Posts Tagged ‘Hebrew University of Jerusalem’

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival.

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @

3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal

See References to articles at the end of this article on

  • ION CHANNEL and Cardiovascular Diseases

  • Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux
  • Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

  • Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
  • single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

  • the whole coding region of KCN5A gene (Kv1.5 channel).
The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used
  • to identify individuals at relatively low-risk for cardiovascular disease
  • an independent protective role of the
    • rs5215_GG against developing CAD and
    • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//
This article is published with open access at


Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

  • a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

  • activity of specific ion-channels, and
  • key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

  • ion-channels expressed in the coronary vasculature and the possible
  • correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

  • analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

  • polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

  • IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

  • influencing the susceptibility for microvascular dysfunction and (IHD,
  • independent of the presence of classic cardiovascular risk factors: atherosclerosis   


Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease


Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

  • endothelial dysfunction and
  • atherosclerosis [11, 53, 6567].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

  • atherosclerotic disease and
  • myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

  • endothelial,
  • nervous,
  • neurohumoral,
  • myogenic, and
  • metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

  • ATP-sensitive potassium (KATP) channels,
  • voltage-gated potassium (Kv) channels,
  • voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

  • coronary smooth muscle and endothelial cells, which
  • modulates the degree of contractile tone in vascular muscle and
  • the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

  • the endothelium and vascular smooth muscle cells of coronary arterioles
  • to the perpetually fluctuating demands of the myocardium for blood flow
    [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

  • the clinical relevance and 
  • causes of microvascular dysfunction in IHD

By altering the overall

  • regulation of blood flow in the coronary system,
  • microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

  • contribute to microvascular dysfunction [29, 60]. But
  • ion channels play a critical role in microvascular endothelial
  • and smooth muscle function.

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

  • microvascular dysfunction and 
  • myocardial ischemia

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

  • IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.


Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

  • In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
  • In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
  • The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

  • hypertension = 17 %,
  • T2DM = 34.1 %,
  • dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

  • rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
  • and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

  • inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
  • rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

  • confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

  • to identify individuals at relatively low-risk for cardiovascular disease,
  • regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

  • endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

  • NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via
  • activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

  • an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
  • association of this SNP with CAD in Asian populations [74]. In addition,
  • this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

  • variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].
Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

  • high-grade coronary stenosis or occlusion [19].
As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells
  • potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].
Several types of K+ channels are expressed in the coronary tree.
  • The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
    [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
  • Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.
K-ATP channel activation results in an outward flux of potassium and

  • consequent hyperpolarization, resulting in
  • voltage-gated calcium channel closure,
  • decreased Ca2+ influx, and ultimately
  • vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

  • an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

  • structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

  • concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

  • may have originated in a common ancestor, further indicating a
  • possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
  • The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
    the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening
  • are both impaired in diabetes mellitus [39].
It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,
  • independent of the presence of either diabetes mellitus or dyslipidemia.
These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,
  • regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

  • future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

  • pergolide [25],
  • 4-amino-pyridine [32], and
  • correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

  • cardiac metabolic demand and
  • coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

  • the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

  • our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

  • catalyzes the hydrolysis of ATP coupled with the
  • translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

  • genetic variants of SERCA and the
  • prevalence of microvascular dysfunction or IHD.


This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients
  • with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.
Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

  • the precise manners by which specific genetic polymorphisms affect ion channel function and expression
have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.
2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.
3. There is a lack of ethnic diversity of our cohort.
4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.
5. There is a lack of functional characterization of the described genetic polymorphisms.
6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

  • sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
  • in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

  • typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).


In this prospective, observational, single-center study – 242 consecutive patients admitted to our department were enrolled with

  • the indication to undergo coronary angiography .

All patients matched inclusion criteria

  1. age [18];
  2. suspected or documented diagnosis of acute coronary syndrome or stable angina
  3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
  4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

  1. previous allergic reaction to iodine contrast,
  2. renal failure,
  3. simultaneous genetic disease,
  4. cardiogenic shock,
  5. non- ischemic cardiomyopathy

All patients signed an informed consent document  –

prior to participation in the study, which included

  • acknowledgement of the testing procedures to be performed
    (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

  1. both endothelium-dependent microvascular function
    [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
  2. nonendothelium-dependent microvascular function
    [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

  • the 242 patients were divided into three groups (see also Fig. 1).
  1. Group 1: 155 patients with anatomic coronary alteration
    (comprising patients with acute coronary syndrome and chronic stable angina).

    • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
    • after IC infusion of acetylcholine and adenosine].
  2. Group 2: 46 patients with functional coronary alteration
    [normal coronary arteries as assessed by angiography, and

    • as assessed by angiography and with normal functional tests
      (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
  3. Group 3: 41 patients with anatomically and functionally normal coronary arteries

BRC 2013 fedele genetic polymorphisms of ion channels.pdf_page_2

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (, Entrez SNP (, and
Ensembl ( were used to select variants of genes involved in signaling pathways

  • related to ion channels and/or reported to be associated with
  • microvascular dysfunction and/or myocardial ischemia and/or
  • diseases correlated to IHD, such as diabetes mellitus.
Polymorphisms for the following genes were analyzed:
  1. NOS3 (endothelial nitric oxide synthase, eNOS),
  2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
  3. SCN5A (voltage-dependent Na+ channel,
  4. Nav1.5),
  5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
  6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
  7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

  • exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
  • the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
  • four previously described variants [26, 47, 71, 72].
We also examined
  • the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

BRC 2013 fedele genetic polymorphisms of ion channels_page_004
BRC 2013 fedele genetic polymorphisms of ion channels_page_005

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit
(Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

  • the prevalence of SNPs in genes encoding  several effectors (including ion channels)
  • involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

  • a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
    undergoing coronary angiography,

we estimated that

  • a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
    • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

  • analysis of multiple inheritance models for SNPs were also tested
    (co-dominant, dominant, recessive, over-dominant and log-additive)
  • using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
  • designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

  • with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

  • the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
  • using a free web-based application  ( [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

  • were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

  • one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

  • the independent impact of genetic polymorphisms on
    • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

  • genetic polymorphisms on coronary artery disease
    and microvascular dysfunction

while adjusting for other confounding variables.  The following parameters were entered into the model:

  • age,
  • male gender,
  • type 2 diabetes mellitus (T2DM),
  • systemic arterial hypertension,
  • dyslipidemia,
  • smoking status, and
  • family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

  • into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

  • fasting levels of glucose of >126 mg/dL in two separate measurements or
  • if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

  • systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
  • in two separate measurements or
  • if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

  • serum cholesterol levels were>220 mg/dL or
  • if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.


Sixty-two polymorphisms distributed among six genes coding for
  • nitric oxide synthase,
  • the SERCA pump, and
  • ion channels
    • were screened for sequence variations using PCR amplification and
    • direct DNA sequencing analysis

in the population of

  • 155 patients with CAD (group 1),
  • 46 patients with microvascular dysfunction (group 2), and
  • 41 patients with normal coronary arteries and
    • normal endothelium dependent and endothelium-independent vasodilation (group 3).
In Group 3, the genotype distribution of

  • SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
In Group 1 (CAD), the polymorphism

  • rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
The genotypic distribution of groups in terms of polymorphisms for
  • eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5
were noticed. However, significant differences (p.05) for the SNPs
  • rs5215_GG, and
  • rs5219_AA of Kir6.2/KCNJ11 were observed,
as shown in Table 2. 

Table 3 displays 
significant differences between normal subjects (group 3) and
  • patients with either CAD (group 1) or microvascular dysfunction (group 2).

BRC 2013 fedele genetic polymorphisms of ion channels_page_006

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

  • significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
  • a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

  • in microvascular dysfunction for rs5219 AA. In contrast,
  • rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

BRC 2013 fedele genetic polymorphisms of ion channels_page_007


BasicResCardiol(2013)108:387   http//

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


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Basic Res Cardiol (2013) 108:387

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Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

Professor David Lichtstein Elected Dean of Hebrew University’s Faculty of Medicine

December 2, 2013

Jerusalem — Professor David Lichtstein has been elected dean of the Faculty of Medicine at The Hebrew University of Jerusalem. Professor Lichtstein is the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He replaces Professor Eran Leitersdorf, who recently completed his four-year term as dean.

According to Professor Lichtstein, “The Hebrew University’s Faculty of Medicine is devoted to creating innovative teaching, research and patient care programs that will meet the demands of 21st century health care. As global health care moves towaProfessor David Lichtsteinrd prevention, wellness and cost effectiveness, we are adapting how we train the next generation of physicians, nurses, pharmacists and biomedical researchers. Through fruitful collaborations between preclinical and clinical faculty, we are also translating basic biomedical insights into clinical treatments. Thus, the Faculty of Medicine is well-positioned to maintain its leading role in the scientific community of Israel and the world.”

Professor Lichtstein was born in Lodz, Poland, and immigrated to Israel with his family in 1957. As a student at The Hebrew University, he completed a Bachelor’s degree in Physiology and Zoology in 1970, followed by a Master’s degree in Physiology in 1972 and a Ph.D. in Physiology in 1977. He joined the Department of Physiology of The Hebrew University-Hadassah Medical School in 1980 as a lecturer, and received full professorship in 1994. Prof. Lichtstein has held many roles at The Hebrew University and its Faculty of Medicine, including Chairman of the Neurobiology Teaching Division, Chairman of the Department of Physiology, Chairman of the Institute for Medical Sciences and, until recently, Chairman of the Faculty of Medicine. From 2007 to 2011, Professor Lichtstein was the Jacob Gitlin Chair in Physiology at The Hebrew University. In 2011 he was named the Walter & Greta Stiel Chair in Heart Studies at The Hebrew University. He also served as the President of the Israel Society for Physiology and Pharmacology from 1996 to 1999.

From 1977-1979 Professor Lichtstein was a Postdoctoral Fellow at the Roche Institute of Molecular Biology in New Jersey. He was a visiting scientist at the National Institute of Child Health and Human Development (1985-1986) and the Eye Institute (1997-1998) at the National Institutes of Health in Maryland, and a visiting professor at the Toledo School of Medicine in Ohio (2007).

Professor. Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that were known to be present in plants and amphibians are actually normal constituents of the human body and have crucial roles, such as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.


Field of Study

Regulation of ion transport across the plasma membrane:
The primary focus of the research in my laboratory is the regulation of ion transport across the plasma membrane of eukaryotic cells. In particular, we study the main transport system for sodium and potassium, the sodium-potassium-ATPase, and its regulation by cardiac steroids.
Specific areas of interest:
Identification of endogenous cardiac steroids in mammalian tissue; The biological consequences of the interaction of cardiac steroids with the sodium-potassium-ATPase; Biosynthesis of the cardiac steroids in the adrenal gland; Effects of endogenous sodium-potassium-ATPase inhibitors on cell differentiation; Determination of the levels of endogenous sodium-potassium-ATPase inhibitors in pathological states, including hypertension, preeclampsia; malignancies (cancer) and manic depressive illnesses; Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders; Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function; Involvement of intestinal signals in the regulation of phosphate homeostasis; Volume regulation and its involvement in the mitogenic response.
Cardiac Steroids and the Na+, K+-ATPase and Cardiac Steroids
Cardiac steroids, such as ouabain, digoxin and bufalin are hormones synthesized by and released from the adrenal gland and the hypothalamus. These compounds, the structure of which resembles that of plant and amphibian and butterfly steroids, interact only with the plasma membrane Na+, K+-ATPase (Figure 1). This interaction elicits numerous specific biological responses affecting the function of cells and organs.
Topics Currently under investigation include
Cardiac Steroids
  • Ouabain
  • Bufalin
  • Dogoxin
Involvement of the sodium-potassium–ATPase/cardiac steroids system in depressive disorders
Depressive disorders, including major depression, dysthymia and bipolar disorder, are a serious and devastating group of diseases that have a major impact on the patients’ quality of life, and pose a significant concern for public health. The etiology of depressive disorders remains unclear. The Monoaminergic Hypothesis, suggesting that alterations in monoamine metabolism in the brain are responsible for the etiology of depressive disorders, is now recognized as insufficient to explain by itself the complex etiology of these diseases. Data from our and other laboratories has provided initial evidence that endogenous cardiac steroids and their only established receptor, the Na+, K+-ATPase, are involved in the mechanism underlining depressive disorders, and BD in particular. Our study (Biol. Psychiatry. 60:491-499, 2006) has proven that Na+, K+-ATPase and DLC are involved in depressive disorders particularly in manic-depression. We have also shown that specific genetic alterations in the Na+, K+-ATPase α isoforms are associated with bipolar disorders (Biol. Psychiatry, 65:985-991, 2009). Our recent study in this project (Eur. Neuropsychopharmacol. 22:72-729, 2012) showed that drugs affecting the Na+, K+-ATPase/cardiac steroids system are beneficial for the treatment of depression. Hence our work is in accordance to the proposition that mal functioning of the Na+, K+-ATPase/cardiac steroids system may be involved in manifestation of depressive disorders and identify new compounds as potential drug for the treatment of these maladies.
Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function
The classical and best documented effect of cardiac steroids, as their name implies, is to increase the force of contraction of heart muscle. Indeed, cardiac steroids were widely used in Western and Eastern clinical practices for the treatment of heart failure and atrial fibrillation. Despite extensive research, the mechanism underlying cardiac steroids actions have not been fully elucidated. The dogmatic explanation for cardiac steroids-induced increase in heart contractility is that the inhibition of Na+, K+-ATPase by the steroids causes an increase in intracellular Na+ which, in turn, attenuates the Na+/Ca++ exchange, resulting in an increased intracellular Ca++ concentration, and hence greater contractility. However, recent observations led to the hypothesis that the ability of cardiac steroids to modulate a number of intracellular signaling processes may be responsible for both short- and long-term changes in CS action on cardiac function. We are addressing this hypothesis using the zebrafish model and our ability to quantify heart function in-vivo. Heart contractility measurements were performed using a series of software tools for the analysis of high-speed video microscopic images, allowing the determination of ventricular heart diameter and perimeter during both diastole and systole. The ejection fraction (EF) and fractional area changes (FAC) were calculated from these measurements, providing two independent parameters of heart contractility (see attached movie bellow). We are currently testing the effect of cardiac steroids in the presence and absence of intracellular signaling pathways (MAP, AKT, IP3R) inhibitors. Reduction in the steroids ability to increase the force of contraction will serve as the first evidence, in-vivo, for the participation of the signaling processes in the molecular mechanisms responsible for the action of cardiac steroids on heart muscle.
Laboratory Techniques
We employ a broad range of preparations and techniques. These include isolated organs (arterial rings, smooth and cardiac muscle strips) and isolated nerve endings, as well as primary and established tissue-cultured cells. Our studies involve the application of biochemical and immunological techniques (transport and enzymatic activity measurements, RIA, ELISA), molecular biological techniques (e.g., Western and Northern blotting, and PCR), protein purification (HPLC), cellular techniques muscle contractility, cell proliferation and differentiation’ in-vivo measurements of heart contractility and blood flow in Zebrafish and behavior measurements in rodents.


B.Sc. in Physiology and Zoology, The Hebrew University, Jerusalem, Israel
1970-1972 M.Sc. in Physiology, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
Ph.D., Department of Physiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. (Thesis: “Increased Production of Gamma Aminobutyryl choline in Cerebral Cortex Caused by Afferent Electrical Stimulation” (Thesis Advisors: Prof. J. Dobkin and Prof. J. Magnes).
Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.
Positions held

Teaching and Research Assistant, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1972-1974 Assistant Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1975-1977 Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.
Lecturer, (REVSON fellowship) Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1981 (summer)
Visiting Scientist, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, USA
1983-1987 Senior Lecturer, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
Visiting Scientist, Laboratory of Theoretical and Physical Biology, NICHD, National Institutes of Health, Bethesda, Maryland, USA
1988-1994 Associate Professor, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1994-present Professor of Physiology, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1997-1998 Visiting Scientist, Laboratory of Mechanisms of Ocular Diseases, NEI, National Institutes of Health, Bethesda, Maryland, USA
2007 (summer)
Visiting Professor, Department of Physiology, Pharmacology, Metabolism and cardiovascular Sciences, Medical Center University of Toledo, Toledo, Ohio, USA
2007-2011 Jacob Gitlin Chair in Physiology, The Hebrew University, Jerusalem, Israel
2011-present ​Walter & Greta Stiel Chair in Heart Studies, The Hebrew University, Jerusalem
Professional Membership
1979-present International Society of Neurochemistry
1979-present Israel Society for Physiological and Pharmacological
1980-present Society of Neurosciences (Europe)
1986-present The American Society of Hypertension
1992-present Israeli Society for Neurosciences
1999-present The American Physiological Society
Editorial Tasks
Serving as a Reviewer for the scientific journals:
American Journal of Hypertension Journal of Neural Transmission
American Journal of Physiology Journal of Neurochemistry
Apoptosis Journal of Pharmacology and Experimental Therapeutics
Biochemical and Biophysical Research Communications Life Sciences
Basic Journal of Physiology and Pharmacology NANO
Brain Research Neurochemistry International
Bioconjugate Chemistry Neuroscience
Cell Calcium Neurotoxicity Research
Clinical Science Pathophysiology
Endocrinology Physiology and Behavior
European Neuropsychopharmacology PNAS
General and Comparative Endocrinology Psychiatry Research
Hypertension Translational Research
Journal of Cell Sciences
University and Other Activities
1982-1985 Chairman of the Neurobiology Teaching Division, The Hebrew University, Jerusalem
1988-1994 Elected representative of the Senior Lecturers and Associate Professors for the University Senate
1989-1997 Member of the admission committee of the Medical School, The Hebrew University, Jerusalem
1990-1996 Member of the Committee for cellular biology of the graduate studies, The Hebrew University, Jerusalem
1992-1996 Member of the Teaching Committee, Faculty of Medicine, The Hebrew University, Jerusalem
Chairman, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem
1994-1997 Member of the Committee for graduate studies, The Hebrew University, Jerusalem
Member of the Management Committee of The Institute for Medical Sciences, Faculty of Medicine, The Hebrew University, Jerusalem
President of the Israel Society for Physiology and Pharmacology
1998- 2002 Chairman, Institute of Medical Sciences, The Hebrew University, Hadassah Medical School, Jerusalem
1999-2002 Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2007–Present Elected representative of the Professors for the executive University Senate
2008-2012 Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2008-2012 Chairman, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem
2009 – Present Elected member of the Senate to the Executive Committee of the Hebrew University

PUBLICATIONS 2006 – 2012

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Dvela, M., Rosen, H., Ben-Ami, H. C., Lichtstein, D.
American journal of physiology. Cell physiology, 302(2), C442-52, 2012
Goldstein, I., Lax, E., Gispan-Herman, I., Ovadia, H., Rosen, H., Yadid, G., Lichtstein, D.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 22(1), 72-9, 2012
Nesher, M., Shpolansky, U., Viola, N., Dvela, M., Buzaglo, N., Cohen Ben-Ami, H., Rosen, H., Lichtstein, D.
British journal of pharmacology, 160(2), 346-54, 2010
Guttmann-Rubinstein, L., Lichtstein, D., Ilani, A., Gal-Moscovici, A., Scherzer, P., Rubinger, D.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 42(4), 230-6, 2010
Jaiswal, M. K., Dvela, M., Lichtstein, D., Mallick, B. N.
Journal of sleep research, 19(1 Pt 2), 183-91, 2010
Nesher, M., Dvela, M., Igbokwe, V. U., Rosen, H., Lichtstein, D.
American journal of physiology. Heart and circulatory physiology, 297(6), H2026-34, 2009
Goldstein, I., Lerer, E., Laiba, E., Mallet, J., Mujaheed, M., Laurent, C., Rosen, H., Ebstein, R. P., Lichtstein, D.
Biological psychiatry, 65(11), 985-91, 2009
Nesher, M., Vachutinsky, Y., Fridkin, G., Schwarz, Y., Sasson, K., Fridkin, M., Shechter, Y., Lichtstein, D.
Bioconjugate chemistry, 19(1), 342-8, 2008
Dvela, M., Rosen, H., Feldmann, T., Nesher, M., Lichtstein, D.
Pathophysiology : the official journal of the International Society for Pathophysiology / ISP, 14(3-4), 159-66, 2007
Feldmann, T., Glukmann, V., Medvenev, E., Shpolansky, U., Galili, D., Lichtstein, D., Rosen, H.
American journal of physiology. Cell physiology, 293(3), C885-96, 2007
Chirinos, J. A., Corrales-Medina, V. F., Garcia, S., Lichtstein, D. M., Bisno, A. L., Chakko, S.
Clinical rheumatology, 26(4), 590-5, 2007
Lichtstein, D. M., Arteaga, R. B.
The American journal of the medical sciences, 332(2), 103-5, 2006
Morla, D., Alazemi, S., Lichtstein, D.
Journal of general internal medicine, 21(7), C11-3, 2006
Chirinos, J. A., Corrales, V. F., Lichtstein, D. M.
Clinical rheumatology, 25(1), 111-2, 2006
Deutsch, J., Jang, H. G., Mansur, N., Ilovich, O., Shpolansky, U., Galili, D., Feldman, T., Rosen, H., Lichtstein, D.
Journal of medicinal chemistry, 49(2), 600-6, 2006
Goldstein, I., Levy, T., Galili, D., Ovadia, H., Yirmiya, R., Rosen, H., Lichtstein, D.
Biological psychiatry, 60(5), 491-9, 2006
Chirinos, J. A., Garcia, J., Alcaide, M. L., Toledo, G., Baracco, G. J., Lichtstein, D. M.
American journal of cardiovascular drugs : drugs, devices, and other interventions, 6(1), 9-14, 2006
Rosen, H., Glukmann, V., Feldmann, T., Fridman, E., Lichtstein, D.
Cellular and molecular biology (Noisy-le-Grand, France), 52(8), 78-86, 2006



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TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

Reporter: Aviva Lev-Ari, PhD, RN

A step toward development of drugs for diseases such as Alzheimer’s, Parkinson’s and Huntington’s

December 3, 2013


Jerusalem – A successful joint collaboration between researchers at The Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.
Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s andHuntington’s diseases share two key features: they stem from toxic proteinaggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at The Hebrew University of Jerusalem‘s Faculty of Medicine.
Dr. Cohen’s first breakthrough in this area occurred when he discovered, working with Dr. Ehud Cohenworms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.
Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Professor Alexander Levitzki from the Department of Biological Chemistry at The Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.
Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.
The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.
Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of The Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with The Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.
Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.


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Four Startups After One Year: Biodesign entrepreneurship program @ Hebrew University-Hadassah Medical Center

Reporter: Aviva Lev-Ari, PhD, RN


Israel’s First Biodesign Program Produces Four Startups After One Year

August 6, 2013

Students in Hebrew University-Hadassah Medical Center program develop “science fiction gadgets”

Biodesign entrepreneurship program is Israel’s first medical innovation accelerator

Jerusalem — As health costs spiraled over the last decade, the need for more cost-effective health care systems has become increasingly urgent. Medical innovation plays a vital role in making medicine both efficient and affordable — not to mention improving the quality of patient care and ensuring positive outcomes. However, the process of creating new medical devices requires an in-depth understanding of multiple disciplines including medicine, engineering, and finance that few could master alone. As a result, most aspiring medical innovators face disappointment as the vast majority of ideas fail before reaching the market.

According to Dr. Yaakov Nahmias, the director of The Hebrew University of Jerusalem’s Center for Bioengineering, “When it comes to bringing an idea to market, there is a huge disparity between Hi-Tech, where a few programmers can succeed, and Bio-Tech, where clinicians, engineers, and business experts must all work together to bring a product to the market.”

To solve this problem, Nahmias partnered with Professor Chaim Lotan, the director of Hadassah Medical Center’s Heart Institute and an expert in clinical innovation. According to Prof. Lotan, “We knew that Stanford University’s Biodesign program was the most successful medical innovation program to date, and considering the outstanding students at The Hebrew University and Hadassah we were certain we could give them a run for their money.”

Developing “science fiction gadgets” GuideIN Tube, MetaboShield, SAGIV, and DCDI at the Biodesign program of the Hebrew University of Jerusalem and Hadassah Medical Center

The two partnered with Professor Dan Galai, the former Dean of the Business School at The Hebrew University, and with the help of Dr. Todd Brighton, a Biodesign program director at Stanford University, established The Hebrew University’s Biodesign Medical Innovation Program, the first academic medical innovation accelerator in Israel.

View videos on the innovations

Biodesign is a multi-disciplinary, team-based approach to medical innovation. The program takes outstanding medical fellows, bioengineering and business graduate students, and tutors them in the science and practice of bringing a medical innovation to the market. The teams receive a list of clinical problems, collected from Israeli and American hospitals, and critically evaluate their commercial potential. Once they identify a clinical need with commercial potential, they find an engineering solution that can be protected by a patent application.

Developing “science fiction gadgets” GuideIN Tube, MetaboShield, SAGIV, and DCDI at the Biodesign program of The Hebrew University of Jerusalem and Hadassah Medical Center

The students are mentored by some of Israel’s best and brightest academic and industrial experts, who bring their experience in scientific discovery, clinical applications, and business development.

According to the Hebrew University’s Nahmias, “This isn’t a pure academic exercise. We have students and clinicians who are eager to bring innovation to the market. The program generated quite of lot of excitement with the business and academic environment. It is exactly this drive that makes Israel a start-up nation.”

One year after starting with 20 students and medical fellows, the program has already produced four projects that passed through the proof-of-concept stage, are protected by provisional patent applications, and are showing excellent market potential.

One of the projects, called SAGIV, is a semi-automatic handheld device for rapid and safe IV insertion, using infrared sights and electrical sensing. SAGIV targets a $900 million market with elements already tested on difficult IV insertion cases at the Hadassah Medical Center.

Another project, called GuideIN Tube, is a robotic intubation device which automatically navigates towards the lungs, targeting a $3 billion market.

“The projects really look like science fiction gadgets,” said Dr. Nahmias. “Even if just a few Biodesign companies succeed, they can completely transform the Israeli medical device sector.”

“We have incredibly driven students at The Hebrew University, and Biodesign gives them critical tools they need to succeed,” added Prof. Lotan. Both directors noted that students accomplished in one academic year what many start-up companies take 2 to 3 years to complete, advancing to the point of having proof-of-principle prototypes.

Yehuda Zisapel, president of RAD-Bynet Group, one of the largest investment groups in Israel, said: “Biodesign is a truly innovative approach to generate and accelerate new ideas. The cooperative efforts of physicians, scientists, engineers and business development people allows for a multidimensional approach which encourages the creation and development of new ideas. I was really impressed by the team work and the spirit created by the program, and also by the impressive achievements of the projects.”

Hadassah Medical Center’s Prof. Lotan attributes the program’s success to several additional factors: “We are based in Jerusalem, where biotechnology ventures are buoyed by sustained government support. We are backed by the strong track record of Yissum and Hadasit, the technology transfer companies of The Hebrew University and Hadassah Medical Center. And we have an important relationship with Stanford’s Biodesign program, which offers knowledge, experience and course materials. The Biodesign program has increased Stanford University biomed startup success rates by 4 to 5 folds over the last decade. We envision a similar revolution in Jerusalem, where 50% of the medical research in Israel is already taking place.”

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Hebrew University’s Professor Haim Sompolinksy and Columbia University Prof. Larry Abbott Win First New $100,000 Mathematical Neuroscience Prize

Curator: Aviva Lev-Ari, PhD, RN

Professor Haim Sompolinsky of The Hebrew University of Jerusalem has been awarded the 1st Annual Mathematical Neuroscience Prize by Israel Brain Technologies (IBT), a non-profit organization committed to advancing Israel’s neurotechnology industry and establishing the country as a global hub of brain technology innovation.

Professor Sompolinsky, who pioneered the field of computational neuroscience, is the William N. Skirball Professor of Neuroscience at The Hebrew University’s Edmond and Lily Safra Center for Brain Sciences (ELSC).

ELSC is one of the most ambitious neuroscience centers in the world, providing a multi-disciplinary environment where theorists, computer scientists, cognitive psychologists and biologists collaborate to revolutionize brain science.

IBT’s $100,000 Mathematical Neuroscience Prize, awarded at the 1st annual BrainTech Israel 2013 Conference in Tel Aviv, honors researchers worldwide who have significantly advanced our understanding of the neural mechanisms of perception, behavior and thought through the application of mathematical analysis and theoretical modeling.

Professor Sompolinsky specializes in building mathematical models that describe the collective behavior and the informational processing in neural circuits in the brain. The principles that emerge from Professor Sompolinsky’s work contribute to our understanding of the system-wide failures that take place in brain diseases, from epilepsy to psychiatric disorders.

According to Sompolinsky, “Computational neuroscience is a vibrant and ambitious field that uses mathematical theories and models to cope with the most daunting challenges — from answering fundamental questions about the brain and its relation to the mind to answering questions posed by the quest to heal the brain’s debilitating diseases.”

Also winning a $100,000 Mathematical Neuroscience Prize was Professor Larry Abbott, Bloor Professor of Theoretical Neuroscience at Columbia University, who developed models ranging from the level of neurons and synapses to large-scale networks, and showed how plasticity mechanisms that change the properties of neural circuits can maintain their proper operation and allow them to change during the learning process.

Nobel Laureate Professor Bert Sakmann, inaugural Scientific Director of the Max Planck Florida Institute, presented the awards at the conference. “This prize honors the founders of mathematical neuroscience, and is a milestone because it gives due recognition to this field,” said Sakmann.

“This prize recognizes leaders in the important field of mathematical neuroscience, whose advances support our ultimate quest to find new solutions for the betterment of all humankind,” said Miri Polachek, Executive Director of IBT.

In the future, the Prize Selection Committee will consist of previous prize winners, including Sompolinsky and Abbott.

IBT’s BrainTech Israel 2013 Conference is exploring developments in brain technology and their commercialization through a “meeting of the minds” among government leaders, entrepreneurs, researchers, leading companies and investors from Israel and around the world.

Inspired by the vision of Israeli President Shimon Peres and building on Israel’s position as a global technology powerhouse, IBT aims to make Israel both the “Startup Nation” and the “Brain Nation.”  IBT is also focused on increasing collaboration between the Israeli neurotechnology ecosystem and its counterparts around the world. IBT is led by a team of technology entrepreneurs and life science professionals and is advised by a panel of renowned academic, industry and public sector representatives including two Nobel Prize Laureates.


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Professor of Physics, Racah Institute of Physics
William N. Skirball Professor of Neuroscience
The Interdisciplinary Center for Neural Computation
The Edmond and Lily Safra Center for Brain Sciences
The Hebrew University
Jerusalem, 91904, Israel
(t) 972-2-658-4563; (f) 972-2-658-4440

Personal Information
Born:  Copenhagen, Denmark, 1949
Israeli citizen: 1951
Married with five children


Sompolinsky’s research goal is to uncover the fundamental principles of the organization, the dynamics and the function of the brain, viewing the brain through multiscale lenses, spanning the molecular, the cellular, and the circuit levels. To achieve this goal, Sompolinsky has developed new theoretical approaches to computational neuroscience based on the principles and methods of statistical physics, and physics of dynamical and stochastic systems. This new field, Neurophysics, builds in part on Sompolinsky’s earlier work on critical phenomena, random systems, spin glasses, and chaos. His research areas cover theoretical and computational investigations of cortical dynamics, sensory processing, motor control, neuronal population coding, long and short-term memory, and neural learning. The highlights of his research include theories and models of local cortical circuits, visual cortex, associative memory, statistical mechanics of learning, chaos and excitation-inhibition balance in neuronal networks, principles of neural population codes, statistical mechanics of compressed sensing and sparse coding in neuronal systems, and the Tempotron model of spike time based neural learning. He also studies the neuronal mechanisms of volition and the impact of physics and neuroscience on the foundations of human freedom and agency.



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Israeli, US Profs win 1st annual Mathematical Neuroscience Prize

$100,000 prizes awarded for outstanding work in human brain modeling at BrainTech Israel 2013 Conference in Tel Aviv.

From left, Nobel Laureate Prof. Bert Sakmann; Hebrew University of Jerusalem Prof. Haim Sompolinsky; Columbia University Prof. Larry Abbott; and Dr. Rafi Gidron, founder and chairman of Israel Brain Technologies, at BrainTech Israel 2013. Sompolinsky won IBT’s inaugural Mathematical Neuroscience Prize.From left, Nobel Laureate Prof. Bert Sakmann; Hebrew University of Jerusalem Prof. Haim Sompolinsky; Columbia University Prof. Larry Abbott; and Dr. Rafi Gidron, founder and chairman of Israel Brain Technologies, at BrainTech Israel 2013. Sompolinsky won IBT’s inaugural Mathematical Neuroscience Prize.

Hebrew University of Jerusalem Prof. Haim Sompolinsky and Columbia University Prof. Larry Abbott are the winners of the 1st Annual Mathematical Neuroscience Prize by Israel Brain Technologies (IBT). The two $100,000 prizes were awarded at the 1st annual BrainTech Israel 2013 Conference in Tel Aviv.

Prof. Haim Sompolinsky (photo: Hebrew University)

IBT’s Mathematical Neuroscience Prize honors researchers worldwide who have significantly advanced our understanding of the neural mechanisms of perception, behavior and thought through the application of mathematical analysis and theoretical modeling.

Prof. Sompolinsky is considered a pioneer in the field of computational neuroscience. He specializes in building mathematical models that describe the collective behavior and the informational processing in neural circuits in the brain. His work helps researchers understand the system-wide failures that take place in brain diseases, from epilepsy to psychiatric disorders.

“Computational neuroscience is a vibrant and ambitious field that uses mathematical theories and models to cope with the most daunting challenges – from answering fundamental questions about the brain and its relation to the mind to answering questions posed by the quest to heal the brain’s debilitating diseases,” said Sompolinsky.

Meanwhile, Prof. Abbott won for showing how plasticity mechanisms that change the properties of neural circuits can maintain their proper operation and allow them to change during the learning process.

Inspired by the vision of Israeli President Shimon Peres, IBT was set up to advance Israel’s neurotechnology industry and establish the country as a global hub of brain technology innovation.

“This prize recognizes leaders in the important field of mathematical neuroscience, whose advances support our ultimate quest to find new solutions for the betterment of all humankind,” said Miri Polachek, Executive Director of IBT.

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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


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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