Technion Quantitative Biology Student Journal Club

UPCOMING: February 12, 2012 Synthetic Biology presented by Elad

2012-02-10T10:15:00.004+02:00

When: February 12, 2012 12:00
Where: Physics 377
Presenter: Elad Stolovicki (Erez Braun's group, physics)
Link to paper: http://www.sciencemag.org/content/333/6047/1307.abstract

Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells

Zhen Xie, Liliana Wroblewska, Laura Prochazka, Ron Weiss, Yaakov Benenson

Engineered biological systems that integrate multi-input sensing, sophisticated information processing, and precisely regulated actuation in living cells could be useful in a variety of applications. For example, anticancer therapies could be engineered to detect and respond to complex cellular conditions in individual cells with high specificity. Here, we show a scalable transcriptional/posttranscriptional synthetic regulatory circuit—a cell-type “classifier”—that senses expression levels of a customizable set of endogenous microRNAs and triggers a cellular response only if the expression levels match a predetermined profile of interest. We demonstrate that a HeLa cancer cell classifier selectively identifies HeLa cells and triggers apoptosis without affecting non-HeLa cell types. This approach also provides a general platform for programmed responses to other complex cell states.

January 22, 2012 Evolution of increased complexity in a molecular machine presented by Lindsay

2012-01-18T11:48:00.002+02:00

When: January 22, 2012 12:00
Where: Physics 377
Presenter: Lindsay Moore (Erez Braun's group, physics)
Link to paper: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10724.html#/affil-auth

Evolution of increased complexity in a molecular machine

Gregory C. Finnigan,
Victor Hanson-Smith,
Tom H. Stevens
& Joseph W. Thornton

Many cellular processes are carried out by molecular ‘machines’—assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine—the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump—increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes.

January 1, 2012 The Evolution of Overconfidence presented by Daniel

2011-12-28T13:49:00.001+02:00

When: January 1, 2012 12:00
Where: Physics 377
Presenter: Daniel Soudry (Electrical Engineering)
Link to paper: http://www.nature.com/nature/journal/v477/n7364/full/nature10384.html

The evolution of overconfidence

Dominic D. P. Johnson
& James H. Fowler

Confidence is an essential ingredient of success in a wide range of domains ranging from job performance and mental health to sports, business and combat. Some authors have suggested that not just confidence but overconfidence—believing you are better than you are in reality—is advantageous because it serves to increase ambition, morale, resolve, persistence or the credibility of bluffing, generating a self-fulfilling prophecy in which exaggerated confidence actually increases the probability of success. However, overconfidence also leads to faulty assessments, unrealistic expectations and hazardous decisions, so it remains a puzzle how such a false belief could evolve or remain stable in a population of competing strategies that include accurate, unbiased beliefs. Here we present an evolutionary model showing that, counterintuitively, overconfidence maximizes individual fitness and populations tend to become overconfident, as long as benefits from contested resources are sufficiently large compared with the cost of competition. In contrast, unbiased strategies are only stable under limited conditions. The fact that overconfident populations are evolutionarily stable in a wide range of environments may help to explain why overconfidence remains prevalent today, even if it contributes to hubris, market bubbles, financial collapses, policy failures, disasters and costly wars.

December 11, 2011 Information Transduction Capacity of Noisy Biochemical Signaling Networks presented by Daniel

2011-12-09T06:27:00.001+02:00

When: December 11, 2011 12:00
Where: Physics 377
Presenter: Daniel Hexner (Dov Levine's group, physics)
Link to paper: http://www.sciencemag.org/content/334/6054/354.full

Information Transduction Capacity of Noisy Biochemical Signaling Networks

Raymond Cheong,
Alex Rhee,
Chiaochun Joanne Wang,
Ilya Nemenman,
Andre Levchenko

Molecular noise restricts the ability of an individual cell to resolve input signals of different strengths and gather information about the external environment. Transmitting information through complex signaling networks with redundancies can overcome this limitation. We developed an integrative theoretical and experimental framework, based on the formalism of information theory, to quantitatively predict and measure the amount of information transduced by molecular and cellular networks. Analyzing tumor necrosis factor (TNF) signaling revealed that individual TNF signaling pathways transduce information sufficient for accurate binary decisions, and an upstream bottleneck limits the information gained via multiple integrated pathways. Negative feedback to this bottleneck could both alleviate and enhance its limiting effect, despite decreasing noise. Bottlenecks likewise constrain information attained by networks signaling through multiple genes or cells.

November 27, 2011 Min Oscillations In Vitro presented by Lindsay

2011-11-25T17:44:00.001+02:00

When: November 27, 2011 12:00
Where: Physics 377
Presenter: Lindsay Moore (Erez Braun's group, physics)
Link to paper: http://www.sciencemag.org/content/320/5877/789.full.pdf

Spatial Regulators for Bacterial Cell Division Self-Organize into Surface Waves in Vitro

Martin Loose,
Elisabeth Fischer-Friedrich,
Jonas Ries,
Karsten Kruse, and
Petra Schwille

Biotechnologisches Zentrum der Technischen Universität Dresden, Tatzberg 47-51, 01307 Dresden, Germany.

Max-Planck-Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.

Max-Planck-Institut für Physik komplexer Systeme, Nöthnitzer Strasse 38, 01187 Dresden, Germany.

Theoretische Physik, Universität des Saarlandes, Postfach 151150, 66041 Saarbrücken, Germany.

In the bacterium Escherichia coli, the Min proteins oscillate between the cell poles to select the cell center as division site. This dynamic pattern has been proposed to arise by self-organization of these proteins, and several models have suggested a reaction-diffusion type mechanism. Here, we found that the Min proteins spontaneously formed planar surface waves on a flat membrane in vitro. The formation and maintenance of these patterns, which extended for hundreds of micrometers, required adenosine 5′-triphosphate (ATP), and they persisted for hours. We present a reaction-diffusion model of the MinD and MinE dynamics that accounts for our experimental observations and also captures the in vivo oscillations.

November 13, 2011 - Intrinsic vs. Extrinsic Fluctuations in Protein Number presented by Yuval

2011-11-06T19:00:00.000+02:00

When: November 13, 2011 12:00
Where: Physics 377
Presenter: Yuval Elhanati (Naama Brenner's group, physics)
Link to paper: http://www.pnas.org/content/early/2011/06/30/1018832108.full.pdf+html

Separating intrinsic from extrinsic fluctuations in dynamic biological systems
Andreas Hilfinger and Johan Paulsson

Department of Systems Biology, Harvard University, 200 Longwood Avenue, Boston, MA 02115

From molecules in cells to organisms in ecosystems, biological populations fluctuate due to the intrinsic randomness of individual events and the extrinsic influence of changing environments. The combined effect is often too complex for effective analysis, and many studies therefore make simplifying assumptions, for example ignoring either intrinsic or extrinsic effects to reduce the number of model assumptions. Here we mathematically demonstrate how two identical and independent reporters embedded in a shared fluctuating environment can be used to identify intrinsic and extrinsic noise terms, but also how these contributions are qualitatively and quantitatively different from what has been previously reported. Furthermore, we show for which classes of biological systems the noise contributions identified by dual-reporter methods correspond to the noise contributions predicted by correct stochastic models of either intrinsic or extrinsic mechanisms. We find that for broad classes of systems, the extrinsic noise from the dual-reporter method can be rigorously analyzed using models that ignore intrinsic stochasticity. In contrast, the intrinsic noise can be rigorously analyzed using models that ignore extrinsic stochasticity only under very special conditions that rarely hold in biology. Testing whether the conditions are met is rarely possible and the dual-reporter method may thus produce flawed conclusions about the properties of the system, particularly about the intrinsic noise. Our results contribute toward establishing a rigorous framework to analyze dynamically fluctuating biological systems.

October 30, 2011 - mRNA vs Protein Abundance presented by Lindsay

2011-10-25T11:53:00.004+02:00

When: October 30, 2011 12:00
Where: Physics 377
Presenter: Lindsay Moore (Erez Braun lab, physics)
Link to paper: http://www.nature.com/nature/journal/v473/n7347/full/nature10098.html

Global quantification of mammalian gene expression control

Björn Schwanhäusser,

Dorothea Busse,

Na Li,

Gunnar Dittmar,

Johannes Schuchhardt,

Jana Wolf,

Wei Chen

& Matthias Selbach

Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13092 Berlin, Germany

Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here we simultaneously measured absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling for more than 5,000 genes in mammalian cells. Whereas mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Using a quantitative model we have obtained the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stability shared functional properties, indicating that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression provides a rich resource and helps to provide a greater understanding of the underlying design principles.

August 21, 2011 - A Quadruplet-Decoding Ribosome presented by Jorge

2011-10-25T11:48:00.004+02:00

When: August 21, 2011 12:00
Where: Physics 377
Presenter: Jorge Verdin Ramos (Benjamin Podbilewicz lab, biology)
Link to paper: http://www.nature.com/nature/journal/v464/n7287/full/nature08817.html

Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome

Heinz Neumann, Kaihang Wang, Lloyd Davis, Maria Garcia-Alai & Jason W. Chin
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge

The in vivo, genetically programmed incorporation of designer amino acids allows the properties of proteins to be tailored with molecular precision¹. The Methanococcus jannaschii tyrosyl-transfer-RNA synthetase–tRNA_CUA (MjTyrRS–tRNA_CUA)^2,³ and the Methanosarcina barkeri pyrrolysyl-tRNA synthetase–tRNA_CUA (MbPylRS–tRNA_CUA)^4,^5,⁶orthogonal pairs have been evolved to incorporate a range of unnatural amino acids in response to the amber codon in Escherichia coli^1,^6,⁷. However, the potential of synthetic genetic code expansion is generally limited to the low efficiency incorporation of a single type of unnatural amino acid at a time, because every triplet codon in the universal genetic code is used in encoding the synthesis of the proteome. To encode efficiently many distinct unnatural amino acids into proteins we require blank codons and mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs that recognize unnatural amino acids and decode the new codons. Here we synthetically evolve an orthogonal ribosome^8,⁹ (ribo-Q1) that efficiently decodes a series of quadruplet codons and the amber codon, providing several blank codons on an orthogonal messenger RNA, which it specifically translates⁸. By creating mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs and combining them with ribo-Q1 we direct the incorporation of distinct unnatural amino acids in response to two of the new blank codons on the orthogonal mRNA. Using this code, we genetically direct the formation of a specific, redox-insensitive, nanoscale protein cross-link by the bio-orthogonal cycloaddition of encoded azide- and alkyne-containing amino acids¹⁰. Because the synthetase–tRNA pairs used have been evolved to incorporate numerous unnatural amino acids^1,^6,⁷, it will be possible to encode more than 200 unnatural amino acid combinations using this approach. As ribo-Q1 independently decodes a series of quadruplet codons, this work provides foundational technologies for the encoded synthesis and synthetic evolution of unnatural polymers in cells.

August 7, 2011 - Phenotypic variability presented by Yuval

2011-10-25T11:39:00.004+02:00

When: August 7, 2011 12:00
Where: Physics 377
Presenter: Yuval Elhanati (Naama Brenner's group, physics)
Link to paper: http://www.pnas.org/content/104/48/18982

Phenotypic variability of growing cellular populations

Ting Lu,

Tongye Shen,

Matthew R. Bennett,

Peter G. Wolynes, and

Jeff Hasty

University of California at San Diego, La Jolla, CA 92093

The dynamics and diversity of proliferating cellular populations are governed by the interplay between the growth and death rates among the various phenotypes within a colony. In addition, epigenetic multistability can cause cells to spontaneously switch from one phenotype to another. By examining a generalized form of the relative variance of populations and classifying it into intracolony and cross-colony contributions, we study the origins and consequences of cellular population variability. We find that the variability can depend highly on the initial conditions and the constraints placed on the population by the growth environment. We construct a two-phenotype model system and examine, analytically and numerically, its time-dependent variability in both unbounded and population-limited growth environments. We find that in unbounded growth environments the overall variability is strictly governed by the initial conditions. In contrast, when the overall population is limited by the environment, the system eventually relaxes to a unique fixed point regardless of the initial conditions. However, the transient decay to the fixed point depends highly on initial conditions, and the time scale over which the variability decays can be very long, depending on the intrinsic time scales of the system. These results provide insights into the origins of population variability and suggest mechanisms in which variability can arise in commonly used experimental approaches.

July 17, 2011 - HIV-1 neutralizing antibodies presented by Ori

2011-10-25T11:32:00.002+02:00

When: July 17, 2011 12:00
Where: Physics 377
Presenter: Ori Avi-No'am (Benjamin Podbilewicz lab, biology)
Link to paper: http://www.sciencemag.org/content/329/5993/856.full

Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

Xueling Wu,

Zhi-Yong Yang,

Yuxing Li, ...

Peter D. Kwong, Gary J. Nabel and

John R. Mascola

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1–infected individuals, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of initial CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1–infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of glycoprotein 120, an important insight for future HIV-1 vaccine design.

July 4, 2011 - The Hydra Model presented by Elad

2011-10-25T11:08:00.001+02:00

When: July 4, 2011 12:00
Where: Physics 377
Presenter: Elad Stolovicki (Erez Braun's lab, physics)
Link to paper: http://www.sciencedirect.com/science/article/pii/S0962892410000991

The Hydra model: disclosing an apoptosis-driven generator of Wnt-based regeneration
Brigitte Galliot, Simona Chera
Department of Zoology and Animal Biology, Faculty of Sciences, University of Geneva

The Hydra model system is well suited for the eludication of the mechanisms underlying regeneration in the adult, and an understanding of the core mechanisms is likely to cast light on pathways conserved in other species. Recent detailed analyses of the activation of the Wnt–β-catenin pathway in bisected Hydra shows that the route taken to regenerate a structure as complex as the head varies dramatically according to the level of the amputation. When decapitation induces direct re-development due to Wnt3 signaling from epithelial cells, head regeneration after mid-gastric section relies first onWnt3 signaling from interstitial cells, that undergo apoptosis-induced compensatory proliferation, and subsequently on activation of Wnt3 signaling in theepithelial cells. The relative distribution between stem cells and head progenitor cells is strikingly different in these two contexts, indicating that the pre-amputation homeostatic conditions define and constrain the route that bridges wound-healing to the re-development program of the missing structure.

June 27, 2011 - Nuclear Actin presented by Lindsay

2011-10-25T10:30:00.000+02:00

When: June 27, 2011 10:30am
Where: Physics 377
Presenter: Lindsay Moore (Erez Braun's lab, physics)
Link to paper: http://genesdev.cshlp.org/content/25/9/946.full.pdf+html
background reading: http://cshperspectives.cshlp.org/content/2/4/a000620.long

Nuclear actin polymerization is required for transcriptional reprogramming of Oct4by oocytes

Kei Miyamoto,

Vincent Pasque,

Jerome Jullien and

John B. Gurdon

Wellcome Trust, Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom

Amphibian oocytes can rapidly and efficiently reprogram the transcription of transplanted somatic nuclei. To explore the factors and mechanisms involved, we focused on nuclear actin, an especially abundant component of the oocyte's nucleus (the germinal vesicle). The existence and significance of nuclear actin has long been debated. Here, we found that nuclear actin polymerization plays an essential part in the transcriptional reactivation of the pluripotency gene Oct4(also known as Pou5f1). We also found that an actin signaling protein, Toca-1, enhances Oct4 reactivation by regulating nuclear actin polymerization. Toca-1overexpression has an effect on the chromatin state of transplanted nuclei, including the enhanced binding of nuclear actin to gene regulatory regions. This is the first report showing that naturally stored actin in an oocyte nucleus helps transcriptional reprogramming in a polymerization-dependent manner.