Posts Tagged ‘Triple Helix’

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.

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.

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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.

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

insert pictures





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.

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.

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


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

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

B. Triplex DNA Structures.

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

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.


Lyamichev VI, Mirkin SM, Frank-Kamenetskii MD.

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

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

Nature 1987; 330:495-97.

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

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

Mirkin SMo Frank-Kamenetskii MD.

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

Hoogsteen K.

Acta Crystallogr. 1963; 16:907-16

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

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

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

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.
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 transcriptomic_Data_Across_Experiments-A-Case_Study_on_the_Identification_ of_Candidate_Target_Genes_of_the Transcription_Factor_PPARα/

Corresponding author email:

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
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 (

  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

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in
transcription, ubiquitination and DNA repair
S Saha

Computational Genomics Center: New Unification of Computational Technologies at Stanford
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Personalized medicine gearing up to tackle cancer
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Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (
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LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2
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GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”
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Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence A Lev-Ari

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition
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The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953
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Directions for genomics in personalized medicine larryhbern

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. SJ Williams Mitochondria: More than just the “powerhouse of the cell” ritu saxena

Mitochondrial fission and fusion: potential therapeutic targets? Ritu saxena

Mitochondrial mutation analysis might be “1-step” away ritu saxena

mRNA interference with cancer expression larryhbern

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Breast Cancer, drug resistance, and biopharmaceutical targets larryhbern

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis
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Gastric Cancer: Whole-genome reconstruction and mutational signatures A Lev-Ari

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis larryhbern

Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology A Lev-Ari

2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 Shift in Human Genomics_/

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Sohan Modak


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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Chapter 1 in

R&D Alliances between Big Pharma and Academic Research Centers: Pharma’s Realization that Internal R&D Groups alone aren’t enough


Helix Model of Innovation in IsraelThe Global Scheme and its Local Application

Prof. Gili S. Drori

Department of Sociology and Anthropology

The Hebrew University of Jerusalem

Senor and Singer’s 2009 book, “Start-Up Nation,” quickly hit the best-sellers list of the Wall Street Journal and the New York Times and was translated into some twenty languages. The book peaked the world’s fascination with Israeli innovation by answering “the trillion dollar question”: “How is it that Israel – a country of 7.1 million, only 60 years old, surrounded by enemies, in a constant state of war since its founding, with no natural resources – produces more start-up companies than large, peaceful, and stable nations?” And, “how is it that Israel has, per person, attracted over twice as much venture capital investment as the US and thirty times more than Europe?” The Israeli “miracle” stands as a code to be cracked, or as an exemplar for countries and regions worldwide that are seeking innovation-based development. The buzz around this book builds on the recognition of innovation as the critical component for success in the global knowledge economy: no longer can firms or nations grow solely off their natural- or human capital resources; rather, growth depends on innovativeness.

In seeking to decode the systemic foundations of innovation, previous studies analyzed the other so-called miracles of the global knowledge economy: Scandinavia, the Boston area and, of course, Silicon Valley. Many of these studies highlight particular causes for such innovation-based regional success – from immigration ties (e.g., Saxenian, 1994, 2006) to legal and financial institutions (e.g., Suchman, 2000, 2001) to network constellation (e.g., Whittington et al., 2009). But the question remains: What combination of such components and what “critical mass” of them would spark an innovation economy? Two conceptual tools, which were delineated in order to model the system components whose assemblage triggers a local innovation economy, dominate discussions throughout the past four decades: Christopher Freeman and Bengt-Åke Lundvall formulated the concept of  “national innovation system” (NIS) and Henry Etzkowitz and Loet Leydesdorff outlined the Triple Helix Model. The work compiled in this volume takes the Triple Helix Model as a point of departure in mapping and analyzing Israel’s innovation economy.

1.1 The Triple Helix Model

Seeking to explain the socio-structural conditions that encourage knowledge-based economic development, Etzkowitz and Leydesdorff proposed in 1995 the Triple Helix Model. The Model links among academia, industry and government and, building on the imagery of the double-helix structure of DNA, the Triple Helix model weaves these three helices into a spiral configuration which allows for multiple reciprocal links among the three institutions. Although Etzkowitz (2003) specifies as many as 10 propositions that express the Model’s tenets, three principles stand at its core: (a) the three helices, or institutions critical for innovation, are academia, industry and government, (b) there exist multiple points of contact and exchange among these three institutions, and (c) each of the institutions is transformed through such intensifying interconnectedness. The outcome is not merely a joint project or a jointly developed product, but rather an integrated, often hybridized, form of knowledge-based development, of nations and regions (see. Meyer, Grant and Kuusisto, 2013). And, this systemic interlacing among the so-called helices maintains the dynamism and flexibility that are core features of any system of innovation.

The three institutions laced into the Triple Helix model are described in Figure 1.1.

These are:

University. The University has always been entrusted with knowledge creation, through learning and research. In today’s knowledge-based economy, universities have been transformed into knowledge producers and market players. Etzkowitz describes this transformation as follows: “The university has traditionally been viewed as a support structure for innovation, providing trained persons, research results, and knowledge to industry. Recently the university has increasingly become involved in the formation of firms, often based on new technologies originating in academic research.” (2003: 294). Such commercialization of academic knowledge also drives universities to guarantee legal protections of their intellectual property and, with that, defy the normative order of public science (see, Bok 2003, Willmott 2003, Ramirez 2006, Rhoten and Powell 2010). And while recent decline in university patenting has been taken to mean a re-trenching of academia to focus on  ‘core business’ of basic research and teaching (see, Meyer, Grant and Kuusisto, 2013: 193), the overall intensification of commercialization and co-production of knowledge is the hallmark that defines the entrepreneurial university, or the “3G university” (see, Wissema 2009).

Industry. With knowledge and innovation becoming the new source of capitalization for firms, firms too are transformed into knowledge producers: firms replace their traditional model of in-house R&D and innovation, which drew solely upon internal capacity, with an open innovation model, which calls for cooperative models of innovation and on outsourcing of innovation functions. As a result, firms not only continue to build in-house labs and sponsor academic research, they now cooperate intensely with academic research and allow – even welcome – the mobility of researchers between academia and industry. This post-Fordist production is a form of open innovation.

Government. As the representative of the public and an advocate of public good, government serves as the third component in the driving of innovation. Whether national, state, or municipal, government serves as an enabler of innovation ties, mostly by sponsoring start-up initiatives or funding “big science” projects in hope of spillover effects. In addition, government guides innovation through its regulatory power, for example by formulating IP arrangements. Still, government’s supervisory role as regulator may also result in suffocating innovation through, for example, regulatory restrictions on types of research or on taxation of foreign investment.


  • Figure 1.1  The Triple Helix Model

Source: adapted from Etzkowitz and Ledesdorff, 2000 (figure 2, page 111)

The important feature of the Model is that the 3 institutions, or helices, are intertwined and link in multiple points. Recalling DNA structure, the Triple Helix model of innovation laces the strands, or helices, and build multiple connects among them; this form is described as a “recursive overlay of interactions among the stakeholders” (Yang et al., 2012: 375). In its form, the Triple Helix Model distinguishes itself from two other possible format of relating academia, industry and government (Figure 1.2). The first alternative is the Lesseiz Faire Model, where a country has all three institutions, yet it is at their initiative and at their pace that any link is made between them. The second alternative is titled the Etatic Model. In this form of relations, government takes the responsibility to guide innovation and also to build innovation-related links between academia and industry. Like Goldylock’s choice of a bed at the bears’ home, Leydesdorff and Etzkowitz regard these two alternative models for innovation as either too loose or too tight. The Triple Helix Model calls for a balance among the three helices, so to prevent a case of tertius gaudens, where one sector benefits from any stress between, or weakness of, the other two helices (see, Etzkowitz and Zhou 2006: 77). Unlike these Lesseiz Faire and Etatic formulations, the Triple Helix model is both flexible and self-reinforced, allowing for appropriate room for agency while offering a structural backbone for links to form and stabilize.


  • Figure 1.2   Lessaiz Faire and Etatic models of relating academia, industry and government

Source: adapted from Etzkowitz and Ledesdorff, 2000 (figure 2, page 111)

1.2 Social Context 

The backdrop for the Triple Helix Model is the discussions since the 1970s on the structural base of the transition into a knowledge economy. The Triple Helix model is, therefore, one of several eco-systemic outlines for innovation, all of which draft the environment, or social context, of innovation and entrepreneurship. Among such systemic maps of the innovation- and knowledge economy, and most clearly in comparison with the notion of NIS of Freeman and Lundvall (see, Nelson 1993), the Triple Helix model stands out due to several of its core features. First, it is a neo-evolutionary model, where the development of social institutions, herein the sectors of an innovation economy, is revealed as a co-evolutionary process. Second, it is a non-linear model of social action, herein of the interaction among the three sectors. In this sense, the development of an innovation economy, while path dependent to some degree upon historical circumstances, is sparked by the interactive and multilateral interactions among multiple stakeholders. Its neo-evolutionary tone makes the Triple Helix model most applicable for policy. Indeed, the model has been a basis for many policy reforms, of regions and nations seeking innovation-spurred development.

Epistemologically, from the perspective of organizational studies, the Triple Helix Model is a part of an overall move to regard organizations as open entities, which are embedded in a wider social context (see, Engwall 2007). For example, university governance is currently analyzed as involving relations with “external” and multiple stakeholders, such as accreditation agencies, international higher education associations, parents groups, and employers of their to-be graduates (see, Tuchman 2009). This understanding of the porous boundaries of each of the three core institutions in the Model does not weaken the positivist approach to social development that underlies the Triple Helix Model. Rather, contrary to the focus on academic capitalism (Slaughter and Leslie 1997, Slaughter and Rhoades 2004, Hoffman 2011), the Triple Helix Model regards university-industry ties as an imperative for innovation and development and as synergetic, rather than exploitative, relations. Overall, it is on such matters – of a model void of power, hierarchy and historical context – that the Triple Helix Model is most criticized.

1.3 Critique of Triple Helix Model

Criticism of the Triple Helix Model comes from two directions. First are those who challenge the premises of the Model and expose its ideological roots. In this group are the many studies of academia-industry relations that highlight power-asymmetries among the sectors. In the words of Yang et al., the Model “treats the roles of different innovation actors (universities, industry and government) symmetrically, which promotes the impression that innovation is the result of non-hierarchical collaborations around mutual development objectives.” (2012: 347). Prominent among such critics is the “Academic Capitalism” school, led by Sheila Slaughter, Gary Rhodes and Larry Leslie. This research tradition stresses the impact of the industrial sector and other commercial interests on academia and the tilting of academic research in the direction of such capitalist, profit-oriented interests. Benner and Sandstrom (2000), for example, call attention to the impact of research funding on the institutionalization of Triple Helix ties: research sponsors, they claim, “steer the attention of potential applicants in a specific direction” by, for example, setting criteria for evaluation and “influence the expectations and orientations of the applicants.”

Others add that the Model is archetypical American and, with that, flattens cross-national variations in the triple-sectoral relations or in innovation systems in general. Therefore, while the Model portrays three-sector relations as a necessary condition, industrial development in Europe has long been anchored in industry-academia partnerships. Therefore, contrary to the Triple Helix Model’s imagery of innovation systems, Fogelberg and Thopenberg show that “[t]he mutual development that Arenas promoted was based on the tradition in the Swedish welfare model, i.e. a two helices industry-government partnership between large organisations, rather than on a Triple Helix process.” (2012: 355). From this perspective, the Triple helix Model reflects American definitions of innovation in the post World War II era, immersed in a culture of commercialization of the public good.

The second line of criticism of the Triple Helix Model includes the many calls for amendments to the Model, rater than replacing it. These calls are not taken as a challenge to the Model, but rather as a way to increase the Model’s relevance to varying conditions worldwide and to adapt it to changing circumstances. In fact, Etzkowitz and Leydesdorff are themselves among those conceiving of extension- models, suggesting “triple helix twins” (Etzkowitz and Zhau 2006) or “N-tuple helices” (Leydesdorff 2011).

One direction for extension and adaptation of the Model, and with that a challenge of-sorts to its original formulation, includes the call for amendment to the geographical scope. Such challenges, which also speak to the American-centric tone of the Triple Helix Model, come on the basis of the adaptation that is required from the Model’s region-based analysis to its aspiration to speak for national systems. Specifically, the Triple Helix Model is scoped for regions, as it was developed from lessons of Silicon Valley and Route 128, yet it is used interchangeably with NIS, which is scoped for whole national economies and is guided by national policy. This “mismatch” between regional-, city- and national systems of innovation challenge the generalizability and applicability of the Triple Helix Model. Gray (2011), for example, calls for STI learning to occur between cities or between regions, rather than between countries. He concludes by saying that “it may make more sense for my international colleagues to spend more of their time visiting Albany, NY, Sacramento, CA, Raleigh, NC or one of the other host of states that have developed highly diversified approaches to supporting economic development via CSRC and less in our nation’s capital.” (2011: 132). Overall, this call for amendment is a call for careful application of the framework suggested by the Triple Helix Model beyond its original formulation for regions onto national-, city- or cross-border innovation layouts.

Most of the calls for amendment to the Triple Helix Model come on the basis of expanding the number of social sectors intertwined into the innovation system. Some calls are for the addition of a single, fourth strand to the university-industry-government model. Most importantly, both Leydesdorff and Etzkowitz (2003), Marcovich and Shinn (2011) and Yang et al. (2012), who wrestle with the definition of this amorphous social sector, suggest the adding of ‘the public,’ ‘society’ or ‘NGOs and local community organizations’ (respectively) as the fourth helix to the original triple–strand formulation. The involvement of civil society, nongovernmental organizations or local community is found to be of particular importance in the development of specific sectors of innovation, such as eco-innovation (Yang et al, 2012). Lately, Leydesdorff (2012) went as far as to suggest an N-tuple Helix model-of-sorts, as an acknowledgement of the diversity of stakeholders involved in the innovation process in the 21st century (see also, Carayannis and Campbell 2009). Yang et al. summarize these various helix models of innovation by comparing among Triple Helix, Triple Helix Twins, Quadruple Helix and N-tuple Helix models (Table 1, 2012: 377).

Others add a time dimension to the helixing. Specifically, Marcovich and Shinn (2011) not only add a strand for ‘society’ but also identify four phases to the formation of a field-level triple helix. They find that in the emergence of the research field of Dip-Pen nanolithography is phased into stages, each of which is characterized by binomial links: phase 1 includes academic instrument research (and involves university/society link); phase 2 describes the transformation from instrument to tool and the start up of a company (university/industry link); Phase3 is includes the development of a mature firm and commercialization (industry/society link); and Phase 4 is when confirming of ‘‘nanofication’’ occurs (society/industry link).

Marcovich and Shinn’s work, while addressing the general theme of time and process, also speaks to the specificity of the model to one sector or another. The possibility that triple helixing is sector specific also emerges from the work of Etzkowitz and Zhou (2006), who suggest that Triple helix Twins are formed due to the gap between innovation and sustainability in some sectors or due to the differences in economic emphases of sectors.

Overall, the many calls for expansion of the Model to additional geographical scopes, additional social contingencies, and most importantly additional helices, reflect the complexity of innovation and the intricacies involved in specifying the system that springs innovation. Our work here follows this line of expansion of the original Triple Helix Model. Through a thorough analysis of the systemic components of Israel’s successful innovation economy, we propose an extension to the original formational of the Model by adding additional helices and, with that, specifying socio-political contingencies for innovation in Israel.

1.4 The Case of Israel

Israel’s innovation economy is flourishing and still many concerted efforts are made to maintain Israel’s edge in the global knowledge- and innovation economy. Israel also boasts a solid foundation for a Triple Helix format, with most active academic, governmental and industrial sectors.

University. Israeli academic institutions, two of which predate the founding of the State of Israel[1], include 9 universities and dozens of colleges and, remarkably, 46% of Israeli adult population attained tertiary education. And while the quality of science education, from elementary to high schools, is in lower middle OECD range, the success of Israeli academia is expressed in a high rate of scientific publication, high ranking of universities, international awards for Israeli science[2], and patent productivity of universities[3] – all of which contribute to Israel’s repeated ranking as #1 worldwide in quality of scientific research institutions according to the Global Competitiveness Report. The leadership of Israeli universities is noted in particular in computer science, mathematics, economics, and chemistry[4] and national plans set several specific scientific fields as national priority[5]. Such leadership is also evident in Israel’s leadership in patenting in specific fields, most notably IT (see, Figure 1.3). In 2011 reports Israel ranked 4th worldwide in patent production ratio[6]. As noted in Chapter 4, all seven of Israel’s research universities have a technology transfer arm, with Weitzmann Institute’s YEDA founded in 1959, much earlier than noted TTOs elsewhere in the world.


  • Figure 1.3  Technology Productivity, by Field 2007-9: Israel in Comparison to OECD Countries   (Index based on PCT[1] patent applications)

Source: OECD STI Outlook 2012, p. 4.

[1] The Patent Cooperation Treaty (PCT) is the 1970 international patent law treaty harmonizing patent registration procedures and patent protections.‬‬

Industry. Israel’s first high-tech firms were Tadiran and Elron Electronics, founded in 1962 and thus Israel’s celebrated software sector came following a strong IT standing was set (see, Braznitz 2007). Israel’s noted standing in education and STI productivity quickly lured high-tech multinationals to invest in Israel, with Motorola being the first US firm to set an Israeli arm in 1964. Notably, the main activity of multinational tech companies in Israel is R&D: Microsoft and Cisco Systems built their first R&D center outside in the US in Israel; Motorola set its largest R&D center in Israel; Intel, which started operating in Israel in 1974 and has 2 manufacturing facilities, has 4 R&D centers in Israel and Google holds 2 R&D centers in Israel. Overall, in 2012 over 240 foreign companies established R&D centers in Israel. By 2000 Israel’s “Silicon Wadi” cluster was recognized as equal in strength to Boston, Helsinki, London, and Kista (Sweden), second only to Silicon Valley (Hillner 2000). R&D-related products comprise more then half of total industrial exports (excluding diamonds). And Israel ranked 11th worldwide in company R&D spending[7] and is leading among OECD countries, in particular in knowledge-intensive industries (see, Figure 1.4). With 2010 gross domestic expenditure of R&D (GERD) standing at 4.40% of GDP (excluding defense) and an average annual growth of 4.1% in 2005-10, Israel stands as an OCED leader in R&D-related expenditure; 52% of GERD in 2008 came from private sector funding. All these factors, including the ingenuity of founders, account for the success of Israel’s knowledge-intensive industry even in the face of the challenges of political uncertainty, wars, and geographical distance (see, Chorev and Anderson, 2005).


  • Figure 1.4   R&D Investments: Israel in Comparison to OECD Countries (% of total business enterprise R&D (BERD), 2009)

Source: OECD STI Outlook 2012, p. 4.

Government. Several laws guide Israeli policy regarding STI, revealing policy emphasis on only on education but particularly on R&D.[8] Several core government program stand successfully: for example, MAGNET program – which was established in 1994, is managed by the Office of the Chief Scientist of the Ministry of Industry, Trade & Labor, aims at supporting technology initiatives in Israeli industry – had a budget of 57 million USD in 2011; the 1991-1998 incubators program which came to alleviate stress of large and highly educated immigration from the former Soviet Union and spun some 500 graduating companies with 50% success rate (Trajtenberg 2000); and a 2010 Ministry of Finance initiative titled “relative advantage” (יחסי יתרון) is aimed at locating financing sources for Israeli start-up companies. In addition, several measures of The Higher Education Plan 2011-15, which aims at improving higher education and research, were implemented: doubling of in Israel Science Foundation funding (from 75 million USD in 2011 to 139 million USD by 2015) and a 362 million USD I-CORE (centers of research excellence) project. Still, Israel’s STI policy is regrettably at the jurisdiction of several ministries (Ministry of Industry, Trade and Labor, Ministry of Science and Technology and Ministry of Education and there is no comprehensive national STI plan or strategy.[9] With that, the path of Israel’s STI policy is unique in comparison to other emerging economies: Israel’s successful IT industry builds upon already present R&D and educational capacity and then was spurred by a “market-failure-focused, industry-neutral S&T policy” (Breznitz, 2007). As noted in OECD reports, in comparison to other OECD-member countries, Israel’s innovation policy is lagging (see, Figure 1.5).


  • Figure 1.5  Overview of National Innovation Policy Mix, 2010: Israel in Comparison to OECD Countries

Source: OECD STI Outlook 2012, p. 4.

Without challenging the important role of these three sectors, which are core to the Triple Helix Model, in the success of Israel’s innovation economy, are these the only institutions involved in spurring innovation in Israel and thus influencing Israel’s innovation economy? What additional institutions shape Israeli innovation? Are these additional institutions “helixed” into the traditional 3-helix model?

Drawing upon discussions of our research team, we concluded that the 3-helix model, which identifying the core institutions and articulating their tights and entangled relations, does not fully capture the institutional complexity of Israel’s innovation. Rather, Israel’s innovation requires the helixing of several additional strands into the traditional 3-strand, Triple Helix Model. Specifically, we propose that any description of Israel’s innovation system by the helix model of innovation requires the addition of at least the following institutions:

Military. In spite of the secrecy concealing much of Israel’s defense-related R&D, the Israeli defense sector has a fundamental impact on the development of Israel’s IST sectors. Much of Israel’s R&D sponsorship was directed at defense projects and the Israeli Defense Forces (IDF), along with the Israeli military industries, stand to be both a client for innovation and a producer of innovation. By 1980s estimates, 65% of the national expenditure on R&D were defense related, with only 13% oriented towards civilian industries) and about half the scientists and engineers employed in the industrial sector worked in defense industries (Peled, 2001: 5). IDF also influences innovation by way of its alumni, through spin-offs and cultural imprinting: many of Israel’s start-up spun off knowledge gained during compulsory military service, much of Israel’s business network is built off ties that were formed during military service, and skills of teamwork and initiative-taking born of military culture heavily imprint Israel’s STI work culture (see, de Fontenay and Carmel, 2004; Senor and Singer, 2009). Overall, the prominence of military R&D in Israel’s STI is fueled not only by Israel’s security concerns but also draws upon the spirit of Vannevar Bush’s Science – The Endless Frontier (1945), which is the constitutive document for STI policy ever since. In addition to the principle of public funding and sponsorship of STI, Bush also set a central role to military R&D thorugh collaboration with university- and industry-labs. The IDF operates according to this logic, also building DARPA-like R&D centers within the military.

Financial sector. With Israeli economy overwhelmingly dominated by the public sector until the early 1980s, much of the funding for education, science and R&D came from government sources (ministries, government-controlled banks and public agencies). Trajtenberg (2000) reports that while until 1980s financial support was directed solely at National R&D Labs, academic and agricultural R&D, and the (presumably weighty) defense-related R&D, the “beginning of government support for industrial (civilian) R&D in Israel dates back to 1968: a government commission, headed by Prof. Ephraim Kachalski (Katzir)[10], called for the creation of the Office of the Chief Scientist (OCS) at the Ministry of Industry and Commerce, with the mandate to subsidize commercial R&D projects undertaken by private firms.” Still, even after the massive privatization of the 1980s and the mounting pressure on sufficiency of higher education institutions, governmental subsidies and government-sponsored programs heavily influenced the sprinting of knowledge-intensive industry in Israel. For example, Lach (2002) calculates that “an extra dollar of [R&D] subsidies increased long-run company-financed expenditure on R&D by 41 cents.” Following the first Israeli firms to register on American stock exchanges, with Elscint beings the first Israeli IT company to go public on NASDAQ in 1972, many more followed to seek private funding.  In 2012, Israel was second only to China in Nasdaq-listed companies: in 2012 over sixty Israeli companies are listed on Nasday, of more than 250 Israeli companies that has IPO on Nasdaq since 1980 and with 33 new Israeli listings in the year 2000 alone. Here emerge a few paths for innovation funding. In comparing Israel R&D intensive companies registered on US- and Israeli stock-exchanges, Blass and Yosha (2002) show that the companies listed in the US use highly equity-based sources of financing and are more profitable and faster-growing, whereas those listed only in Israel rely more on bank financing and government funding and are slower to grow. With the global opening of Israeli industry and financial sector, and with added boost from the Yozma government initiative to give tax incentives to foreign VC investments, came the entry of venture capital into Israel: between 1991 and 2000, Israel’s annual venture-capital expenditures rose nearly 60-fold, from $58 million to $3.3 billion and the number of companies launched by Israeli venture funds rose from 100 to 800 (IVC, 2012). With that, Israel is the largest venture capital in the world outside the US (Breznitz, 2007). This VC infusion has been found to directly impact high-tech growth in Israel (Avimelech and Teubal, 2006). In addition to the shift from public- to private funding, as of late there is also a shift from venture capital to private equity funding and a growing number of “angels” and “angel funds” (IVC, 2012). Overall, over the course of the past four decades we see a dramatic change in the finance base for STI in Israel, while Israel is also turning into a global player in STI financing.

Social sector, civil society or the non-profit sector.  Following in the steps of earlier discussion by Leydesdorff and Etzkowitz (2003), Marcovich and Shinn (2011) and Yang et al. (2012), it is evident that Israeli civil society is indeed increasingly influencing the course of STI development. Under the canopy of social sector innovation and entrepreneurship come many different initiatives, varying by goal (to create socially-minded ventures or to close social gaps in ICT access, use and creation), by sponsorship (governmental, corporate philanthropy or non-profit bodies) and therefore by being more or less formal. Operating formally as drivers of social innovation and entrepreneurship, many more Israeli NGOs are focusing their attention to innovation and social-innovation-minded international NGOs, such as Ashoka (see Chapter 6), are now operating in Israel. Some, like Olim BeYakhad (ביחד עולים) which works with educated and skilled Ethiopian immigrants, focus on social innovation, especially among weakened populations; others, like or The Hub TLV, give home also to tech or artistic innovation; and other, like Presenentse mentorship club, focus on supporting business and tech ventures. And, such socially-minded innovation and entrepreneurship initiatives are increasingly professionalized (see, ואשכנזי אברוצקי, 2011). With that, Israeli civil society is spurring the redefinition of innovation and development to include social innovation and social entrepreneurship. For one, the Prime Minister’s Prize for Innovation, which is distributed since 2010 and is a part of Israeli participation in Global Entrepreneurship Week, is giving equal credence annually to technology- and social inventors. In addition, Israeli civil society is imprinting STI industrial connections. For example, Rothchild and Darr (2005) show how much of the links between academia and industry in Israel depend on informal networks of affinity: much of the exchange of know-how and practice between the Technion and a partnering incubator depend on cyclical models of network relations among Israeli-born managers or, separately, among Russian-born scientists. And, as noted earlier, much of Israeli high-tech sector is traceable to social ties formed during military service, which still remains a “melting pot” for the Jewish non-Orthodox segment of Israeli society. This results also in the isolation, and marginalization, of any Israeli-Arab tech venture; this itself sprung civil society initiative to close the Jewish-Arab gap, with for example The Arab-Israeli Center for Technology and Hi-Tech working as a non-profit organization since 2008 in response to the high unemployment rates among highly educated Arab Israelis by encouraging their placement with Israel high-tech firms.

Diaspora, Social network relations closely tie Israeli society with two social groups outside its borders: the Jewish- and Israeli diasporas. It is estimated that in 2010 Israel was home to only 35% of the world’s Jewish population, with Israel’s Jewish population only slightly bigger than the Jewish population in the US alone. Still, with Israel declarably the home for the Jewish people, the worldwide Jewish diaspora ha strong relations with Israel and, specifically, has also impacted STI sectors. Initial support of Israeli institutions, most notably of academia, were philanthropic donations; many of the buildings, programs, and prizes in Israeli universities are named after their sponsors. As of late, it seems, more such sponsorship comes as a form of investment (Shimoni 2008 and Silver 2008 in Schmid et al., 2009): sponsorship medical- and agriculture research that comes as a form of partnership and investment.

In addition, Israel is also linked with an Israel diaspora, comprising of Israelis who reside outside of Israel: By 2008 estimates of the Ministry of Immigration and Absorption, the Israeli diapora is estimated at 12.5% of Israel’s Jewish population, with some 60% residing in the US. While decreed as Yordim for many years, the stigma that came with emigration from Israel has slowly been lifted and Israelis who found success abroad have followed in the way of Jewish philanthropist and investors to contribute to Israel’s growth. Such “circular immigration” or “Brain Circulation” (Saxenian, 1994, 2006) has been translated to IST: Israeli-heritage ties were the bridges to bring several global high-techs firms, most notably Intel in the 1970s, to establish branches in Israel (Orpaz, 2012). More formally, several government initiatives reach out to the highly educated and affluent Israeli diaspora: programs targeting “returning scientists” and activities such as that of the California-Israel Chamber of Commerce Israeli foster and maintain relations with the aim of linking business and academic communities of Israelis outside of Israel with Israel’s innovation economy.

In addition to the impact of these two diasporic communities outside of Israel, it is upon Jewish diasporic ties that Israel’s high-tech sector grew. Specifically, Israel’s knowledge-intensive industries, and particularly its post-1990 high-tech boom, relied upon waves of high-skill immigration: the 19991-1993 wave of immigration from the former Soviet Union served as a critical human capital infusion for Israel’s high-tech sector (see, Avimelech and Teubal, 2006; Chorev and Anderson, 2006).

In summary, in attempting to apply the Triple Helix Model to the Israeli case we came to the realization that the three-strand formation does not cover the full breadth of institutions, or sectors, that are tightly involved in the success of Israel’s innovation economy. Rather, we find that to the university-industry-government formation, one must add 4 so-called strands: the military, financial sector, civil society and the diaspora. With that, the Israeli innovation system is best described as a 7-helix model. The structure of this book follows this logic: each team member focused her or his research on a specific strand, regrettably with the exception of the “strand” of diasporic ties.

1.5 Structure of this Book

Following on the review of the conceptual background and critique here (Chapter 1) and the introductory note by Henry Etzkowitz (Chapter 2), the book offers a total of 6 chapters, each devoted to the exploration of a single innovation helix in Israel.

Chapter 3, written by Alexandr Bucevschi, focuses on innovation in Israel’s industrial sector, by focusing patent as and on the inter-helix relations that are reflected in patenting. With empirical verification of the Israeli industry (Teva Pharmaceuticals Industries Ltd. and Elbit Systems Ltd.), looking at the affiliations of patent owners and inventors appearing in applications, he demonstrates the connections between one helix and its different sectors and between it a other helices. With that, Alexandr identifies patterns that set a basis for future causal studies as well as allowing for an early look into the influences global changes have over local industries and their patenting policy.

Chapter 4, written by Navah Berger, sets to map out the characteristics of the mechanisms used for translating academic knowhow into commercialized technologies, namely university technology transfer offices. All seven[11] Israeli research universities have a cohesive model of technology transfer that plays a role in innovation creating the field of study. By exploring their three technology transfer strategies (patenting, licensing and spin-offs), Navah reveals the extent to which commercialization of academic knowledge is well ingrained into Israeli academia, thus setting Israeli academia is a solid basis for Israel’s booming innovation economy.

Chapter 5, written by Amy Ben-Dor, analyzes the role that government initiative splay in fostering innovation in Israel, specifically exploring the gender bias in such government initiatives. Specifically focusing on the Tnufa[12] Program of Israel’s Ministry of Trade and Industry, which is aimed at supporting young entrepreneurs, Amy reveals the maintenance of social inequalities and reproduction of gender differences through the review procedures of proposals coming before the Program. In this manner, Tnufa Program is a gendered program, exposing the gendered, specifically masculine tone of the different helices.

Chapter 6, written by Noga Caspi, offers a study of Ashoka-Israel as an exemplar of the impact that civil society, or non-profit, organizations have on the field of innovation and entrepreneurship. Studying the project portfolio of Ashoka-Israel, Noga reveals that through promoting the creation of social value, A-I has reframed social activity with notions of innovation and entrepreneurship. In this way, she argues, Ashoka-Israel becomes involved in innovation work in Israel.

Chapter 7, written by Ohad Barkai, centers on the funding of research. Relying on his own compilation of research funding information that is publically available, he creates a series of network maps of Israeli institutions that are involved in funding of research, specifically medical research, in Israel. Ohad Barkai then concludes that a variety of organizations are involved in funding of medical research in Israel: government agencies (such as Israel Science Foundation), pharmaceutical and medical firms (such as Novartis), and non-profit organizations (such as Israel Cancer Association). And since Ohad studied the number of research projects funded, rather than the size of the funding, it is clear that the major sponsors of research in Israel are not the big-budget organizations but rather the non-profit organizations. Ohad’s conclusions reinforce the importance of the civil society “helix.”

Chapter 8, written by Avida Netivi, focuses his study on Talpiyot[13] Project, which is a military program designed to build a cadre of innovative R&D personnel for the Israeli Defense Forces (IDF). The selected excelling recruits are sent for physics, CS, or mathematics studies at The Hebrew University of Jerusalem, while also going through military training and introduction to defense-related industries. Avidah’s study, which started with the assumption that the military is an N-th helix in Israel’s system of innovation, concludes that Telpiyot project is in itself an expression of a Triple Helix Model. Talpiyot’s curriculum triangulates among university studies, industry experience, and officers’ military training. On the basis of such analysis, Avidah continues with a consideration of the innovation system as helixed (interlinked strands) versus hybrid (fused).

One helix proposed for Israel’s N-Tuple helix model, namely diaspora, was not analyzed because of shortage of research collaborators. We encourage others who are interested in studying Israel’s miraculous entry into the global innovation economy to explore the importance of long-standing relations between Israel and the Jewish worldwide diaspora as well as the new and still tenuous relations between Israel and the worldwide Israeli diaspora.

1.6 Concluding Comments

The Triple Helix Model offers us a starting point for an analysis of the innovation system in Israel. We are inspired by the Model’s highlighting of multi-sectoral formation and its emphasis on the interlacing and recursive relations among these many stakeholders. In this work, we take the Triple Helix Model to be a methodological tool for generalizing innovation formation and dynamics. First, relying on the Model’s triple-sectoral formation and accepting its metaphor of intertwined helices, we here expand to analyze the Israeli case as a 7-sector innovation-economy. Second, relying on the Model’s suggestion of multiple points of interaction among the helices and the transformative effects that such interaction has on each of the involved institutions, we analyze the cross-cutting relations among the Israeli military, academia, industry, financial sector, civil society sector, and the Israeli government. We contend that Israel’s innovation was spurred, and still thrive upon, the helixed relations among all 6 strands 9and by extension also the 7th helix of diasporas). It is these helixed strands that formed the “critical mass” of innovation in Israel and turned the once isolated and labor-driven economy into the hothouse of innovation for the global knowledge economy.


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[1] Technion (Israeli Institute of Technology) held classes starting in 1924 and The Hebrew University of Jerusalem in 1925.

[2] Most notably, of the 10 Israeli Nobel Prize laureates, 6 received the award for scientific excellence: 4 in chemistry and 2 in economics.

[3] In terms of PCT patents field by universities and public labs; OCED 2012.

[4] According to Shanghai ranking of universities 2001: in computer science Weitzmann Institute ranks 11th worldwide; Technion 15th, Hebrew University 26th and Tel Aviv University 28; in Mathematics, Hebrew University 22nd, Tel Aviv University 32nd and Technion in group 51-75; in Economics both Hebrew University and Tel Aviv University in group 51-75.

[5] Specifically, the national I-CORE project specifies policy priority for the following higher education and research fields: molecular basis of human diseases, cognitive science, computer sciences, and renewable and sustainable sources of energy. And the Israeli Biotechnology Fund set brain research, nanotechnology and biotechnology as its priority sectors.

[6] Utility patents granted per million population: 195.0; outranked by Taiwan (287), Japan (279) and US (261); Global Competitiveness Report 2010-11.

[7] Israel’s score 4.7 (on scale of 6); Global Competitiveness Report 2010-11.

[8] Encouragement of Industrial Research and Development Law 5744-1984 (amended as late as 2006); Law for the Encouragement of Capital Investment, 5719-1959 (amended as late as 2011); and laws for preferential treatment of R&D investments in the Negev and Galilee.

[9] For comprehensive review of policy, updated to 2007, see Getz and Segal (2008).

[10] Prof. Ephraim Kachalski was a chemist and among the founders of the Weizmann Institute. Upon his appointment as the 4th President of the State of Israel (1973-1978), he Hebraicized his last name to Katzir.

[11] Israel’s two additional universities do not have TTOs: Open University is primarily a distance-learning institution and Ariel University of Samaria was given the status of a university only in 2011.

[12] “Tnufa” translates to momentum, or upswing

[13] “Talpiyot” translated to solid and magnificent structure, or fortress.

[14] The classic Trivium and Quadrivium were the core and supporting academic disciplines that constituted the knowledge-base of medieval Europe. See Etzkowitz, Ranga and Dzisah, 2012.

[15] Author discussion with Yozma founders at the 3rd Triple Helix Conference in Rio de Janeiro, 1999. FINEPE, the Brazil Development Agency invited Yozma representatives to the conference and held side meetings to arrange transfer of the Yozma model to Brazil. FINEPE added an additional element, “FINEPE University,” a series of workshops held around the country to train entrepreneurs in “pitching” to venture firms.

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R&D Alliances between Big Pharma and Academic Research Centers: Pharma’s Realization that Internal R&D Groups alone aren’t enough 

Israel’s Innovation System: A Triple Helix with Four Sub-helices

Prof. Henry Etzkowitz

It is fitting that the Triple Helix, with universities as a key innovation actor, along with industry and government, has been taken up in Israel, a knowledge-based society, rooted in Talmudic scholarship and scientific research. Biblical literature provided legitimation for the creation of the Jewish state while science helped create the economic base that made state formation feasible. In this case, the establishment of a government followed the creation of  (agricultural) industry and academia as the third element in a triple helix.  Nevertheless, a triple helix dynamic can be identified in the earliest phases of the formation of Israeli society, well before a formal state apparatus was constructed. Founding a state was a key objective of industry and academia but these intertwined helical strands did not accomplish the objective without assistance from other sources nor is innovation in contemporary Israel, along with many other societies, solely a triple helix phenomenon.

Several analysts have identified additional helices as relevant to innovation (Drori, Ch. 1). However, if everything is relevant than nothing is especially significant and a model that originally posited the transformation of the university from a secondary supporting institution of industrial society to a primary institution of a knowledge based society is vitiated. A second academic revolution expanded academic tasks from education and research to include entrepreneurship as a third mission. An entrepreneurial university, interacting closely with industry and government, is the core of a Triple Helix. By engaging in such relations an academic sector may, depending upon its previous experience, maintain or gain, relative independence. Triple Helix actors must also continually renew their commitment to entrepreneurship and innovation, lest they fall back into traditional roles and relationships.

What is the source of the Israeli Triple Helix? The contributors to this volume have identified seven helical strands as constitutive of the Israeli innovation system. I suggest that these strands may be grouped into primary and secondary categories: the primary strands are the classic triple helix (university-industry-government) while the secondary strands are supporting linkages, like the two diasporas (Israeli and foreign), or hybrid organizations like the military and non-governmental organizations (NGO’s). Thus, the resulting Israeli innovation system takes the form of a Trivium and a Quadrivium consisting of three primary and four secondary strands, in a variety of relationships with each other in different historical periods. The Innovation Trivium and Quadrivium are the constellation of core and supporting actors that constitute a knowledge-based innovation system. [1]

2.1 Triple Helix Origins

The triple helix innovation model originated in the analysis of MIT’s role in the renewal of New England, a region suffering industrial decline from the early 20th century (Etzkowitz, 2002).  MIT was founded in the mid 19th century, with industry and government support to raise the technological level of the regions’ industries but by the time it had developed research capabilities many of those industries had already left the region, to move closer to sources of raw materials, lines of distribution and less expensive labor. It was in this context, during the 1920’s, that the governors of New England called together the leadership of the region in a Council to address the region’s economic decline. Given a unique feature of the region, its extensive network of academic institutions, it is not surprising that the governors included the academic leadership of the region in their call.

However, their inclusion of academia had an unexpected consequence, transforming the usual public-private partnership model into a unique configuration- a proto-triple helix with a proclivity to originality. Triads are more flexible than dyads that typically take a strong common direction or devolve into opposition and stasis (Simmel, 1950).  Industry-government groups typically repeat timeworn strategies to attract industries from other regions in a zero sum game or attempt to revive local declining industries that may be beyond resuscitation. The inclusion of academia along with industry and government introduced an element of novelty into the government-industry dyad.  A moment of collective creativity occurred, during the discussions of the New England Council, inspired by the leadership of MIT’s President Karl Compton.  A triple helix dynamic, with the university as a key actor in an innovation strategy, was instituted that was highly unusual at the time.

The Council made an analysis of the strengths and weakness of the New England region and invented the venture capital firm to fill a gap in its innovation system, expanding a previously sporadic and uneven process of firm-formation from academic research into a powerful stream of start-ups and growth firms. A coalition of industry, government and university leaders invented a new model of knowledge-based economic and social development, building upon the superior academic resources of the region. This was not an isolated development but built upon previous financial and organizational innovations in the whaling industry and in academia.  In New England, industry and government, inspired by an academic entrepreneur and visionary, William Barton Rogers, earlier came together in the mid 19th century to found MIT, the first entrepreneurial university, thereby establishing the preconditions for a triple helix dynamic in that region.

2.2 From a Double to a Triple Helix

In a remote province of the Ottoman Empire in the early 20th century, Jewish agricultural settlements and an agricultural research institute created a triple helix dynamic that assisted the formation of the State of Israel. An industry-academia double helix provided the knowledge-based foundation for the Israeli triple helix. It preceded the founding of the state of Israel and indeed supplied many of the building blocks from which it was constructed. In a possibly unique configuration, state formation built upon scientific research and an agricultural industrial base. Before the Technion, the Weizmann Institute and the Hebrew University, there was the Jewish Agricultural Experiment Station in Atlit, founded in 1909 by agronomist Aaron Aaronsohn, with the support of Julius Rosenwald, an American-Jewish philanthropist (Florence, 2007).

Hints in the Bible of agricultural surplus, a land flowing with “milk and honey,” were investigated in an early 20th century context of desertification in Palestine.  The station’s researchers hypothesized that a seeming desert had a greater carrying capacity than was expected and thus could support a much larger population. Aronsohn and his colleagues’ advances in  “arid zone agriculture” opened the way to the transformation of a network of isolated agricultural settlements into a modern urban society.  The Atlit research program, conducted in collaboration with the US Department of Agriculture, was then introduced to California.

However, in California, arid zone methods were soon made superfluous by hydraulic transfer projects, from north to south, of enormous water resources. Arid agricultural methods remained relevant in the Israeli context of scarce water resources. Israel’s first high tech industry was based upon the development of drip irrigation techniques in the late 1950’s that preceded the IT wave by decades. Labor saving methods of agricultural production were also driven by ideological concerns of not wanting to be dependent upon hired Arab labor.  Science-based technology was thus at the heart of a developing Israeli society as well as a key link to a Diaspora that supplied infusions of support from abroad.

The Atlit agricultural research institute transformed itself into an intelligence network on behalf of the British during the First World War, betting that assisting the exit of Palestine from the Ottoman Empire could provide a pathway for the creation of a Jewish state (Florence, 2007). The Atlit network was uncovered, and some of its members perished, but it had already provided significant information on invasion routes that assisted the British takeover of Palestine. Its leader, Aaron Aaronsohn, died in a plane crash over the English channel in 1919 while bringing maps to the post-war Paris peace conference. The Institute itself did not survive its repurposing but its mission was taken up by other agricultural research units.

A linkage between helices and the translation of social capital from one sphere to another was another element of the state building project. The Balfour Declaration, issued by the British government in 1917, favored a “national home” for the Jewish people in Palestine, without prejudicing the rights of other peoples, and was the first such statement by a major power. Although the Declaration was part of a geopolitical balancing act to gain support for the British war effort, and may have occurred for that reason alone, British-Jewish scientist Chaim Weizmann’s accomplishments gave it a boost (Weizmann, 1949).

Weizmann’s invention of a bacterial method of producing the feedstock for explosives assisted the British war effort. Weizmann, a professor at Manchester University was able to transmute this discovery into support for a projected Jewish state through his relationship with Arthur Balfour, the Foreign Secretary, and an MP from Manchester. Weizmann dual roles as an eminent scientist and as a political leader in the Zionist movement coincided and he used an achievement in one arena to advance his goals in another. The Diaspora, of which he was a member in that era, aggregated international support for the state-building project.

Science also served to legitimate the new state of Israel. Albert Einstein was offered the presidency of the newly founded state of Israel. While the aura of his renown was one reason for the offer, that fame was primarily based on his scientific achievements. When Einstein turned down the position, the presidency was offered to another scientist, Chaim Weizmann, who accepted. The fact that the position was offered to two scientists in a row suggests that science was implicitly seen as legitimating the state, while also recognizing its role in the founding of Israel.

2.3 Innovation Trivium and Quadrivium

Identification of additional secondary contributors to innovation is a useful task but their relationship to the primary helices, and the roles that they play, should be specified. For example, the Israeli military may be viewed as a hybrid entity. In addition to the usual functions of a military, the Israel Defense Forces also serves as an educational institution for virtually the entire society, intermediating between secondary and university education and as an industrial development platform, spinning off aircraft and software industries. It has some of the characteristics of an independent helix but remains a part of the state, embodying hybrid elements that give it some of the characteristics of an independent institutional sphere.

It is a significant actor in Israeli society, having a significantly higher profile than the militaries in most societies. Therefore we locate it in the “Quadrivium” of support helices that comprise hybrid organizations or links with other societies. The military derived from the “Shomrim”, watches mounted by isolated settlements while nascent governmental institutions were a confluence between the networks of settlements and more general support structures such as the Jewish Agency, a mix of local and Diaspora efforts. A proto-state was constructed from these elements prior to independence.

The Israeli Diaspora played a key role, along with government, in founding Israel’s venture capital industry. After several unsuccessful attempts at developing a venture industry, government hit on the idea of combining public and private elements, providing government funds to encourage private partners to participate by reducing their risk. Key to the efforts success was the recruitment of members of the Israeli Diaspora, working in financial and venture capital firms in the US, to return to Israel and participate in the Yozma project and the funds that emanated from it. [2]

2.4 Israel: A Triple Helix Society

This volume, analyzing Israel’s innovation actors, makes a significant contribution to triple helix theory and practice by providing evidence of their relative salience. Identifying multiple contributors to the innovation project is a useful exercise but not all helices are equal. A key contribution of the triple helix model is that it identified the increased significance of the university in a knowledge based society and the fundamental importance of creative triple helix interactions and relationships to societies that wish to increase their innovation potential (Durrani et al., 2012).

We can also identify the qualities of an emergent social structure that encourages innovation. Multiple sources of initiative, organizational venues that combine different perspectives and experiences and persons with dual roles across the helices are more likely to produce innovation and hybridization than isolated rigid structures, even with great resources behind them. The Israeli experience takes the triple helix model a step beyond organizational innovation by demonstrating the significance of triple helix roles and relationships to the creation of an innovative society.


Durrani, Tariq and Jann Hidajat Tjakraatmadja and Wawan Dhewanto Eds. 2012. 10th Triple Helix Conference 2012 Procedia – Social and Behavioral Sciences, Volume 52.

Etzkowitz, Henry. 2002. MIT and the Rise of Entrepreneurial Science. London: Routledge.

Etzkowitz, Henry, Marina Ranga and James Dzisah, 2012. “Wither the University? The Novum Trivium and the transition from industrial to knowledge society.” Social Science Information June 2012 51: 143-164.

Florence, Ronald. 2007. Lawrence and Aaronsohn: 
T. E. Lawrence, Aaron Aaronsohn, and the Seeds of the Arab-Israeli Conflict 
New York: Viking.

Simmel, Georg. 1950. Conflict and the Web of Group Affiliations. Glencoe: Free Press.

Weizmann, Chaim. 1949. Trial and Error: the autobiography of Chaim Weizmann. New York: Harper & Bros.

[1] The classic Trivium and Quadrivium were the core and supporting academic disciplines that constituted the knowledge-base of medieval Europe. See Etzkowitz, Ranga and Dzisah, 2012.

[2] Author discussion with Yozma founders at the 3rd Triple Helix Conference in Rio de Janeiro, 1999. FINEPE, the Brazil Development Agency invited Yozma representatives to the conference and held side meetings to arrange transfer of the Yozma model to Brazil. FINEPE added an additional element, “FINEPE University,” a series of workshops held around the country to train entrepreneurs in “pitching” to venture firms.


Other articles by same author were published in this Open Access Online Scientific Journal, include the following:


 Professor Henry Etzkowitz 8/1/2012



Hélice  Triple Helix X, 2012, Bandung,Indonesia . . .

by Professor Henry Etzkowitz, President of the Triple Helix Association,  Senior Researcher, H-STAR Institute, Stanford University, Visiting Professor, Birkbeck, London University and Edinburgh University Business School

Professor Henry Etzkowitz paper is based on his Keynote Address to the FemTalent Conference, Barcelona, Spain 2011


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