Cure for Clostridium

A News Focus article in Science describes a procedure used to treat intestinal bacterial infections by flushing the colon and transferring stool containing healthy bacterial flora from a donor into the patient. The story recounted goes as follows. An 81-year-old woman was seriously ill from an intestinal bacterial infection. She was treated with the antibiotic vancamycin, but antibiotic resistant bacteria developed. Her physician, Max Nieuwdorp at the Academic Medical Center in Amsterdam, didn't give up and searched PubMed. He found a paper from 1958 in the journal Surgery by Ben Eisenman of the University of Colorado, Denver. In that paper, Eisenman described an anal infusion of liquidized stool in patients suffering from an intestinal malady called pseudomembranous enterocolitis; the infusion cured them of the disease. So Nieuwdorp decided to flush the woman's colon out and replaced it with healthy bacterial flora by transferring a saline solution containing her son's feces into her intestine. She got better.

Nieuwdorp and co-workers went on to successfully repeat this fecal transplant procedure in other patients, publishing their results in January of 2013 in the New England Journal of Medicine. Other physicians have independently discovered and applied this procedure to patients, two notable pioneers being Thomas Borody and Lawrence Brandt of the Montefiore Medical Center in New York City. It is now an established mode of treatment and is known as fecal bacteriotherapy (or fecal microbiota transplantation or stool transfer) and has promise for the treatment of other diseases as well. Despite the initial yuck factor, a doctor near you may recommend that you undergo this treatment one day. It's even going DIY.

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Science 30 August 2013: 
Vol. 341 no. 6149 pp. 954-957 
DOI: 10.1126/science.341.6149.954

NEWS FOCUS

MEDICAL RESEARCH

The Promise of Poop

1. Jop de Vrieze*

A controlled clinical trial published in January 2013 has shown that fecal transplants can help cure recurrent infections with Clostridium difficile. Researchers think patients with other diseases, too, may benefit from the procedure, but much more study is needed. Meanwhile, scientists are trying to understand the underlying mechanisms and hoping that, in the future, they will be able to transplant selected bacterial strains instead of human stool.

Bacteria Grow Rather Efficiently

Things that live and grow must, like all things, obey the laws of physics, including the Second Law of Thermodynamics, even if living organisms appear highly ordered. In closed systems (ones that are isolated from their surroundings), the degree of disorder (entropy) always increases until they reach thermodynamic equilibrium, at which point entropy change becomes zero. Similarly, the total entropy of the universe is always increasing. A living organism is not a closed system but an open one, since it exchanges energy with its surroundings. If the entropy of an open system is decreasing, then it must increase the entropy of its surroundings by an even greater degree so that the total entropy of the universe increases.

Living organisms increase the entropy of their surroundings over the course of their lives by generating heat (largely through the controlled burning - or oxidation - of glucose, which produces carbon dioxide and heat). The localized decrease in entropy that occurs during biosynthesis is compensated for by the greater increase in entropy of the universe that results from the production of heat through catabolic metabolism. This raises the following question. How much heat must an organism produce in order to live and grow and how does this compare to the minimum that would be required to obey the Second Law of Thermodynamics?

Jeremy L. England addresses this question in a paper in the Journal of Chemical Physics. It turns out that bacterium Escherichia coli produces only about six times the amount of heat than the minimum required to live and divide in accordance with with the Second Law of Thermodynamics. This implies a high though not maximal degree of efficiency, since the experimental value (previously determined by others and not the author of this particular article) is within an order of magnitude of the minimum value calculated by the author of this paper. So E. coli are substantially but not perfectly optimized for efficient growth.

It is possible that, even though E. coli evolved to grow rapidly when the conditions were good, all life requires at least some amount of "waste" for the sake of robustness. Having some excess energetic capacity allows for mobilization of resources needed for appropriate responses when environmental conditions change, even if that capacity is not needed under ideal conditions.

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J. Chem. Phys. 139, 121923 (2013); http://dx.doi.org/10.1063/1.4818538 (8 pages)

Statistical physics of self-replication

Jeremy L. England

Department of Physics, Massachusetts Institute of Technology, Building 6C, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA 

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(Received 28 April 2013; accepted 1 August 2013; published online 21 August 2013)

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• Abstract
• References (27)

Self-replication is a capacity common to every species of living thing, and simple physical intuition dictates that such a process must invariably be fueled by the production of entropy. Here, we undertake to make this intuition rigorous and quantitative by deriving a lower bound for the amount of heat that is produced during a process of self-replication in a system coupled to a thermal bath. We find that the minimum value for the physically allowed rate of heat production is determined by the growth rate, internal entropy, and durability of the replicator, and we discuss the implications of this finding for bacterial cell division, as well as for the pre-biotic emergence of self-replicating nucleic acids.

Journal of Chemical Physics Article

Empathy

Empathy for familiar friends appears to be hardwired into our brains, according to a recent MRI study by Lane Beckes, James A. Coan and Karen Hasselmo published in the journal Social Cognitive and Affective Neuroscience. The regions of the brain responsible for threat response become active when faced with the threat of harm to friends just as with a threat to ourselves, while there is virtually no response to a threat to a stranger. Sticking with the empathy theme, it seems we have more empathy for victims of abuse when they are puppies, full-grown dogs and human infants than adult humans, according to a recent presentation by Jack Levin and Arnold Arluke at the annual meeting of the American Sociological Association. Levin says that age is the most important determinant of the level of empathy people feel, with adult dogs perhaps viewed as just large puppies that are still dependent and need protection. He speculates that battered cats might also elicit a high level of empathy. All of this does not bode well for world peace, unless we can train our brains to view strangers as cats and dogs.

Article in Social Cognitive and Affective Neuroscience

Program for 2013 meeting of the American Sociological Association

Review on Tissue Mechanics, Cell Signaling and Transcriptional Regulation

Apropos of a recent post, here is a review article that summarizes recent work on the control of signaling cascades and transcriptional programs by the mechanical forces; in this way, changes in the mechanical environment of cells and tissues can result in a range of normal and pathological cellular responses.

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Differentiation. 2013 Aug 20. pii: S0301-4681(13)00061-3. doi: 10.1016/j.diff.2013.07.004. [Epub ahead of print]

From tissue mechanics to transcription factors.

Janmey PA, Wells RG, Assoian RK, McCulloch CA.

Source

Departments of Physiology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: janmey@mail.med.upenn.edu.

Abstract

Changes in tissue stiffness are frequently associated with diseases such as cancer, fibrosis, and atherosclerosis. Several recent studies suggest that, in addition to resulting from pathology, mechanical changes may play a role akin to soluble factors in causing the progression of disease, and similar mechanical control might be essential for normal tissue development and homeostasis. Many cell types alter their structure and function in response to exogenous forces or as a function of the mechanical properties of the materials to which they adhere. This review summarizes recent progress in identifying intracellular signaling pathways, and especially transcriptional programs, that are differentially activated when cells adhere to materials with different mechanical properties or when they are subject to tension arising from external forces. Several cytoplasmic or cytoskeletal signaling pathways involving small GTPases, focal adhesion kinase and transforming growth factor beta as well as the transcriptional regulators MRTF-A, NFκB, and Yap/Taz have emerged as important mediators of mechanical signaling.

© 2013 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Mechanical stress, Mechanosensing, Mechanotransduction, Substrate stiffness

Differentiation Article

Visiting Assistant Professorships: Ladder or Dead End?

This question is pondered over at Chemistry Reflux.

http://chemreflux.blogspot.com/2013/08/vaps-ladder-or-dead-end.html

Mechanical Forces Regulate Signaling Proteins via Actin-Processing Factors to Control Cell Growth

Here is another good paper that shows how extracellular physical forces influence intracellular biochemistry and elicit cellular responses like proliferation. This is a growth area in cell biology.

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A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors

Cell, 15 August 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.07.042

Authors

Mariaceleste Aragona,Tito Panciera,Andrea Manfrin,Stefano Giulitti,Federica Michielin,Nicola Elvassore,Sirio Dupont,Stefano PiccoloSee Affiliations

Highlights

• Tissue form shapes epithelial growth pattern by YAP/TAZ regulation
• A mechanical checkpoint controls contact inhibition of proliferation
• F-actin-capping/severing proteins are epithelial gatekeepers limiting YAP/TAZ activity
• Mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts

Summary

Key cellular decisions, such as proliferation or growth arrest, typically occur at spatially defined locations within tissues. Loss of this spatial control is a hallmark of many diseases, including cancer. Yet, how these patterns are established is incompletely understood. Here, we report that physical and architectural features of a multicellular sheet inform cells about their proliferative capacity through mechanical regulation of YAP and TAZ, known mediators of Hippo signaling and organ growth. YAP/TAZ activity is confined to cells exposed to mechanical stresses, such as stretching, location at edges/curvatures contouring an epithelial sheet, or stiffness of the surrounding extracellular matrix. We identify the F-actin-capping/severing proteins Cofilin, CapZ, and Gelsolin as essential gatekeepers that limit YAP/TAZ activity in cells experiencing low mechanical stresses, including contact inhibition of proliferation. We propose that mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts, setting responsiveness to Hippo, WNT, and GPCR signaling.

Cell Article

Romans Used Nanoparticules to Make Color-Changing Goblets

Those clever Romans: they used nanoparticles of silver and gold to make jade-green cups that turn red when lit from behind. Hat tip to Eric Ederer.

Smithsonian Article

New Chemistry Blog

My friend Shawn Burdette has a new chemistry blog. It's definitely worth a visit!

http://chemreflux.blogspot.com

Little Octopus Climbing Over Rock - Parry Gripp

Very cool...

Little Octopus Climbing Over Rock - Parry Gripp

"Do you think you're Mr. Spock?

The little octopus was filmed at the beach in Santa Barbara, California, just south of UCSB."

Neutrophil Chasing a Bacterium

This is a video of a crawling neutrophil, the most abundant white blood cell in the body, "chasing" and then engulfing a Staphylococcus aureus bacterium (from BioChemWeb.org).

New Species of Carnivorous Mammal Discovered in South America

Olinguito

A new carnivorous mammalian species, called the olinguito, has been discovered in South America. It's a relative of raccoons and lives in the cloud forests of the northern Andes. This is not our first brush with the olinguito. It seems it was misidentified in the past.

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"For all of modern history, a small, carnivorous South American mammal in the raccoon family has evaded the scientific community. Untold thousands of these red, furry creatures scampered through the trees of the Andean cloud forests, but they did so at night, hidden by dense fog. Nearly two dozen preserved samples—mostly skulls or furs— were mislabeled in museum collections across the United States. There’s even evidence that one individual lived in several American zoos during the 1960s—its keepers were mystified as to why it refused to breed with its peers." Smithsonian Article

"A fuzzy fog-dweller with a face like a teddy bear is the first carnivore found in the Western Hemisphere in more than three decades, a new study says.

The 2-pound (0.9-kilogram) creature, called an olinguito, didn't make itself easy to find. The orange-brown mammal lives out a solitary existence in the dense, hard-to-study cloud forests of Colombia and Ecuador, which inspired part of its Latin name Bassaricyon neblina: Neblina is Spanish for "fog."" National Geographic Article

Amazing Hungarian Flask-Containing-Red-Liquid-on-Your-Head Dance

Fascinating. It's the Amazing Hungarian Flask-Containing-Red-Liquid-on-Your-Head Dance.

YouTube Video

The Top Ten Cool Schools

The Sierra Club has ranked schools for how "cool" (i.e., "green") they are and the results are certainly cool.

The top ten ranking is:

1. University of Connecticut
2. Dickinson College
3. University of California, Irvine
4. University of California, Davis
5. Cornell University
6. Green Mountain College
7. Stanford University
8. Georgia Institute of Technology
9. American University
10. University of California, Santa Barbara

Sierra magazine

Neanderthals Made High-End Handbags

Neanderthal Bone Tools

I always suspected that Neanderthals were makers of luxury handbags.

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NATURE | NEWS

Neanderthals made leather-working tools like those in use today

Archaic humans may have invented bone implements still used to make expensive handbags.

• Ewen Callaway

12 August 2013

Excavations of Neanderthal sites more than 40,000 years old have uncovered a kind of tool that leather workers still use to make hides more lustrous and water resistant. The bone tools, known as lissoirs, had previously been associated only with modern humans. The latest finds indicate that Neanderthals and modern humans might have invented the tools independently.

Nature News

PNAS Article

Drug Target Validation Through "Experiments of Nature" in Humans

Here's a thought-provoking article on drug target validation through function-phenotype dose-response profiles in humans by mining naturally occurring mutations and evaluating their phenotypic manifestation.

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NATURE REVIEWS DRUG DISCOVERY | REVIEW

Validating therapeutic targets through human genetics

• Robert M. Plenge,
• Edward M. Scolnick
• & David Altshuler

• Affiliations
• Corresponding author

Nature Reviews Drug Discovery 12, 581–594 (2013) doi:10.1038/nrd4051
Published online 19 July 2013

More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' — naturally occurring mutations in humans that affect the activity of a particular protein target or targets — can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose–response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug–gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics.

Nature Review Drug Discovery Article

Common Male and Female Ancestors

It was thought that the most recent common paternal ancestor of contemporary humans lived considerably later than the most recent maternal ancestor. The male lineage is inferred from Y chromosome sequences (the Y chromosome of course, is passed on only to male descendants), while the female lineage is inferred from mitochondrial DNA sequences (mitochondrial DNA is passed on only through the mother since mitochondria in the offspring come from the mother's egg and not the father's sperm). Now two reports (Poznik et al., Francalacci et al.), through sequencing of Y chromosomes from many men, suggest that the most recent common male and female ancestors lived around the same time. Wow, what a relief! Still, they are very unlikely to have directly interbred and probably lived apart in time and space. Geneticists think that you can trace the Y chromosome and mitochondrial DNA to a single man and a single woman. This does not mean that they were the only breeding humans alive by any means; the rest of the genome was recombined and passed on through many more individuals. It simply means that the non-recombining Y chromosome and mitochondrial DNA of other individuals were lost over time in the relatively small breeding populations (in other words, since on average males have only one surviving male offspring, it is easy to imagine that in most cases the Y chromosome could be lost in a given lineage, unless a specific male has a lot of male offspring, and the same with the maternal mitochondrial DNA inheritance). So it's still no comfort to literal biblicists: "Adam" and "Eve" lived apart roughly 100,000 years ago (commentary in LiveScience and Nature). 

Caveat emptor, though, another report suggests an even older common male ancestor (Mendez et al.). Genealogy is messy business.

Your Brain on Meditation: Practice Makes Perfect

Judson Alyn Brewer of the Yale School of Medicine talks about the use of functional magnetic resonance imaging to study what happens in the brain during meditation.

YouTube Video

On Henrietta Lacks' Cells

Henrietta Lacks (1920–1951)

HeLa cells, derived from a tumor from a woman named Henriettta Lacks, were the first human cells to survive in culture. They became an intensely and widely studied cell line in the biological and biomedical sciences. Many important discoveries in human cell biology were made with this cell line. The case of Henrietta Lacks, who did not know her cells were cultured and propagated (neither did her family until later; this is something that now would be unacceptable), was resolved in unprecedented ways by NIH to the family's satisfaction (Nature article).

The case raises bioethical questions. What rights does a patient and their family have over the use of a cell line derived from a patients' tissue? Does the patient or his/her family have rights to some of the profits made from commercialization of discoveries made with these cells? Most importantly, what privacy rights does the family have over DNA sequence information derived from the cells' genome?

The solution going forward seems obvious. Consent and legally backed guarantees of anonymity and privacy with regards to genomic data (so nobody can trace the cells to a specific individual, unless that individual wishes it). That genomic data could be misused is a legitimate fear; for instance, if a genetic predisposition for a certain disease is made public this could be used, without proper laws and safeguards, to refuse health benefits to a person, etc. Consent, anonymity and legal safeguards are the only solution. In terms of the issue of whether a person would be entitled to profits gained from use of his/her cells: a resounding no. It would be ridiculous to attribute a discovery to the use of a cell line. The discovery was not the cell line but what was done with it, and any patents stemming from it would include many elements that are independent of that cell line in most cases. Moreover, the discovery that led to a patent would be the work of researchers and not the patient. So it would be not make any sense to award any part of the profits to the cell donor.

Nuclear Pore Scaffold Structure

Very interesting. Fluorescence microscopy combined with particle averaging to attain a precision below one nanometer; used to look at the organization of a macromolecular structure: the nuclear pore.

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Published Online July 11 2013Science 9 August 2013: 
Vol. 341 no. 6146 pp. 655-658 
DOI: 10.1126/science.1240672
REPORT

Nuclear Pore Scaffold Structure Analyzed by Super-Resolution Microscopy and Particle Averaging

1. Anna Szymborska¹, 
2. Alex de Marco², 
3. Nathalie Daigle¹, 
4. Volker C. Cordes³, 
5. John A. G. Briggs²,
6. Jan Ellenberg¹,*

+Author Affiliations

1. ¹Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
2. ²Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3. ³Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

1. ↵*Corresponding author. E-mail: jan.ellenberg@embl.de

• ABSTRACT
• EDITOR'S SUMMARY

Much of life’s essential molecular machinery consists of large protein assemblies that currently pose challenges for structure determination. A prominent example is the nuclear pore complex (NPC), for which the organization of its individual components remains unknown. By combining stochastic super-resolution microscopy, to directly resolve the ringlike structure of the NPC, with single particle averaging, to use information from thousands of pores, we determined the average positions of fluorescent molecular labels in the NPC with a precision well below 1 nanometer. Applying this approach systematically to the largest building block of the NPC, the Nup107-160 subcomplex, we assessed the structure of the NPC scaffold. Thus, light microscopy can be used to study the molecular organization of large protein complexes in situ in whole cells.

Science Article