed on her, and really only behind her back. Throughout The Double Helix, Watson refers to her as Rosy, even while calling other people by their formal last names. Or, at least, by names they would have called themselves.

But one of the interesting things this edition of The Double Helix does is shine some light on the initial conflict. On the page opposite the description I quoted above, you can see a photocopy of a letter, sent to Franklin by the department head, where he basically tells her that she’s been hired to lead the DNA project — not to work for Maurice Wilkins.

Basically, Franklin was right in thinking that she wasn’t Wilkins’ assistant.

Reading Watson’s perspective alongside the letter and a footnote explaining how Wilkins saw the situation, it becomes clear that one of the most famous conflicts in the history of science started because the department head wasn’t communicating very well with either Franklin orWilkins. In this reading, Watson kind of becomes the catty best friend, attacking somebody his pal was angry with even though he didn’t know all the details of what was going on. It’s Facebook drama in the laboratory.

And that brings me to the questions I asked Watson.

Maggie Koerth-Baker: I very much enjoyed this edition of the book, and the fact that it contained all these documents that provided some contrasting viewpoints and added to the depth of your perspective. And it seems like, in some cases, you’d originally written the book without having seen certain documents that end up significantly changing the story. In particular, I’m thinking of the letter from John Randall to Rosalind Franklin showing that she was right in thinking she hadn’t been hired to be Maurice Wilkins’ assistant, but rather his colleague. I’m curious about when you finally found out about that letter and what you thought about it. Did it change your perspective on the conflicts between Wilkins and Franklin?

James Watson: The Randall letter was discussed in Brenda Maddox’s biography of Franklin [in 2003] and that’s probably where I first became aware of it. But in this edition, Alex and Jan reproduce the whole letter – one of the pleasures of this edition is the number of letters and other documents they reproduce as facsimiles. Its fun to see letters just as their recipients saw them.

This letter makes me think even more what a tragic situation Wilkins and Franklin found themselves in. Wilkins had begun the DNA work at King’s and had it taken away from him and given to Franklin, without understanding why–that Randall had made the arrangements described in this letter. The situation would have been intolerable for anyone, let alone two such incompatible characters as Wilkins and Franklin.

MKB: I’d like to ask you a question about your treatment of Franklin, given that it’s one of the things The Double Helix is rather famous for. Or, perhaps, infamous. You set out to write a book that captured your thoughts and feelings and viewpoint as a young man, in this specific time period, in an often-contentious working environment. But I’m curious about how your perspective on those events has changed over time. If you were to sit down and write about the events in this book now, not through your at-the-time perspective, but as you think about the past today, would it change the way that you portrayed Dr. Franklin? How has the way you think about her changed as you’ve gotten older?

JW: We didn’t know Franklin well–I only met her perhaps three times and Francis once in this period. So, my view of her was inevitably colored by our friendship with Wilkins and what he told us about her.

I am not an historian and wouldn’t want to write the book you describe. But if I were to do so, I would, of course, refer to the Randall letter and show how it set up the misunderstanding. I would write more sympathetically about the plight of both Wilkins and Franklin. I would also be able to write about her views of life at King’s College, including her dislike of her colleagues, in particular Maurice. This is made vivid in her correspondence, especially in one letter reproduced in the book.

In this new edition, I notice that Ray [Gosling – her student] has rather a good line in response to my comments about her appearance. He notes that I never saw her dressed up to go out in the evening, and that she had an elegance that I probably never saw.

I mentioned that Francis and I hardly knew Franklin at this time. Later, of course, we both saw more of her, as she was very much part of the elite structural biology community – her excellent work on TMV ensured that (though is often over-looked in popular accounts of her life). [He’s referring to her work with tobacco mosaic virus, which she spent the last few years of her life studying. TMV was the first virus ever discovered and Franklin’s work was instrumental in our understanding of RNA viruses. Franklin died in 1958 from ovarian cancer. — MKB]

************************
Rosalind Franklin’s Photo 51, an x-ray crystallography image of DNA.

There’s a bit more to the Franklin-Watson/Crick story than just office squabbling. One of the most controversial points concerns a particular x-ray crystallography image that she took, which was shown to Watson without Franklin’s knowledge or permission. That image ended up playing an important role in Watson’s and Crick’s ability to figure out the structure of DNA. But this edition of the book — and Watson’s answers — provide a deeper view of what was going on in the background — how a personality conflict and bad management led to a much bigger controversy that people are still arguing about today.

I asked James Watson three other questions about the book, as well. His answers to these were less substantive, but you can read them below. In general, I’d definitely recommend this edition of The Double Helix. If you’re going to read the book, this is the way it ought to be read. As James Watson’s limited view of his own life, it’s interesting. But the history really comes alive when you can see more of what everybody around him was thinking, as well. Among the gems: three pages of Francis Crick’s six-page letter urging Watson to not publish The Double Helix, to begin with.

************************

MKB: I’m curious about what got you interested in writing a book like The Double Helix to begin with. At the time, it was far out of the norm for the way that scientists wrote about science and, in fact, it was fairly far out of the norm for the way anyone wrote about anything. Narrative non-fiction was still a developing field, even from the perspective of journalists. What influenced your desire to write a story this way and what did you look to for inspiration?

James Watson: The story was too good not to be told as it actually happened!

MKB: One of the things that stands out to me in the book is your frustration with stuffy and bureaucratic social expectations within the scientific community. In particular, I’m thinking about some of the early chapters, where you talk about Francis Crick being unable to study DNA because Maurice Wilkins already was and it would have been poor form for another English scientist to try and “scoop” him, as it were. How have you seen this aspect of science change in the years since you wrote The Double Helix? Have some of those formalities fallen away? What are the new social twists you see young scientists having to navigate?

JW: Friendships almost have to evaporate when a scientist chooses unilaterally to work toward a scientific objective also pursued by a friend.

MKB: I was really struck by your description of Linus Pauling and the way he announced his findings in theatrical lectures. It reminded me a bit of some of the more theatrical, hyped-up scientific pronouncements of recent years, especially the now-discredited findings like arsenic life and faster-than-light neutrinos. In the wake of those events, there was a lot of hand-wringing about how this was so outside the norm for scientists, but it doesn’t seem much different from Pauling’s tactics. It’s just that he was usually right. I’m curious about your thoughts on this. Do you see more theatrics in science today? How do you think the increased media spotlight has influenced the way scientists announce their work to the public? And how do you see your role in that, given the fact that The Double Helix was a major part of popularizing science and making it something more breathless and story-driven?

JW: I find theatrical performances even rarer than when Pauling lived. Almost no one now risks offending pompous individuals in the audience who later might review either their research articles or judge their applications for research money. Today’s science stifles individuality.

• The annotated and illustrated edition of The Double Helixby James Watson is available in hardcoverKindle, and eBook.

Maggie Koerth-Baker is the science editor at BoingBoing.net. She writes a monthly column for The New York Times Magazine and is the author of Before the Lights Go Out, a book about electricity, infrastructure, and the future of energy. You can find Maggie on Twitter and Facebook

SOURCE:

http://boingboing.net/2012/11/08/the-turn-of-the-screw-james-w.html

Shining a Light on the ‘Dark Lady of DNA’

By Josh Fischman
Posted Sunday, August 6, 2006

Four people in England, back in 1953, gazed at the mysterious image called Photo 51. It wasn’t much–a grainy picture showing a black X. But three of these people won the Nobel Prize for figuring out what the photo really showed–the shape of DNA, the basic unit of life on Earth. The discovery brought fame and fortune to scientists James Watson, Francis Crick, and Maurice Wilkins. The fourth, the one who actually made the picture, was left out.

Her name was Rosalind Franklin. “She should have been up there,” says Mary Ellen Bowden, a historian at the Chemical Heritage Foundation in Philadelphia. “If her images hadn’t been there, the others couldn’t have come up with the structure.” One reason Franklin was missing was that she had died of cancer four years before the Nobel decision, and it can’t be awarded after death. But there is a growing suspicion among scholars that Franklin was not only robbed of her life by disease but robbed of credit by her competitors. She, as much as the men around her, was first in the race to understand DNA.

Scientists knew, in the 1940s, that DNA was the thing carrying hereditary information from an organism to its descendants. But because it was too small to see directly, they had no idea how the molecule performed this feat.

Cutouts. So at Cambridge University in the 1950s, Watson and Crick went at it indirectly, by making models; they cut up shapes of DNA’s constituents and tried to piece them together. Meanwhile, at King’s College in London, Franklin and Wilkins shined X-rays at the molecule. The rays produced patterns reflecting the shape.

But Wilkins and Franklin’s relationship was a lot rockier than the celebrated teamwork of Watson and Crick. Wilkins thought Franklin was hired to be his assistant. But the college actually brought her on to take over the DNA imaging project.

Which is what she did, producing X-ray pictures that, among other things, told Watson and Crick that one of their early models was inside out. And she was not shy about saying so. That antagonized Watson, who lambasted her in his 1968 book, The Double Helix: “Mere inspection suggested that she would not easily bend. By choice she did not emphasize her feminine qualities. … Clearly Rosy had to go or be put in her place.” (Other colleagues remember her as a supportive and highly skillful scientist.)

As Franklin’s rivals, Watson and Wilkins had much to gain by cutting her out of the clubby little group of researchers, says science historian Pnina Abir-Am of Brandeis University. Exclusion was made easy by her gender–King’s banned women from important dining rooms. And Wilkins grew closer to Watson. Close enough to show to Watson, casually, Franklin’s Photo 51. “My mouth fell open,” Watson wrote. That X shape was in fact a double helix, two strands wrapped around one another but running in opposite directions. This made it a biological copying machine, able to transmit mirror images of information from one cell to a daughter cell, from a parent to a child.

Watson and Crick, Wilkins, and Franklin published separate papers describing this code of life in the same 1953 issue of Nature. Franklin went on to study viruses, and then took sick, and in 1962 the others took to the Nobel podium. Wilkins gave a speech in which he thanked 13 colleagues by name before he mentioned Franklin. Watson wrote his book deriding her. Crick wrote in 1974 that “Franklin was only two steps away from the solution.”

No, says Abir-Am: Franklin was the solution. “She contributed more than any other player to solving the structure of DNA. She must be considered a codiscoverer.” Lynne Osman Elkin, a biographer of Franklin, agrees, saying that Franklin’s notebooks show she was on to the double helix–a claim backed up by Aaron Klug, who worked with Franklin on viruses and later won a Nobel Prize himself. Once described as the “Dark Lady of DNA,” Franklin is finally coming into the light.


This story appears in the August 14, 2006 print edition of U.S. News & World Report. Article available online: <http://www.usnews.com/usnews/news/articles/060806/14dna.htm>

SOURCE:

http://pgabiram.scientificlegacies.org/dna-at-50/usnews-rosalind-franklin

Photo 51—A Recent Addition to History-of-Science-Inspired Theatre

Pnina G. Abir-Am, PhD, Brandeis University

The play Photograph 51, named after the sharpest image in a series of DNA X-ray photos taken by Rosalind Franklin (1920–1958) in a biophysics lab at King’s College, London in 1952, played this past spring at the Central Square Theatre1 in Cambridge, MA.

This Theatre is fittingly located between M.I.T. (which co-sponsors it) and Harvard, two institutions still recovering from a few scandals on the under-representation of women in science. The play is thus timely, coming as it does on the heels of “Barriers and Bias,” the National Academy of Science Reports (2006, 2007, 2009) that try to address the persisting gender inequality in science. But the play has a wider connection to the history of science because it deals not only with gender bias in science, but also with the paramount issue of credit allocation in scientific discovery.

HSS Newsletter readers may recall that the 2003 HSS Annual Meeting2 (incidentally held in Cambridge, MA. not too far from this Theatre) featured two sessions on “DNA at 50” which explored new perspectives on the discovery of DNA structure at its 50th anniversary. But unlike our HSS speakers who explored archival material, (in the regular session) or their own memories (in the panel at which attendees, including former HSS President Gerald Holton, posed questions to local DNA luminaries, Paul Doty, Wally Gilbert, and Alex Rich), this well-received play relies mainly on biographies,3 and on a namesake PBS documentary, aired in 2003: “DNA: Secret of Photo 51.”

The discovery of DNA’s structure, having been embroiled in controversy for decades,4 provides a perfect opportunity for playwrights to apply their dramatic license. The controversy revolves around the unacknowledged use of Rosalind Franklin’s work in the famous paper announcing the double helix conformation of DNA. Franklin’s premature death enabled others to both obscure her role and take all the credit for themselves,5 much as the premature death of the discoverer of the Nile’s origins provided an opportunity for another “colleague” to claim all the credit for himself.6

It is thus impossible to grasp the importance of a play7such as Photograph 51, that “succeeds in focusing a long-overdue spotlight on Rosalind Franklin…the playwright makes Franklin seem worthy of that spotlight, not just as a neglected figure of science but as a compelling character,”8 without recalling the insightful “cultural background” that precedes the play. According to The Double Helix, which is included on the reading lists of many courses and remains the only “source” most theatre goers would have read, Crick and Watson had to leave their official scientific missions in protein and virus structure, respectively, so as to rescue scientific progress in DNA from its blockage at the hands of Rosalind Franklin. She is portrayed as a recalcitrant woman scientist who refused to collaborate with their friend, the more-veteran lab member Wilkins, even though she was presumably unable to interpret her own results because of her supposed “anti-helical” bias. Consequently, the three men had no choice but to obtain the golden data by whatever means they could. (Those means were still debated half a century later.)

Though the transition from Photo 51 to the model of the double helix raises interesting questions on the relationship between the context of discovery and the context of justification, which could have been pursued in the manner of Copenhagen,9 Photograph 51 opts for interrogating the role of gender bias in preventing Franklin from both completing the discovery of DNA structure on her own, as well as in not getting credit for it. This “take” is justified by the fact that in addition to her “scientific sins,” (i.e. not being content in the role of an assistant and making discoveries on her own) Franklin was further demonized as “Rosy.” That nickname, used behind her back, captured a female character as negative as the male imagination of the early 1950s could sustain, i.e. a glasses-wearing bluestocking, poorly dressed, ignorant of lipstick, lashing at more veteran men, asocial and hence lonely, and last, but not least, lacking romantic prospects at the ripe age of 31. That “Rosy” was the very opposite of historical reality did not seem to matter to its “creators” who openly pandered to their audience’s sexism.

Photograph 51 thus revolves around the sensible idea that if there was a failure to collaborate, then the blame for it must be shared more equitably among the involved parties. Since the charge that Franklin was uncooperative originated with Wilkins, the play focuses on the role of gender in poisoning the work relationships between him and Franklin. But the play is unable to project a “balance of blame,” not for lack of talent on the part of the playwright whose dialogues are crisp and punchy, but rather because our culture remains so suffused with gender stereotypes that a mere balancing effort is not sufficient to better distribute blame across the gender divide. For example, Wilkins’ portrayal as smug and entitled does not strike the audience as so bad when compared to its portrayal of Franklin as a combative, fierce, unbendingly serious, and uncompromising female character.

However, the play’s portrayal of Wilkins as a captive of sexism who persists in regarding his colleague first and foremost as a woman whom he must date instead of seeing in her a scientist with complementary skills with whom he might collaborate, evokes well the predicament of women scientists in an era of “unmitigated sexism.” One scene revolves around a box of chocolate that Wilkins tries to force on Franklin who, to his endless surprise, declines it firmly. Women such as Franklin who chose not to surrender their bodies, were expected at the very least to surrender their body of work; if they refused, then the work was snatched anyway. The pretext that she was uncooperative was invented to justify such a scenario.10

By focusing on Franklin and her diverse relationships with men colleagues, (bad with Wilkins, but great with the graduate student Ray Gosling, and would-be boyfriend, scientist Don Caspar) Photograph 51 relegates the better-known saviors of scientific progress, Watson and Crick, further portrayed as a comic duo, to the margins, which is the way they must have looked in Franklin’s eyes. The play further contrasts the work ethics of seriousness of purpose and dedication on the part of Rosalind Franklin with the three men constantly bonding over drinks and having fun as they relax in gender-segregated dining halls. Since they spend so much time socializing and have no results of their own, they seem aware that their only way to fame is to “sniff” Franklin’s crucial data. I borrow this term from a theatre reviewer who also observed: “Franklin…is the clear intellectual hero. She is the purest, most genuinely curious scientist. The men, a casual bunch next to the burning, all-business Franklin, tend to be various strains of pig—ambitious, sexist, anti-Semitic, etc.”11

Indeed, this play dramatizes not only gender bias but also racial bias. In dialogues between Wilkins and Watson, Jews are referred to as difficult people or “ornerous,” whose loyalty to England should be questioned. There is enough in the play to suggest that race/ethnicity, as well as gender, were factors in Franklin’s decision to move to another lab. But perhaps both factors were even more important in providing the men with culturally endorsed motives for “blaming” her for their own problems, scientific and otherwise, thus paving the way for justifying their eventual “acquisition” of her data, data that she refused to surrender. In my own studies of the interaction between British science policy makers and Franklin’s lab, I came across references to “Jews and foreigners” as an undesirable trait of the lab. Apparently that trait was sufficient to require a special oversight committee over the lab, which ironically became yet another avenue for leaking Franklin’s results.12

Photo 51 does not explore another major component of the politics of identity that also played a key role in the discovery of DNA structure, that of class. This is an odd omission since in the predominantly British context of the play, class may well have been more crucial than either gender or race/ethnicity in explaining behavior (still, the sheer combination of all three variables over-determined this case). As it “happened,” all three men who sniffed Franklin’s data belonged to families that lost their middle class status during the Great Depression and hence, became obsessed with regaining their prior social respectability. For all three, the only way up at the time meant an association with a major scientific breakthrough.

By contrast, Franklin belonged to an upper-class family with a distinguished record in both civic affairs and philanthropy. One great-uncle, Viscount Herbert Samuel, was Head of the Liberal Party before WW1. Another was Lord Mayor of London.13 This social background, further coupled with gossip that her family was wealthy, (Lord Rothschild, a scientist whose namesake Report played a major role in British science policy in the 1970s was a second cousin) and that she had an allowance (though she insisted on living mainly from her modest salary) would have positioned Rosalind Franklin in the mind of these three men, all resentful at being demoted to the verge of genteel poverty, as a perfect target for revenge.

If we further recall that Wilkins and Crick were left by their first wives, (the play includes a line to that effect) and that Wilkins and Watson constantly solicited help from Crick (who lived in an open marriage with his second wife, an artist) in “finding women,” a vexing subject discussed endlessly; (apparently the women did not stick around since Wilkins and Watson continued to search for them until age 40) then, the unavailable Franklin was a constant reminder of their own far-from-shining predicament. No wonder they obsessed about her all the time and projected upon her their own social and scientific anxieties. The three men would have almost had to step outside their culture and society not to take advantage of an opportunity to become famous at the expense of a well to do, or “rich” in common parlance, Jewish woman who in their opinion didn’t even “need” a career in science. Class, race, gender, and sexuality melted any moral or ethical dilemma they might have faced. How could the playwright miss an opportunity to make more of the class, race and sex aspects of such material?!

Most of the reviews I have seen14 were appreciative of the production. (The sleek lab set is often praised, as well as the direction, and the acting.) To my delight they were also receptive of the main idea that a woman scientist with a compelling character, commitment to her vocation, and major scientific achievement was robbed of her share of glory by three men: her “emotionally constipated, professionally unsupportive colleague Maurice Wilkins,” a “bluff, worldly Crick” and an “intensely disagreeable Watson.”15 But at least one theatre critic, was sufficiently troubled by what he calls an “ideological version of her story” in this play to conduct his own research.16 Though he praises the playwright for treading “a mostly sure-footed middle ground between the ideological version of the story and the more prosaic historical one,” the critic believes that his own research lowers the play’s dramatic impact (which revolves around the disparity of fortune between those who do the work and those who take the credit). That critic, who kept the nature of his “research” to himself, tries to salvage the status quo (i.e. that the distribution of credit for this discovery is problematic but it does not require major revision17) by invoking Franklin’s departure from King’s, among related insights. I omit them here not only for reason of space but also because they are already known to historians of science to be factually incorrect.

By highlighting the profound dependence of the double helix model upon Franklin’s work, the play joins those who raised questions as to why the scientific community continues to misallocate credit for this discovery for half a century. Though not as dramatic as “Proof,” David Auburn’s Pulitzer and Tony award winning play, at which audiences of hundreds gasp at once when the mathematician’s daughter tells his male student heirs “I did not find the proof in my father’s drawer; I wrote it,” Photograph 51 exposes the audience to the perspective of a woman scientist who made a major discovery on her own, not as the daughter, wife, or relative of a male scientist. The play also caters to post-feminist sensibilities by suggesting that even a woman who prioritized a career in science over marriage can eventually meet a man who can both understand her passion for discovery and be romantically involved with her; this is so, especially if she is smart enough to look at younger men.

Finally, Photo 51 also raises more general questions on the usefulness of such theatrical dramatizations for STEM initiatives, along with stimulating historians of science to reexamine a historiography that has accepted too easily the scientists’ version of discovery. In conclusion, despite its dependence on historiographically outdated material (the lack of collaboration between Franklin and Wilkins, or these materials’ key role in the case of Crick and Watson, pillars of the play and of the received view, are both red herrings, invoked to justify problematic outcomes) and its avoidance of many other key issues in the discovery of DNA structure, as a comparison with the BBC movie Life Story, (1987) can easily reveal, this play can be seen as breaking new ground by calling attention to the key role of gender in the process and outcome of a major discovery.

From a more personal perspective, I hope that the play will prove useful in preparing the public, including historians of science and scientists, for a new, more radical interpretation of the history of the discovery of DNA structure. Soon audiences will need to cope with the historical evidence that I have been assembling for my book DNA at 50, evidence that is bound to surprise those who believe that we already know how the discovery of DNA’s structure was made. Unlike the playwright, I do not need to use artistic license for the simple reason that the actual history of this discovery proved to be dramatic in its own right.

Footnotes

1 The play’s run was February 9 to March 18, 2012; for information on the playwright, director, and actors in this production see CentralSquareTheatre.org; see also the review in the Boston Globe, http://www.bostonglobe.com/arts/
2012/02/15/picture-scientific-and-human-complexity-photograph/
h97DSsvBapHTJFHmJy4viN/story.html
. The play had previously been staged in LA and WDC, where it was also well received.

2 http://www.hssonline.org/Meeting/oldmeetings/archiveprogs/
2003archiveprogs/2003cambridgemeeting.pdf
 [co-organized with Bill Summers of Yale]

3 Rosalind Franklin, The Dark Lady of DNA, by Brenda Maddox, 2003, was better received than Rosalind Franklin and DNA; (Anne Sayre, 1975) the latter was initially dismissed as a “feminist plot,” but was reissued in 2000. One of the speakers in our HSS session in 2003, Lynn Osman Elkin, a Professor of Biology at UC-Berkeley, is transforming Sayre’s book into an educational manual. Her talk was based on her essay, “Rosalind Franklin and the Double Helix,” Physics Today, March 2003, 42-48. She also served as a consultant to the namesake PBS documentary.

4 For example, Francis Crick and Maurice Wilkins, who shared the 1962 Nobel Prize in Physiology with James D. Watson for their work on DNA, succeeded in blocking the latter’s The Double Helix, A Personal Account of the Discovery of DNA Structure from being published by Harvard University Press but they did not object to a commercial press. Crick referred to it as a “pack of nonsense.” But the pertinent correspondence on the controversy surrounding the 1968 publication became available at a much later time.

5 Elkin 2003, Maddox 2003, Sayre 1975, op.cit. These authors were concerned to establish Franklin’s centrality rather than providing a full historical account of the discovery of DNA structure. I aim to provide such an account in my forthcoming book, DNA at 50: From Memory to History, which reexamines all the various players, both known and unknown, in the discovery of DNA structure, including Franklin, in light of new archival sources.

6 The discoverer, John H. Spelke died accidentally on the day of a projected debate with Francis F. Burton, who then proceeded to claim the discovery for himself. To this day Burton is known as the Victorian explorer who solved a riddle that preoccupied civilization since ancient Greek and Roman times, while the actual discoverer remained obscured for a century and a half. See Tim Jeal, Explorers of the Nile: The Triumph and Tragedy of a Great Victorian Adventure. (2011)

7 Photo 51 is so far the more successful among several plays written on Rosalind Franklin. Commissioned in 2008 it won the STAGE prize for plays on science and technology.

8 Dan Aucoin, The Boston Globe, 2-15-2012 (bostonglobe.com/arts/2012/02/15)

9 By Michael Frayn. (London: Methuen Drama, 1998) For its resonance among historians of science see “Copenhagen and Beyond: The Interconnections between Science, Drama, and History,” Seminar at the Niels Bohr Institute (NBI) organized by Finn Aaserud, Director of NBI Archive, November 19, 1999; “Drama Meets History of Science,” Symposium, NBI Archive, September 22-23, 2001. Mara Beller, Cathy Carson, Mathias Dorries, Robert Friedman, Jan Golinsky, Klaus Henschel, among others, address the issue of “blurred genres” in the dramatization of episodes from the history of science in ways that are suggestive for my analysis of Photo 51. See also “Creating Copenhagen, A Symposium Exploring Scientific, Historical, and Theatrical Perspectives Surrounding the Events of the Acclaimed Play ‘Copenhagen’, GC-CUNY, New York City, March 27, 2000, Chris Smith and Brian B. Schwartz, “producers.”

10 For other such cases see, for example, that of a woman scientist at an Ivy League university in the Northeast who complained that she felt mugged when the lab director put his name, as well as those of his three male protégées, on a discovery that she had made and was trying to publish; she was told to be content since she had not been raped; for further details see Catherine Brady, Elizabeth Blackburn and the Story of Telomeres, (The MIT Press, 2007) p. 43. The issue of misallocation of scientific credit affects of course both women and men, but this play deals with misallocation affecting a woman.

11 Nelson Pressley, “Theater Review: ‘Photograph 51’ at Theater J,” The Washington Post, April 4, 2011.

12 Nature Reviews – Molecular Cell Biology, 3, January 2002, 65-70.

13 See Maddox 2003 for information on Franklin’s many relatives in public life.

14 E.g. The Boston Globe, 2-15-2012; The Washington Post, 4-4-2011; Los Angeles Chronicle, 3-31-2009; among other theatre specific outlets, e.g. DC Theatre Scene, see note 16.

15 Trey Graham, “Theatre J discovers DNA”, Washingtoncitypaper.com (4-1-11)

16 Steven McKnight, dctheatrescene.com, 3-31-11.

17 In 2003, the British government marked the 50th anniversary of the discovery of DNA’s structure as “50 years of excellence in British science” and included Rosalind Franklin among the (now four) discoverers. In my above-mentioned book I also include Rosalind Franklin as a discoverer, a conclusion that differs from the current historiographic status-quo, as to the number of discoverers.

SOURCES:


Photo 51—A Recent Addition to History-of-Science-Inspired Theatre

Pnina G. Abir-Am, Brandeis University Newsletter of the History of Science Society, Vol. 41, No. 3, July 2012

http://www.hssonline.org/publications/Newsletter2012/July-Photo-51.html

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