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Functional Correlates of Signaling Pathways

Posted in Academic Publishing, Biochemical pathways, Biological Networks, Ca2+ triggered activation, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiomyopathy, Chemical Biology and its relations to Metabolic Disease, Curation, Cytoskeleton, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Genome Biology, Historical relevance, Human Immune System in Health and in Disease, Innovations in Neurophysiology & Neuropsychology, Ionic Transporters Na+, Metabolism, Metabolomics, Mg++, Molecular Genetics & Pharmaceutical, Na-K transport, Neurohumoral Transmission, Neurological Diseases, Nitric Oxide in Health and Disease, Nutrition, Nutrition and Phytochemistry, Pharmaceutical Analytics, Population Health Management, Proteomics, Synaptic vesicle, Technology Advance Assessment of, tagged enzymes, pathways, Proteins, signaling, therapeutics on November 4, 2014| Leave a Comment »

Functional Correlates of Signaling Pathways

Author and Curator: Larry H. Bernstein, MD, FCAP

 

We here move on to a number of specific, key published work on signaling, and look at the possible therapeutic applications to disease states.

Scripps Research Professor Wolfram Ruf and colleagues have identified a key connection between

• the signaling pathways and the immune system spiraling out of control involving
• the coagulation system and vascular endothelium that,
• if disrupted may be a target for sepsis. (Science Daily, Feb 29, 2008).

It may be caused by a bacterial infection that enters the bloodstream, but

• we now recognize the same cascade not triggered by bacterial invasion.

The acute respiratory distress syndrome (ARDS) has been defined as

• a severe form of acute lung injury featuring
• pulmonary inflammation and increased capillary leak.

ARDS is associated with a high mortality rate and accounts for 100,000 deaths annually in the United States. ARDS may arise in a number of clinical situations, especially in patients with sepsis. A well-described pathophysiological model of ARDS is one form of

• the acute lung inflammation mediated by

1. neutrophils,
2. cytokines, and
3. oxidant stress.

Neutrophils are major effect cells at the frontier of

• innate immune responses, and they play
• a critical role in host defense against invading microorganisms.

The tissue injury appears to be related to

• proteases and toxic reactive oxygen radicals
• released from activated neutrophils.

In addition, neutrophils can produce cytokines and chemokines that

enhance the acute inflammatory response.

Neutrophil accumulation in the lung plays a pivotal role in the pathogenesis of acute lung injury during sepsis. Directed movement of neutrophils is

• mediated by a group of chemoattractants,
• especially CXC chemokines.

Local lung production of CXC chemokines is intensified during experimental sepsis induced by cecal ligation and puncture (CLP).

Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

http://pharmaceuticalintelligence.com/2012/10/13/sepsis-multi-organ-dysfunction-syndrome-and-septic-shock-a-conundrum-of-signaling-pathways-cascading-out-of-control/

Integrins and extracellular matrix in mechanotransduction

ligand binding of integrins

Integrins are a family of cell surface receptors which

mediate cell–matrix and cell–cell adhesions.

Among other functions they provide an important

mechanical link between the cells external and intracellular environments while

the adhesions that they form also have critical roles in cellular signal-transduction.

Cell–matrix contacts occur at zones in the cell surface where

adhesion receptors cluster and when activated

the receptors bind to ligands in the extracellular matrix.

The extracellular matrix surrounds the cells of tissues and forms the

structural support of tissue which is particularly important in connective tissues.

Cells attach to the extracellular matrix through

specific cell-surface receptors and molecules

including integrins and transmembrane proteoglycans.

The integrin family of αβ heterodimeric receptors act as

cell adhesion molecules

connecting the ECM to the actin cytoskeleton.

The actin cytoskeleton is involved in the regulation of

1.cell motility,

2.cell polarity,

3.cell growth, and

4.cell survival.

The combination of αβ subunits determines

binding specificity and

signaling properties.

Both α and β integrin subunits contain two separate tails, which

penetrate the plasma membrane and possess small cytoplasmic domains which facilitate

the signaling functions of the receptor.

There is some evidence that the β subunit is the principal site for

binding of cytoskeletal and signaling molecules,

whereas the α subunit has a regulatory role. The integrin tails

link the ECM to the actin cytoskeleton within the cell and with cytoplasmic proteins,

such as talin, tensin, and filamin. The extracellular domains of integrin receptors bind the ECM ligands.

binding of integrins depends on ECM divalent cations ch19

integrin coupled to F-actin via linker

http://www.nature.com/nrm/journal/vaop/ncurrent/images/nrm3896-f4.jpg

Schematic of the ‘focal adhesion clutch’ on stiff (a) versus soft (b) extracellular matrix (ECM). In all cases, integrins are coupled to F-actin via linker proteins (for example, talin and vinculin). The linker proteins move backwards (as indicated by the small arrows) as F-actin also moves backwards, under pushing forces from actin polymerization and/or pulling forces from myosin II activity. This mechanism transfers force from actin to integrins, which pull on the ECM. A stiff ECM (a) resists this force so that the bound integrins remain immobile. A compliant matrix (b) deforms under this force (as indicated by the compressed ECM labelled as deformed matrix) so that the bound integrins can also move backwards. Their movement reduces the net loading rate on all the force-bearing elements, which results in altered cellular responses

The ECM is a complex mixture of matrix molecules, including –

• glycoproteins, collagens, laminins, glycosaminoglycans, proteoglycans,
• and nonmatrix proteins, – including growth factors

The integrin receptor formed from the binding of α and β subunits is

• shaped like a globular head supported by two rod-like legs (Figure 1).

Most of the contact between the two subunits occurs in the head region, with

• the intracellular tails of the subunits forming the legs of the receptor.

Integrin recognition of ligands is not constitutive but

• is regulated by alteration of integrin affinity for ligand binding.

For integrin binding to ligands to occur

• the integrin must be primed and activated, both of which involve
• conformational changes to the receptor.

Linking integrin conformation to function

Figure  Integrin binding to extracellular matrix (ECM). Conformational changes to integrin structure and clustering of subunits which allow enhanced function of the receptor.

Integrins work alongside other proteins such as

cadherins,

immunoglobulin superfamily

cell adhesion molecules,

selectins, and

syndecans

to mediate

cell–cell and

cell–matrix interactions and communication.

Activation of adhesion receptors triggers the formation of matrix contacts in which

bound matrix components,

adhesion receptors,

and associated intracellular cytoskeletal and signaling molecules

form large functional, localized multiprotein complexes.

Cell–matrix contacts are important in a variety of different cell and

tissue properties including

1.embryonic development,

2.inflammatory responses,

3.wound healing,

4.and adult tissue homeostasis.

Integrin extracellular binding activity is regulated from inside the cell and binding to the ECM induces signals that are transmitted into the cell. This bidirectional signaling requires

dynamic,

spatially, and

temporally regulated formation and

disassembly of multiprotein complexes that

form around the short cytoplasmic tails of integrins.

Ligand binding to integrin family members leads to clustering of integrin molecules in the plasma membrane and recruitment of actin filaments and intracellular signaling molecules to the cytoplasmic domain of the integrins. This forms focal adhesion complexes which are able to maintain

not only adhesion to the ECM

but are involved in complex signaling pathways

which include establishing

1.cell polarity,

2.directed cell migration, and

3.maintaining cell growth and survival.

Initial activation through integrin adhesion to matrix recruits up to around 50 diverse signaling molecules

to assemble the focal adhesion complex

which is capable of responding to environmental stimuli efficiently.

Mapping of the integrin

adhesome binding and signaling interactions

a network of 156 components linked together which can be modified by 690 interactions.

Genetic programming occurs with the binding of integrins to the ECM

Signal transduction pathway activation arising from integrin-ECM binding results in

• changes in gene expression of cells and
• leads to alterations in cell and tissue function.

Various different effects can arise depending on the

1.cell type,

2.matrix composition, and

3.integrins activated

It has been suggested that integrin-type I collagen interaction is necessary for

• the phosphorylation and activation of osteoblast-specific transcription factors
• present in committed osteoprogenitor cells.

During mechanical loading/stimulation of chondrocytes there is an

1. influx of ions across the cell membrane resulting from
2. activation of mechanosensitive ion channels
3. which can be inhibited by subunit-specific anti-integrin blocking antibodies or RGD peptides.

Using these strategies it was identified that

• α5β1 integrin is a major mechanoreceptor in articular chondrocyte
• responses to mechanical loading/stimulation.

Osteoarthritic chondrocytes show a depolarization response to 0.33 Hz stimulation

• in contrast to the hyperpolarization response of normal chondrocytes.

The mechanotransduction pathway in chondrocytes derived from normal and osteoarthritic cartilage

• both involve recognition of the mechanical stimulus
• by integrin receptors resulting in
• the activation of integrin signaling pathways
• leading to the generation of a cytokine loop.

Normal and osteoarthritic chondrocytes show differences

• at multiple stages of the mechanotransduction cascade.

Signaling pathways activated in chondrocytes

http://dx.doi.org/10.1016/j.matbio.2014.08.007

Chondrocyte integrins are important mediators of cell–matrix interactions in cartilage

• by regulating the response of the cells to signals from the ECM that

1. control cell proliferation,
2. survival,
3. differentiation,
4. matrix remodeling.

Integrins participate in development and maintenance of the tissue but also

• in pathological processes related to matrix destruction, where
• they likely play a role in the progression of OA.

Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels

Cells exhibited four types of mechanical responses:

(1) an immediate viscoelastic response;

(2) early adaptive behavior characterized by pulse-to-pulse attenuation in response to oscillatory forces;

(3) later adaptive cell stiffening with sustained (>15 second) static stresses; and

(4) a large-scale repositioning response with prolonged (>1 minute) stress.

Importantly, these adaptation responses differed biochemically.

The immediate and early responses were affected by

chemically dissipating cytoskeletal prestress (isometric tension), whereas

the later adaptive response was not.

The repositioning response was prevented by

inhibiting tension through interference with Rho signaling,

similar to the case of the immediate and early responses, but it was also prevented by

blocking mechanosensitive ion channels or

by inhibiting Src tyrosine kinases.

All adaptive responses were suppressed by cooling cells to 4°C to slow biochemical remodeling. Thus, cells use multiple mechanisms to sense and respond to static and dynamic changes in the level of mechanical stress applied to integrins.

Microtubule-Stimulated ADP Release, ATP Binding, and Force Generation In Transport Kinesins

All three classes of molecular motor proteins are now known to be

• large protein families with diverse cellular functions.

Both the kinesin family and the myosin family have been defined and their proteins grouped into subfamilies. Finally, the elusive cytoplasmic version of dynein was identified and a multigene family of flagellar and cytoplasmic dyneins defined. Members of a given motor protein family share

• significant homology in their motor domains with the defining member,
• kinesin, dynein or myosin; but they also contain
• unique protein domains that are specialized for interaction with different cargoes.

This large number of motor proteins may reflect

• the number of cellular functions that require force generation or movement,
• ranging from mitosis to morphogenesis to transport of vesicles.

Kinesins are a large family of microtubule (MT)-based motors that play important roles in many cellular activities including

mitosis,

motility, and

intracellular transport

Their involvement in a range of pathological processes

• also highlights their significance as therapeutic targets and
• the importance of understanding the molecular basis of their function

They are defined by their motor domains that contain both

• the microtubule (MT) and
• ATP binding sites.

Three ATP binding motifs—

1. the P-loop,
2. switch I,
3. switch II–

are highly conserved among

1. kinesins,
2. myosin motors, and

• small GTPases.

They share a conserved mode of MT binding such that

• MT binding,
• ATP binding, and
• hydrolysis

are functionally coupled for efficient MT-based work.

The interior of a cell is a hive of activity, filled with

• proteins and other items moving from one location to another.

A network of filaments called microtubules forms tracks

• along which so-called motor proteins carry these items.

Kinesins are one group of motor proteins, and a typical kinesin protein has

• one end (called the ‘motor domain’) that can attach itself to the microtubules.

The other end links to the cargo being carried, and a ‘neck’ connects the two. When two of these proteins work together,

• flexible regions of the neck allow the two motor domains to move past one another,
• which enable the kinesin to essentially walk along a microtubule in a stepwise manner.

Although the two kinesins have been thought to move along the microtubule tracks in different ways, Atherton et al. find that the core mechanism used by their motor domains is the same.

When a motor domain binds to the microtubule, its shape changes,

• first stimulating release of the breakdown products of ATP from the previous cycle.

This release makes room for a new ATP molecule to bind. The structural changes caused by ATP binding

• produce larger changes in the flexible neck region that
• enable individual motor domains within a kinesin pair to
• co-ordinate their movement and move in a consistent direction.

The major and largely invariant point of contact between kinesin motor domains and the MT is helix-α4,

• which lies at the tubulin intradimer interface.

The conformational changes in functionally important regions of each motor domain are described,

• starting with the nucleotide-binding site,
• from which all other conformational changes emanate.

The nucleotide-binding site (Figure 2) has three major elements:

(1) the P-loop (brown) is visible in all our reconstructions;

(2) loop9 (yellow, contains switch I) undergoes major conformational changes through the ATPase cycle; and

(3) loop11 (red, contains switch II) that connects strand-β7 to helix-α4, the conformation and flexibility of which is

• determined by MT binding and motor nucleotide state.

Movement and extension of helix-α6 controls neck linker docking

the N-terminus of helix-α6 is closely associated with elements of the nucleotide binding site suggesting that

• its conformation alters in response to different nucleotide states.

Further,

• because the orientation of helix-α6 with respect to helix-α4 controls neck linker docking and
• because helix-α4 is held against the MT during the ATPase cycle,
  • conformational changes in helix-α6 control movement of the neck linker.

Mechanical amplification and force generation involves conformational changes across the motor domain

A key conformational change in the motor domain following Mg-ATP binding is

• peeling of the central β-sheet from the C-terminus of helix-α4 increasing their separation;
• this is required to accommodate rotation of helix-α6 and consequent neck linker docking

ATP binding draws loop11 and loop9 closer together; causing

(1) tilting of most of the motor domain not contacting the MT towards the nucleotide-binding site,

(2) rotation, translation, and extension of helix-α6 which we propose contributes to force generation, and

(3) allows neck linker docking and biases movement of the 2nd head towards the MT plus end.

In both motors, microtubule binding promotes

ordered conformations of conserved loops that

stimulate ADP release,

enhance microtubule affinity and

prime the catalytic site for ATP binding.

ATP binding causes only small shifts of these nucleotide-coordinating loops but induces

large conformational changes elsewhere that

allow force generation and

neck linker docking towards the microtubule plus end.

The study presents evidence provide evidence for a conserved ATP-driven

mechanism for kinesins and

reveals the critical mechanistic contribution of the microtubule interface.

Phosphorylation at endothelial cell–cell junctions: Implications for VE-cadherin function

This review summarizes the role of VE-cadherin phosphorylation in the regulation of endothelial cell–cell junctions and highlights how this affects vascular permeability and leukocyte extravasation.

The vascular endothelium is the inner lining of blood vessels and

forms a physical barrier between the vessel lumen and surrounding tissue;

controlling the extravasation of fluids,

plasma proteins and leukocytes.

Changes in the permeability of the endothelium are tightly regulated. Under basal physiological conditions, there is a continuous transfer of substances across the capillary beds. In addition the endothelium can mediate inducible,

transient hyperpermeability

in response to stimulation with inflammatory mediators,

which takes place primarily in post-capillary venules

However, when severe, inflammation may result in dysfunction of the endothelial barrier

• in various parts of the vascular tree, including large veins, arterioles and capillaries.

Dysregulated permeability is observed in various pathological conditions, such as

• tumor-induced angiogenesis,
• cerebrovascular accident and
• atherosclerosis.

Two fundamentally different pathways regulate endothelial permeability,

1. the transcellular and
2. paracellular pathways.

Solutes and cells can pass through the body of endothelial cells via the transcellular pathway, which includes

• vesicular transport systems,
• fenestrae, and
• biochemical transporters.

The paracellular route is controlled by

• the coordinated opening and closing of endothelial junctions and
• thereby regulates traffic across the intercellular spaces between endothelial cells.

Endothelial cells are connected by

tight, gap and

adherens junctions,

of which the latter, and particularly the adherens junction component,

vascular endothelial (VE)-cadherin,

are of central importance for the initiation and stabilization of cell–cell contacts.

Although multiple adhesion molecules are localized at endothelial junctions,

• blocking the adhesive function of VE-cadherin using antibodies
• is sufficient to disrupt endothelial junctions and
• to increase endothelial monolayer permeability both in vitro and in vivo.

Like other cadherins, VE-cadherin mediates adhesion via

• homophilic, calcium-dependent interactions.

This cell–cell adhesion

is strengthened by binding of cytoplasmic proteins, the catenins,

to the C-terminus of VE-cadherin.

VE-cadherin can directly bind

• β-catenin and plakoglobin, which
• both associate with the actin binding protein α-catenin.

Initially, α-catenin was thought to directly anchor cadherins to the actin cytoskeleton, but recently it became clear that

• α-catenin cannot bind to both β-catenin and actin simultaneously.

Numerous lines of evidence indicate that p120-catenin

• promotes VE-cadherin surface expression and stability at the plasma membrane.

Different models are proposed that describe how

• p120-catenin regulates cadherin membrane dynamics, including the hypothesis
• that p120-catenin functions as a ‘cap’ that prevents the interaction of VE-cadherin
• with the endocytic membrane trafficking machinery.

In addition, p120-catenin might regulate VE-cadherin internalization

• through interactions with small GTPases.

Cytoplasmic p120-catenin, which is not bound to VE-cadherin, has been shown to

decrease RhoA activity,

elevate active Rac1 and Cdc42, and thereby is thought

to regulate actin cytoskeleton organization and membrane trafficking.

The intact cadherin-catenin complex is required for proper functioning of the adherens junction.

Several mechanisms may be involved in the

• regulation of the organization and function of the cadherin–catenin complex, including

1. endocytosis of the complex,
2. VE-cadherin cleavage and
3. actin cytoskeleton reorganization.

The remainder of this review primarily focuses on the

role of tyrosine phosphorylation in the control of VE-cadherin-mediated cell–cell adhesion.

Regulation of the adhesive function of VE-cadherin by tyrosine phosphorylation

It is a widely accepted concept that tyrosine phosphorylation of

• components of the VE–cadherin-catenin complex
• Correlates with the weakening of cell–cell adhesion.

A general idea has emerged that

tyrosine phosphorylation of the VE-cadherin complex

leads to the uncoupling of VE-cadherin from the actin cytoskeleton

through dissociation of catenins from the cadherin.

However, tyrosine phosphorylation of VE-cadherin

• is required for efficient transmigration of leukocytes.

This suggests that VE-cadherin-mediated cell–cell contacts

1.are not just pushed open by the migrating leukocytes, but play

2.a more active role in the transmigration process.

A schematic overview of leukocyte adhesion-induced signals leading to VE-cadherin phosphorylation

Regulation of the integrity of endothelial cell–cell contacts by phosphorylation of VE-cadherin.

Regulation of the integrity of endothelial cell–cell contacts by phosphorylation of VE-cadherin

N-glycosylation status of E-cadherin controls cytoskeletal dynamics through the organization of distinct β-catenin- and γ-catenin-containing AJs

N-glycosylation of E-cadherin has been shown to inhibit cell–cell adhesion.

Specifically, our recent studies have provided evidence that

• the reduction of E-cadherin N-glycosylation
• promoted the recruitment of stabilizing components,
• vinculin and serine/ threonine protein phosphatase 2A (PP2A), to adherens junctions (AJs)
• and enhanced the association of AJs with the actin cytoskeleton.

Here, we examined the details of how

N-glycosylation of E-cadherin affected the molecular organization of AJs and their cytoskeletal interactions.

Using the hypoglycosylated E-cadherin variant, V13, we show that

V13/β-catenin complexes preferentially interacted with PP2A and with the microtubule motor protein dynein.

This correlated with dephosphorylation of the microtubule-associated protein tau, suggesting that

increased association of PP2A with V13-containing AJs promoted their tethering to microtubules.

These studies provide the first mechanistic insights into how N-glycosylation of E-cadherin drives changes in AJ composition through

• the assembly of distinct β-catenin- and γ-catenin-containing scaffolds that impact the interaction with different cytoskeletal components

Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle

MacKinnon. Fig 1 Ion channels exhibit three basic properties

In order to contract and accommodate the repetitive morphological changes induced by the cardiac cycle, cardiomyocytes

depend on their highly evolved and specialized cytoskeletal apparatus.

Defects in components of the cytoskeleton, in the long term,

affect the ability of the cell to compensate at both functional and structural levels.

In addition to the structural remodeling,

the myocardium becomes increasingly susceptible to altered electrical activity leading to arrhythmogenesis.

The development of arrhythmias secondary to structural remodeling defects has been noted, although the detailed molecular mechanisms are still elusive.

subjects with severe left ventricular chamber dilation such as in DCM can have left bundle branch block (LBBB), while right bundle branch block (RBBB) is more characteristic of right ventricular failure.  LBBB and RBBB have both been repeatedly associated with AV block in heart failure.

The impact of volume overload on structural and electro-cardiographic alterations has been noted in cardiomyopathy patients treated with left ventricular assist device (LVAD) therapy, which puts the heart at mechanical rest.

In LVAD-treated subjects,

QRS- and both QT- and QTc duration decreased,

suggesting that QRS- and QT-duration are significantly influenced by mechanical load and

that the shortening of the action potential duration contributes to the improved contractile performance after LVAD support.

An early postoperative period study after cardiac unloading therapy in 17 HF patients showed that in the first two weeks after LVAD implantation,

HF was associated with a relatively high incidence of ventricular arrhythmias associated with QTc interval prolongation.

In addition, a recent retrospective study of 100 adult patients with advanced HF, treated with an axial-flow HeartMate LVAD suggested that

• the rate of new-onset monomorphic ventricular tachycardia (MVT) was increased in LVAD treated patients compared to patients given only medical treatment,

The myocardium is exposed to severe and continuous biomechanical stress during each contraction-relaxation cycle. When fiber tension remains uncompensated or simply unbalanced,

it may represent a trigger for arrhythmogenesis caused by cytoskeletal stretching,

which ultimately leads to altered ion channel localization, and subsequent action potential and conduction alterations.

Cytoskeletal proteins not only provide the backbone of the cellular structure, but they also

maintain the shape and flexibility of the different sub-cellular compartments, including the

1.plasma membrane,

2.the double lipid layer, which defines the boundaries of the cell and where

ion channels are mainly localized.

The interaction between the sarcomere, which is the basic for the passive force during diastole and for the restoring force during systole.

Sarcomeric Proteins and Ion Channels

besides fiber stretch associated with mechanical and hemodynamic impairment, cytoskeletal alterations due to primary genetic defects or indirectly to alterations in response to cellular injury can potentially

1.affect ion channel anchoring, and trafficking, as well as

2.functional regulation by second messenger pathways,

3.causing an imbalance in cardiac ionic homeostasis that will trigger arrhythmogenesis.

Intense investigation of

the sarcomeric actin network,

the Z-line structure, and

chaperone molecules docking in the plasma membrane,

has shed new light on the molecular basis of

• cytoskeletal interactions in regulating ion channels

Actin disruption using cytochalasin D, an agent that interferes with actin polymerization, increased Na+ channel activity in 90% of excised patches tested within 2 min, which indicated that

the integrity of the filamentous actin (F-actin) network was essential for the maintenance of normal Na+ channel function

These data were the first to support a role for the cytoskeleton in cardiac arrhythmias.

Molecular interactions between the cytoskeleton and ion channels

The figure illustrates the interactions between the ion channels on the sarcolemma, and the sarcomere in cardiac myocytes. Note that the Z-line is connected to the cardiac T-tubules. The diagram illustrates the complex protein-protein interactions that occur between structural components of the cytoskeleton and ion channels. The cytoskeleton is involved in regulating the metabolism of ion channels, modifying their expression, localization, and electrical properties.

sarcomere structure

It is important to be aware of the enormous variety of clinical presentations that derive from distinct variants in the same pool of genetic factors. Knowledge of these variants could facilitate tailoring the therapy of choice for each patient. In particular,

the recent findings of structural and functional links between

the cytoskeleton and ion channels

could expand the therapeutic interventions in

arrhythmia management in structurally abnormal myocardium, where aberrant binding

between cytoskeletal proteins can directly or indirectly alter ion channel function.

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Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, HTN, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Proteomics, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged Apolipoprotein C3, Aviva Lev-Ari, Coronary artery disease, DNA, Doctor of Philosophy, genetic engineering, genetics, Kickstarter, Novo Mutations, pathways, Stephen J. Williams, Synthetic biology on May 17, 2013| 12 Comments »

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Curator: Aviva Lev-Ari, PhD, RN

Article ID #52: Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging. Published on 5/17/2013

WordCloud Image Produced by Adam Tubman

UPDATED on 7/12/2021

• Abstract. Synthetic biology is a field of scientific research that applies engineering principles to living organisms and living systems.
• Introduction. This article is intended as a perspective on the field of synthetic biology. …
• Genetic Manipulation—Plasmids. …
• Genetic Manipulations—Genome. …
• An Early Example of Synthetic Biology. …

Engineering Life: A Review of Synthetic Biology | Artificial Life | MIT Press

direct.mit.edu/artl/article/26/2/260/93249/Engineering-Life-A-Review-of-Synthetic-Biology

UPDATED on 11/6/2018

Which biological systems should be engineered?

To solve real-world problems using emerging abilities in synthetic biology, research must focus on a few ambitious goals, argues Dan Fletcher, Professor of bioengineering and biophysics, and chair of the Department of Bioengineering at the University of California, Berkeley, USA. He is also a Chan Zuckerberg Biohub Investigator.

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Artificial blood cells. Blood transfusions are crucial in treatments for everything from transplant surgery and cardiovascular procedures to car accidents, pregnancy-related complications and childhood malaria (see go.nature.com/2ozbfwt). In the United States alone, 36,000 units of red blood cells and 7,000 units of platelets are needed every day (see go.nature.com/2ycr2wo).

But maintaining an adequate supply of blood from voluntary donors can be challenging, especially in low- and middle-income countries. To complicate matters, blood from donors must be checked extensively to prevent the spread of infectious diseases, and can be kept for only a limited time — 42 days or 5 days for platelets alone. What if blood cells could be assembled from purified or synthesized components on demand?

In principle, cell-like compartments could be made that have the oxygen-carrying capacity of red blood cells or the clotting ability of platelets. The compartments would need to be built with molecules on their surfaces to protect the compartments from the immune system, resembling those on a normal blood cell. Other surface molecules would be needed to detect signals and trigger a response.

In the case of artificial platelets, that signal might be the protein collagen, to which circulating platelets are exposed when a blood vessel ruptures⁵. Such compartments would also need to be able to release certain molecules, such as factor V or the von Willebrand clotting factor. This could happen by building in a rudimentary form of exocytosis, for example, whereby a membrane-bound sac containing the molecule would be released by fusing with the compartment’s outer membrane.

It is already possible to encapsulate cytoplasmic components from living cells in membrane compartments^6,7. Now a major challenge is developing ways to insert desired protein receptors into the lipid membrane⁸, along with reconstituting receptor signalling.

Red blood cells and platelets are good candidates for the first functionally useful synthetic cellular system because they lack nuclei. Complex functions such as nuclear transport, protein synthesis and protein trafficking wouldn’t have to be replicated. If successful, we might look back with horror on the current practice of bleeding one person to treat another.

Designer immune cells. Immunotherapy is currently offering new hope for people with cancer by shaping how the immune system responds to tumours. Cancer cells often turn off the immune response that would otherwise destroy them. The use of therapeutic antibodies to stop this process has drastically increased survival rates for people with multiple cancers, including those of the skin, blood and lung⁹. Similarly successful is the technique of adoptive T-cell transfer. In this, a patient’s T cells or those of a donor are engineered to express a receptor that targets a protein (antigen) on the surface of tumour cells, resulting in the T cells killing the cancerous cells (called CAR-T therapies)¹⁰. All of this has opened the door to cleverly rewiring the downstream signalling that results in the destruction of tumour cells by white blood cells¹¹.

What if researchers went a step further and tried to create synthetic cells capable of moving towards, binding to and eliminating tumour cells?

In principle, untethered from evolutionary pressures, such cells could be designed to accomplish all sorts of tasks — from killing specific tumour cells and pathogens to removing brain amyloid plaques or cholesterol deposits. If mass production of artificial immune cells were possible, it might even lessen the need to tailor treatments to individuals — cutting costs and increasing accessibility.

To ensure that healthy cells are not targeted for destruction, engineers would also need to design complex signal-processing systems and safeguards. The designer immune cells would need to be capable of detecting and moving towards a chemical signal or tumour. (Reconstituting the complex process of cell motility is itself a major challenge, from the delivery of energy-generating ATP molecules to the assembly of actin and myosin motors that enable movement.)

Researchers have already made cell-like compartments that can change shape¹², and have installed signalling circuits within them¹³. These could eventually be used to control movement and mediate responses to external signals.

Smart delivery vehicles. The relative ease of exposing cells in the lab to drugs, as well as introducing new proteins and engineering genomes, belies how hard it is to deliver molecules to specific locations inside living organisms. One of the biggest challenges in most therapies is getting molecules to the right place in the right cell at the right time.

Harnessing the natural proclivity of viruses to deliver DNA and RNA molecules into cells has been successful¹⁴. But virus size limits cargo size, and viruses don’t necessarily infect the cell types researchers and clinicians are aiming at. Antibody-targeted synthetic vesicles have improved the delivery of drugs to some tumours. But getting the drug close to the tumour generally depends on the vesicles leaking from the patient’s circulatory system, so results have been mixed.

Could ‘smart’ delivery vehicles containing therapeutic cargo be designed to sense where they are in the body and move the cargo to where it needs to go, such as across the blood–brain barrier?

This has long been a dream of those in drug delivery. The challenges are similar to those of constructing artificial blood and immune cells: encapsulating defined components in a membrane, incorporating receptors into that membrane, and designing signal-processing systems to control movement and trigger release of the vehicle’s contents.

The development of immune-cell ‘backpacks’ is an exciting step in the right direction. In this, particles containing therapeutic molecules are tethered to immune cells, exploiting the motility and targeting ability of the cells to carry the molecules to particular locations¹⁵.

A minimal chassis for expression. In each of the previous examples, the engineered cell-like system could conceivably be built to function over hours or days, without the need for additional protein production and regulation through gene expression. For many other tasks, however, such as the continuous production of insulin in the body, it will be crucial to have the ability to express proteins, upregulate or downregulate certain genes, and carry out functions for longer periods.

Engineering a ‘minimal chassis’ that is capable of sustained gene expression and functional homeostasis would be an invaluable starting point for building synthetic cells that produce proteins, form tissues and remain viable for months to years. This would require detailed understanding and incorporation of metabolic pathways, trafficking systems and nuclear import and export — an admittedly tall order.

It is already possible to synthesize DNA in the lab, whether through chemically reacting bases or using biological enzymes or large-scale assembly in a cell¹⁶. But we do not yet know how to ‘boot up’ DNA and turn a synthetic genome into a functional system in the absence of a live cell.

Since the early 2000s, biologists have achieved gene expression in synthetic compartments loaded with cytoplasmic extract¹⁷. And genetic circuits of increasing complexity (in which the expression of one protein results in the production or degradation of another) are now the subject of extensive research. Still to be accomplished are: long-lived gene expression, basic protein trafficking and energy production reminiscent of live cells.

End Quote

SOURCE

https://www.nature.com/articles/d41586-018-07291-3?utm_source=briefing-dy&utm_medium=email&utm_campaign=briefing&utm_content=20181106

UPDATED on 10/14/2013

Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease

372/3:15 Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enriched GWAS study among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial. L. Warren, L. Li, D. Fraser, J. Aponte, A. Yeo, R. Davies, C. Macphee, L. Hegg, L. Tarka, C. Held, R. Stewart, L. Wallentin, H. White, M. Nelson, D. Waterworth.

Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enrichedGWASstudy among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial.

L. Warren1, L. Li1, D. Fraser1, J. Aponte1, A. Yeo2, R. Davies3, C. Macphee3, L. Hegg3,

L. Tarka3, C. Held4, R. Stewart5, L. Wallentin4, H. White5, M. Nelson1, D.

Waterworth3.

1) GlaxoSmithKline, Res Triangle Park, NC;

2) GlaxoSmithKline, Stevenage, UK;

3) GlaxoSmithKline, Upper Merion, Pennsylvania, USA;

4) Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden;

5) 5Green Lane Cardiovascular Service, Auckland Cty Hospital, Auckland, New Zealand.

STABILITY is an ongoing phase III cardiovascular outcomes study that compares the effects of darapladib enteric coated (EC) tablets, 160 mg versus placebo, when added to the standard of care, on the incidence of major adverse cardiovascular events (MACE) in subjects with chronic coronary heart disease (CHD). Blood samples for determination of the LpPLA2 activity level in plasma and for extraction of DNA was obtained at randomization. To identify genetic variants that may predict response to darapladib, we genotyped ~900K common and low frequency coding variations using Illumina OmniExpress GWAS plus exome chip in advance of study completion. Among the 15828 Intent-to-Treat recruited subjects, 13674 (86%) provided informed consent for genetic analysis. Our pharmacogenetic (PGx) analysis group is comprised of subjects from 39 countries on five continents, including 10139 Whites of European heritage, 1682 Asians of East Asian or Japanese heritage, 414 Asians of Central/South Asian heritage, 268 Blacks, 1027 Hispanics and 144 others. Here we report association analysis of baseline levels of LpPLA2 to support future PGx analysis of drug response post trial completion. Among the 911375 variants genotyped, 213540 (23%) were rare (MAF < 0.5%).

Our analyses were focused on the drug target, LpPLA2 enzyme activity measured at baseline. GWAS analysis of LpPLA2 activity adjusting for age, gender and top 20 principle component scores identified 58 variants surpassing GWAS-significant threshold (5e-08).

Genome-wide stepwise regression analyses identified multiple independent associations from PLA2G7, CELSR2, APOB, KIF6, and APOE, reflecting the dependency of LpPLA2 on LDL-cholesterol levels. Most notably, several low frequency and rare coding variants in PLA2G7 were identified to be strongly associated with LpPLA2 activity. They are V279F (MAF=1.0%, P= 1.7e-108), a previously known association, and four novel associations due to I1317N (MAF=0.05%, P=4.9e-8), Q287X (MAF=0.05%, P=1.6e-7), T278M (MAF=0.02%, P=7.6e-5) and L389S (MAF=0.04%, P=4.3e-4).

All these variants had enzyme activity lowering effects and each appeared to be specific to certain ethnicity. Our comprehensive PGx analyses of baseline data has already provided great insight into common and rare coding genetic variants associated with drug target and related traits and this knowledge will be invaluable in facilitating future PGx investigation of darapladib response.

SOURCE

http://www.ashg.org/2013meeting/pdf/46025_Platform_bookmark%20for%20Web%20Final%20from%20AGS.pdf

Synthetic Biology: On Advanced Genome Interpretation for

• Gene Variants and
• Pathways,
• Inversion Polymorphism,
• Passenger Deletions,
• De Novo Mutations,
• Whole Genome Sequencing w/Linkage Analysis

What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging?

In a recent publication by my colleague, Stephen J. Williams, Ph.D. on  5/15/2013 titled

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

http://pharmaceuticalintelligence.com/2013/05/15/finding-the-genetic-links-in-common-disease-caveats-of-whole-genome-sequencing-studies/

we learned that:

• Groups of variants in the same gene confirmed link between APOC3 and higher risk for early-onset heart attack
• No other significant gene variants linked with heart disease

APOC3 – apolipoprotein C-III – Potential Relevance to the Human Aging Process

Main reason for selection

Entry selected based on indirect or inconclusive evidence linking the gene product to ageing in humans or in one or more model systems

Description

APOC3 is involved in fat metabolism and may delay the catabolism of triglyceride-rich particles. Changes in APOC3 expression levels have been reported in aged mice [1754]. Results from mice suggest that FOXO1 may regulate the expression of APOC3 [1743]. Polymorphisms in the human APOC3 gene and promoter have been associated with lipoprotein profile, cardiovascular health, insulin (INS) sensitivity, and longevity [1756]. Therefore, APOC3 may impact on some age-related diseases, though its exact role in human ageing remains to be determined.

Cytogenetic information

Cytogenetic band

11q23.1-q2

Location

116,205,833 bp to 116,208,997 bp

Orientation

Plus strand

Display region using the UCSC Genome Browser

Protein information

Gene Ontology

Process:

GO:0006869; lipid transport GO:0016042; lipid catabolic process GO:0042157; lipoprotein metabolic process

Function:

GO:0005319; lipid transporter activity

Cellular component:

GO:0005576; extracellular region GO:0042627; chylomicron

Protein interactions and network

No interactions in records.

Retrieve sequences for APOC3

Promoter

Promoter

ORF

ORF

CDS

CDS

Homologues in model organisms

Bos taurus

APOC3_BOVI

Mus musculus

Apoc3

Pan troglodytes

APOC3

In other databases

AnAge

This species has an entry in AnAge

Selected references

• [2125] Pollin et al. (2008) A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection., PubMed
• [1756] Atzmon et al. (2006) Lipoprotein genotype and conserved pathway for exceptional longevity in humans, PubMed
• [1755] Araki and Goto (2004) Dietary restriction in aged mice can partially restore impaired metabolism of apolipoprotein A-IV and C-III, PubMed
• [1743] Altomonte et al. (2004) Foxo1 mediates insulin action on apoC-III and triglyceride metabolism, PubMed
• [1754] Araki et al. (2004) Impaired lipid metabolism in aged mice as revealed by fasting-induced expression of apolipoprotein mRNAs in the liver and changes in serum lipids, PubMed
• [1753] Panza et al. (2004) Vascular genetic factors and human longevity, PubMed
• [1752] Anisimov et al. (2001) Age-associated accumulation of the apolipoprotein C-III gene T-455C polymorphism C 

http://genomics.senescence.info/genes/entry.php?hgnc=APOC3

Apolipoprotein C-III is a protein component of very low density lipoprotein (VLDL). APOC3 inhibitslipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake^[1] of triglyceride-rich particles. The APOA1, APOC3 and APOA4 genes are closely linked in both rat and human genomes. The A-I and A-IV genes are transcribed from the same strand, while the A-1 and C-III genes are convergently transcribed. An increase in apoC-III levels induces the development of hypertriglyceridemia.

Clinical significance

Two novel susceptibility haplotypes (specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23; these confer approximately threefold higher risk ofcoronary heart disease in normal^[2] as well as non-insulin diabetes mellitus.^[3]Apo-CIII delays the catabolism of triglyceride rich particles. Elevations of Apo-CIII found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease.

1. ^ Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM (2009). “Metabolism of VLDL and LDL containing apolipoprotein C-III and not other small apolipoproteins – R2”.Arteriosclerosis, Thrombosis and Vascular Biology 30 (2): 239–45. doi:10.1161/ATVBAHA.109.197830. PMC 2818784. PMID 19910636.
2. ^ Singh PP, Singh M, Kaur TP, Grewal SS (2007). “A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease”. Int J Cardiol 130 (3): e93–5. doi:10.1016/j.ijcard.2007.07.029. PMID 17825930.
3. ^ Singh PP, Singh M, Gaur S, Grewal SS (2007). “The ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype”. Diab Vasc Dis Res 4 (2): 124–29. doi:10.3132/dvdr.2007.030. PMID 17654446.

In 2013 we reported on the discovery that there is a

Genetic Associations with Valvular Calcification and Aortic Stenosis

N Engl J Med 2013; 368:503-512

February 7, 2013DOI: 10.1056/NEJMoa1109034

METHODS

We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.

CONCLUSIONS

Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

SOURCE:

N Engl J Med 2013; 368:503-512

Related Research by Author & Curator of this article:

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Cardiovascular Biomarkers

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Genomics Orientations for Individualized Medicine Volume One

Market Readiness Pulse for Advanced Genome Interpretation and Individualized Medicine

We present below the MARKET LEADER in Interpretation of the Genomics Computations Results in the emerging new ERA of Medicine:  Genomic Medicine, Knome.com and its home grown software power house.

A second Case study in the  Advanced Genome Interpretation and Individualized Medicine presented following the Market Leader, is the Genome-Phenome Analyzer by SimulConsult, A Simultaneous Consult On Your Patient’s Diagnosis, Chestnut Hill, MA

http://www.simulconsult.com/index.html

 

2012: The Year When Genomic Medicine Started Paying Off

Luke Timmerman

An excerpt of an interesting article mentioning Knome [emphasis ours]…

Remember a couple of years ago when people commemorated the 10-year anniversary of the first draft human genome sequencing? The storyline then, in 200, was that we all went off to genome camp and only came home with a lousy T-shirt. Society, we were told, invested huge scientific resources in deciphering the code of life, and there wasn’t much of a payoff in the form of customized, personalized medicine.

That was an easy conclusion to reach then, when personalized medicine advocates could only point to a couple of effective targeted cancer drugs—Genentech’s Herceptin and Novartis’ Gleevec—and a couple of diagnostics. But that’s changing. My inbox the past week has been full of analyst reports from medical meetings, which mostly alerted readers to mere “incremental” advances with a number of genomic-based medicines and diagnostics. But that’s a matter of focusing on the trees, not the forest. This past year, we witnessed some really impressive progress from the early days of “clinical genomics” or “medical genomics.” The investment in deep understanding of genomics and biology is starting to look visionary.

The movement toward clinical genomics gathered steam back in June at the American Society of Clinical Oncology annual meeting. One of the hidden gem stories from ASCO was about little companies like Cambridge, MA-based Foundation Medicine and Cambridge, MA-based Knome that started seeing a surprising surge in demand from physicians for their services to help turn genomic data into medical information. The New York Times wrote a great story a month later about a young genomics researcher at Washington University in St. Louis who got cancer, had access to incredibly rich information about his tumors, and—after some wrestling with his insurance company—ended up getting a targeted drug nobody would have thought to prescribe without that information. And last month, I checked back on Stanford University researcher Mike Snyder, who made headlines this year using a smorgasbord of “omics” tools to correctly diagnose himself early with Type 2 diabetes, and then monitor his progress back into a healthy state–read the entire article

http://www.knome.com/knome-blog/2012-the-year-when-genomic-medicine-started-paying-off/

Knome and Real Time Genomics Ink Deal to Integrate and Sell the RTG Variant Platform on knoSYS™100 System

Partnership to bring accurate and fast genome analysis to translational researchers

CAMBRIDGE, MA –  May 6, 2013 – Knome Inc., the genome interpretation company, and Real Time Genomics, Inc., the genome analytics company, today announced that the Real Time Genomics (RTG) Variant platform will be integrated into every shipment of the knoSYS™100 interpretation system. The agreement enables customers to easily purchase the RTG analytics engine as an upgrade to the system. The product will combine two world-class commercial platforms to deliver end-to-end genome analytics and interpretation with superior accuracy and speed. Financial terms of the agreement were not disclosed.

“In the past year demand for genome interpretation has surged as translational researchers and clinicians adopt sequencing for human disease discovery and diagnosis,” said Wolfgang Daum, CEO of Knome. “Concomitant with that demand is the need for accurate and easy-to-use industrial grade analysis that meets expectations of clinical accuracy. The RTG platform is both incredibly fast and truly differentiating to customers doing family studies, and we are excited to add such a powerful platform to the knoSYS ecosystem.”

The partnership simplifies the purchasing process by allowing knoSYS customers to purchase the RTG platform directly from Knome sales representatives.

“The Knome system is a perfect complementary channel to further expand our commercial effort to bring the RTG platform to market,” said Steve Lombardi, CEO of Real Time Genomics. “Knome has built a recognizable brand around human clinical genome interpretation, and by delivering the RTG platform within their system, both companies are simplifying genomics to help customers understand human disease and guide clinical actions.”

About Knome

Knome Inc. (www.knome.com) is a leading provider of human genome interpretation systems and services. We help clients in two dozen countries identify the genetic basis of disease, tumor growth, and drug response. Designed to accelerate and industrialize the process of interpreting whole genomes, Knome’s big data technologies are helping to pave the healthcare industry’s transition to molecular-based, precision medicine.

About Real Time Genomics

Real Time Genomics (www.realtimegenomics.com) has a passion for genomics.  The company offers software tools and applications for the extraction of unique value from genomes.  Its competency lies in applying the combination of its patented core technology and deep computational expertise in algorithms to solve problems in next generation genomic analysis.  Real Time Genomics is a private San Francisco based company backed by investment from Catamount Ventures, Lightspeed Venture Partners, and GeneValue Ltd.

http://www.knome.com/knome-blog/knome-and-real-time-genomics-ink-deal-to-integrate-and-sell-the-rtg-variant-platform-on-knosys100-system/

Direct-to-Consumer Genomics Reinvents Itself

Malorye Allison

An excerpt of an interesting article mentioning Knome [emphasis ours]:

…Cambridge, Massachusetts–based Knome made one of the splashiest entries into the field, but has now turned entirely to contract research. The company began providing DTC whole-genome sequencing to independently wealthy individuals at a time when the price was still sky high. The company’s first client, Dan Stoicescu, was a former biotech entrepreneur who paid $350,000 to have his genome sequenced in 2008 so he could review it “like a stock portfolio” as new genetic discoveries unfolded⁴. About a year later, the company was auctioning off a genome, with such frills as a dinner with renowned Harvard genomics researcher George Church, at a starting price of $68,000; at the time, a full-genome sequence came at the price of $99,000, indicating that the cost of genome sequencing has been plummeting steadily.

Now, the company’s model is very different. “We stopped working with the ‘wealthy healthy’ in 2010,” says Jonas Lee, Knome’s chief marketing officer. “The model changed as sequencing changed.” The new emphasis, he says, is now on using Knome’s technology and technical expertise for genome interpretation. Knome’s customers are researchers, pharmaceutical companies and medical institutions, such as Johns Hopkins University School of Medicine in Baltimore, which in January signed the company up to interpret 1,000 genomes for a study of genetic variants underlying asthma in African American and African Caribbean populations.

Knome is trying to advance the clinical use of genomics, working with groups that “want to be prepared for what’s ahead,” Lee says. “We work with at least 50 academic institutions and 20 pharmaceutical companies looking at variants and drug response.” Cancer and idiopathic genetic diseases are the first sweet spots for genomic sequencing, he says. Although cancer genomics has been hot for a while, a recent string of discoveries of Mendelian diseases⁵ made by whole-genome sequencing has lit up that field, too. Lee is also confident, however, that “chronic diseases like heart disease are right behind those.” The company also provides software tools. The price for its KnomeDiscovery sequencing and analysis service starts at about $12,000 per sample–read the entire article here.

http://www.knome.com/knome-blog/direct-to-consumer-genomics-reinvents-itself/

Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves

VIEW VIDEO

http://www.colbertnation.com/the-colbert-report-videos/419824/october-04-2012/george-church

 

Knome Software Makes Sense of the Genome

The startup’s software takes raw genome data and creates a usable report for doctors.

• By Susan Young on June 12, 2012

DNA decoder: Knome’s software can tease out medically relevant changes in DNA that could disrupt individual gene function or even a whole molecular pathway, as is highlighted here—certain mutations in the BRCA2 gene, which affects the function of many other genes, can be associated with an increased risk of breast cancer.

A genome analysis company called Knome is introducing software that could help doctors and other medical professionals identify genetic variations within a patient’s genome that are linked to diseases or drug response. This new product, available for now only to select medical institutions, is a patient-focused spin on Knome’s existing products aimed at researchers and pharmaceutical companies. The Knome software turns a patient’s raw genome sequence into a medically relevant report on disease risks and drug metabolism. The software can be run within a clinic’s own network—rather than in the cloud, as is the case with some genome-interpretation services—which keeps the information private.

Advances in DNA sequencing technology have sharply reduced the amount of time and money required to identify all three billion base pairs of DNA in a person’s genome. But the use of genomic information for medical decisions is still limited because the process creates such large volumes of data. Less than five years ago, Knome, based in Cambridge, Massachusetts, made headlines by offering what seemed then like a low price—$350,000—for a genome sequencing and profiling package. The same service now costs just a few thousand dollars.

Today, genome profiling has two main uses in the clinic. It’s part of the search for the cause of rare genetic diseases, and it generates tumor-specific profiles to help doctors discover the weaknesses of a patient’s particular cancer. But within a few years, the technique could move beyond rare diseases and cancer. The information gleaned from a patient’s genome could explain the origin of specific disease, could help save costs by allowing doctors to pretreat future diseases, or could improve the effectiveness and safety of medications by allowing doctors to prescribe drugs that are tuned to a person’s ability to metabolize drugs.

But teasing out the relevant genetic information from a patient’s genome is not trivial. To find the particular genetic variant that causes a specific disease or drug response can require expertise from many disciplines—from genetics to statistics to software engineering—and a lot of time. In any given patient’s genome, millions of places in that genome will differ from the standard of reference. The vast majority of these differences, or variants, will be unrelated to a patient’s medical condition, but determining that can take between 20 minutes and two hours for each variant, says Heidi Rehm, a clinical geneticist who directs the Laboratory for Molecular Medicine at Partners Healthcare Center for Personalized Genetic Medicine in Boston, and who will soon serve on the clinical advisory board of Knome. “If you scale that to … millions of variants, it becomes impossible.”

A software package like Knome’s can help whittle down the list based on factors such as disease type, the pattern of inheritance in a family, and the effects of given mutations on genes. Other companies have introduced Web- or cloud-based services to perform such an analysis, but Knome’s software suite can operate within a hospital’s network, which is critically important for privacy-concerned hospitals.

The greatest benefit of the widespread adoption of genomics in the clinic will come from the “clinical intelligence” doctors gain from networks of patient data, says Martin Tolar, CEO of Knome. Information about the association between certain genetic variants and disease or drug response could be anonymized—that is, no specific patient could be tied to the data—and shared among large hospital networks. Knome’s software will make it easy to share that kind of information, says Tolar.

“In the future, you could be in the situation where your physician will be able to pull the most appropriate information for your specific case that actually leads to recommendations about drugs and so forth,” he says.

http://www.technologyreview.com/news/428179/knome-software-makes-sense-of-the-genome/

An End-to-end Human Genome Interpretation System

The knoSYS™100 seamlessly integrates an interpretation application (knoSOFT) and informatics engine (kGAP) with a high-performance grid computer. Designed for whole genome, exome, and targeted NGS data, the knoSYS™100 helps labs quickly go “from reads to reports.”

 

---

Advanced Interpretation and Reporting Software

The knoSYS™100 ships with knoSOFT, an advanced application for managing sequence data through the informatics pipeline, filtering variants, running gene panels, classifying/interpreting variants, and reporting results.

knoSOFT has powerful and scalable multi-sample comparison features–capable of performing family studies, tumor/normal studies, and large case-control comparisons of hundreds of whole genomes.

Multiple simultaneous users (10) are supported, including technicians running sequence data through informatics pipeline, developers creating next-generation gene panels, geneticists researching causal variants, and production staff processing gene panels.

http://www.knome.com/knosys-100-overview/

Publications

View our collection of journal articles and genome research papers written by Knome employees, Knome board members, and other industry experts.

Publications by Knome employees and board members

21 Aug 2012

Discerning the Ancestry of European Americans in Genetic Association Studies

Co-authored by Dr. David Goldstein, Clinical and Scientific board member for Knome

Author summary: Genetic association studies analyze both phenotypes (such as disease status) and genotypes (at sites of DNA variation) of a given set of individuals. … more

20 Aug 2012

Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence

Co-authored by Dr. George Church and Dr. Heidi Rehm, Clinical and Scientific Board Members for Knome

Author summary: An individual’s genetic profile plays an important role in determining risk for disease and response to medical therapy. The development of technologies that facilitate rapid whole-genome sequencing will provide unprecedented power in the estimation of disease risk. Here we develop methods to characterize genetic determinants of disease risk and … more

20 Aug 2012

A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

Co-authored by Dr. David Goldstein, Clinical and Scientific board member for Knome

Author summary: Schizophrenia is a highly heritable disease. While the drugs commonly used to treat schizophrenia offer important relief from some symptoms, other symptoms are not well treated, and the drugs cause serious adverse effects in many individuals. This has fueled intense interest over the years in identifying genetic contributors to … more

20 Aug 2012

Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene

Co-authored by Dr. David Goldstein, Clinical and Scientific board member for Knome

Author summary: Metachondromatosis (MC) is an autosomal dominant condition characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests. MC exostoses may regress or even resolve over time, and short stature … more

19 Aug 2012

Exploring Concordance and Discordance for Return of Incidental Findings from Clinical Sequencing Co-authored by Dr. Heidi Rehm, Clinical and Scientific board member for Knome

Introduction: There is an increasing consensus that whole-exome sequencing (WES) and whole-genome sequencing (WGS) will continue to improve in accuracy and decline in price and that the use of these technologies will eventually become an integral part of clinical medicine.1–7 … more

Publications by industry experts and thought-leaders

22 Aug 2012

Rate of De Novo Mutations and the Importance of Father’s Age to Disease Risk

Augustine Kong, Michael L. Frigge, Gisli Masson, Soren Besenbacher, Patrick Sulem, Gisli Magnusson, Sigurjon A. Gudjonsson, Asgeir Sigurdsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Wendy S. W. Wong, Gunnar Sigurdsson, G. Bragi Walters, Stacy Steinberg, Hannes Helgason, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Agnar Helgason, Olafur Th. Magnusson, Unnur Thorsteinsdottir, & Kari Stefansson

Abstract: Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 … more

15 Aug 2012

Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer

Florian L. Muller, Simona Colla, Elisa Aquilanti, Veronica E. Manzo, Giannicola Genovese, Jaclyn Lee, Daniel Eisenson, Rujuta Narurkar, Pingna Deng, Luigi Nezi, Michelle A. Lee, Baoli Hu, Jian Hu, Ergun Sahin, Derrick Ong, Eliot Fletcher-Sananikone, Dennis Ho, Lawrence Kwong, Cameron Brennan, Y. Alan Wang, Lynda Chin, & Ronald A. DePinho

Abstract: Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally … more

1 Jul 2012

Structural Diversity and African Origin of the 17q21.31 Inversion Polymorphism

Karyn Meltz Steinberg, Francesca Antonacci, Peter H Sudmant, Jeffrey M Kidd, Catarina D Campbell, Laura Vives, Maika Malig, Laura Scheinfeldt, William Beggs, Muntaser Ibrahim, Godfrey Lema, Thomas B Nyambo, Sabah A Omar, Jean-Marie Bodo, Alain Froment, Michael P Donnelly, Kenneth K Kidd, Sarah A Tishkoff, & Evan E Eichler

Abstract: The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes … more

http://www.knome.com/publications/

knome’s Systems & Software

• • knoSYS™100
  • knoSOFT™
  • Specs

Knome blog

Technical specifications

Connections and communications

Two networks: 40-Gigabit Infiniband QDR via a Mellanox Switch for storage traffic and HP ProCurve switch for network traffic

High performance computing cluster

Four nodes, each node with two 8-core/16 thread, 2.4Ghz, 64 bit Intel® Xeon® E5-2660 processor with 20MB cache, 128GB of DDR3 ECC 1600 memory; 2x2TB SATA drives (7,200RPM)

Metadata server

2x2TB 3.5″ drives with 6GB/sec SATA, RAID 1 and 2x300GB SSD (RAID 1)

Object storage server

Lustre array: Two 12x4TB arrays of 12 3.5″ drives with 6GB/sec serial SATA channels, each OSS powered by a 6-core Intel Xeon 64-bit processor running at 20GHz with 32GB RAM.

96TB total, 64TB useable storage (redundancy for failure tolerance). Expandable 384TB total.

Data sources

Reference genome GRCh37 (HG19)

dbSNP, v137

Condel (SIFT and PolyPhen-2)

HPO

OMIM

Exome Variant server, with allelisms and allele frequencies

1000 Genomes, with allelisms and allele frequencies

Human Gene Mutation db (HGMD)

Phastcons 46, mammalian conservation

PhyloP

Input/output formats

Input formats: kGAP accepts Illumina FASTQ and VCF 4.1 files as inputs

Output formats: annotated VCF files

Electrical and operating requirements

Line voltage: 110V to 120V AC, 200-240V (single phase)

Frequency: 50Hz to 60Hz

Current: 30A, RoSH compliant

Connection: NEMA L5-30

Operating temperature: 50° to 95° F

UPS included

Maximum operating altitude: 10,000 feet

Power consumption: 2,800 VA (peak)

Size and weight

Height	49.2 Inches (1250 mm)
Width	30.7 Inches (780 mm)
Depth	47.6 Inches (1210 mm)
Weight	394 lbs (179 kg)

Noise generation and heat dissipation

Enclosure provides 28dB of acoustic noise reduction; system suitable for placing in working lab environment

7200w of active heat dissipation

Included in the package

knoSYS™100 hardware

Knome software: knoSOFT, kGAP

Operating system: Linux (CentOS 6.3)

http://www.knome.com/knosys-100-specifications/

Our research services group uses a set of advanced software tools designed for whole genome and exome interpretation. These tools are also available to our clients through our knomeBASE informatics service. In addition to various scripts, libraries, and conversion utilities, these tools include knomeVARIANTS and knomePATHWAYS.

knomeVARIANTS

knome VARIANTS is a query kit that lets users search for candidate causal variants in studied genomes. It includes a query interface (see above), scripting libraries, and data conversion utilities.

Users select cases and controls, input a putative inheritance mode, and add sensible filter criteria (variant functional class, rarity/novelty, location in prior candidate regions, etc.) to automatically generate a sorted short-list of leading candidates. The application includes a SQL query interface to let users query the database as they wish, including by complex or novel sets of criteria.

In addition to querying, the application lets users export subsets of the database for viewing in MS Excel. Subsets can be output that target common research foci, including the following:

• Sites implicated in phenotypes, regardless of subject genotypes
• Sites where at least one studied genome mismatches the reference
• Sites where a particular set of one or more genomes, but no other genomes, show a novel variant
• Sites in phenotype-implicated genes
• Sites with nonsense, frameshift, splice-site, or read-through variants, relative to reference
• Sites where some but not all subject genome were called

knomePATHWAYS

knomePATHWAYS is a visualization tool that overlays variants found in each sample genome onto known gene interaction networks in order to help spot functional interactions between variants in distinct genes, and pathways enriched for variants in cases versus controls, differential drug responder groups, etc.

knomePATHWAYS integrates reference data from many sources, including GO, HPRD, and MsigDB (which includes KEGG and Reactome data). The application is particularly helpful in addressing higher-order questions, such as finding candidate genes and protein pathways, that are not readily addressed from tabular annotation data alone.

http://www.knome.com/interpretation-toolkit/

Genome-Phenome Analyzer by SimulConsult

A Simultaneous Consult On Your Patient’s Diagnosis

Clinicians can get a “simultaneous consult” about their patient’s diagnosis using SimulConsult’s diagnostic decision support software.

Using the free “phenome” version, medical professionals can enter patient findings into the software and get an initial differential diagnosis and suggestions about other useful findings, including tests.  The database used by the software has > 4,000 diagnoses, most complete for genetics and neurology.  It includes all genes in GeneTests and all diseases in GeneReviews.  The information about diseases is entered by clinicians, referenced to the literature and peer-reviewed by experts.  The software takes into account pertinent negatives, temporal information, and cost of tests, information ignored in other diagnostic approaches.  It transforms medical diagnosis by lowering costs, reducing errors and eliminating the medical diagnostic odysseys experienced by far too many patients and their families.

http://www.simulconsult.com/index.html

Using the “genome-phenome analyzer” version, a lab can combine a genome variant table with the phenotypic data entered by the referring clinician, thereby using the full power of genome + phenome to arrive at a diagnosis in seconds.  An innovative measure of pertinence of genes focuses attention on the genes accounting for the clinical picture, even if more than one gene is involved.  The referring clinician can use the results in the free phenome version of the software, for example adding information from confirmatory tests or adding new findings that develop over time.  For details, click here.

http://www.simulconsult.com/genome/index.html

Michael M. Segal MD, PhD, Founder,Chairman and Chief Scientist.  Dr. Segal did his undergraduate work at Harvard and his MD and PhD at Columbia, where his thesis project outlined rules for the types of chemical synapses that will form in a nervous system.  After his residency in pediatric neurology at Columbia, he moved to Harvard Medical School, where he joined the faculty and developed the microisland system for studying small numbers of brain neurons in culture.  Using this system, he developed a simplified model of epilepsy, work that won him national and international young investigator awards, and set the stage for later work on the molecular mechanism of attention deficit disorder.  Dr. Segal has a long history of interest in computers, and patterned the SimulConsult software after the way that experienced clinicians actually think about diagnosis.  He is on the Electronic Communication Committee of the Child Neurology Society and the Scientific Program Committee of the American Medical Informatics Association.

http://www.simulconsult.com/company/management.html

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