May 30, 2008

Merck halts natural products research

Streptomyces cattleya, a microbe that produces thienamycinBad news: Merck has decided to close down its natural product research facilities. This means the end of CIBE (Centro de Investigación Básica de España) — or Spanish Center for Biological Research — located in Madrid, Spain. Since its creation in 1954, this center has been dedicated to the discovery of new compounds of therapeutical potential produced by microbes. These efforts led to the development of several useful medicines, including antibiotics (fosfomycin, cefoxitin, thienamycin), cholesterol-lowering drugs (lovastatin), and antifungal agents (caspofungin). In May 2006, Merck researchers hit the news with the discovery of platensimycin, a natural product belonging to a new class of antibiotics.

According to Chemical & Engineering News, the high costs are behind the decision to eliminate natural products research. Merck spokesman Ian R. McConnell explains to C&EN:

"The investment involved in finding these chemicals in the environment is significant. The products that came out of our effort have been significant as well, but that was over a 50-year period"
Sad, but true. Many thousands of natural samples need to be screened in order to detect a bunch of potentially useful compounds, most of which will never become a marketed drug. Turning a promising natural product into a useful medicine takes much effort and time (over 10 years) and, hence, money. So, perhaps it is understandable that most pharmaceutical companies dedicate only a very small fraction of their resources, if any, to natural product drug discovery.

However, even with that little dedication, many medicines in the market have a natural origin, being based in substances originally isolated from plants, microbes, etc. Can we imagine the possible results of investing in natural product research as many resources as those dedicated to chemical synthesis?

Natural compounds often have bizarre, complicated chemical structures and exert their biological effects through unexpected mechanisms. They are the result of an on-going combinatorial chemistry performed by organisms since the origin of life.

Are chemists that good?



Related links

A) About job cuts at Merck:
B) About CIBE:
C) About natural products in drug discovery:


Image credits:
Digital Atlas of Actinomycetes. Copyright: Society for Actinomycetes Japan. Contributor: S. Mochales. This strain produces β-lactam antibiotics, thienamycins. It has the color of cattleya orchids.

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May 29, 2008

EcoliHub: all together now


EcoliHub is a website sponsored by the U.S. National Institutes of Health, trying to bring together researchers interested in Escherichia coli with the most up-to-date information and data. From the EcoliHub site:

Sixty years of study have made Escherichia coli the most deeply understood organism at the molecular level. Much of what we know about cellular processes can be traced to fundamental discoveries in E. coli.
In spite of its great importance as a model organism, information about E. coli is distributed among many online resources. EcoliHub uses web services to make seamless bidirectional connections between E. coli resources, thereby enabling the full use of existing knowledge and supporting cutting-edge research into the molecular basis of life.

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May 26, 2008

Immune Atack, a video game

From the official Immune Attack website:

"The Federation of American Scientists (FAS) presents Immune Attack™, an educational video game that introduces basic concepts of human immunology to high school and entry-level college students. Designed as a supplemental learning tool, Immune Attack aims to excite students about the subject, while also illuminating general principles and detailed concepts of immunology."



(I can't help thinking of Fantastic Voyage...)

Related links:

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May 20, 2008

To sporulate or not to sporulate

Microscopic image of Bacillus subtilis, from Wikipedia When nutrients are scarce, Bacillus subtilis cells are able to form highly resistant endospores. However, even in a clonal population, only some cells engage in the sporulation process. This is explained in terms of a bet-hedging strategy: a mixed population composed of both vegetative cells and spores is prepared for a variety of unknown future environments. But how does an individual cell determine its own fate? In a recent report, J. W. Veening et al. showed that the decision (to sporulate or not to sporulate) is not taken by the cell itself ― it is determined a few generations earlier, and the command is inherited as a “memory”.

ResearchBlogging.orgBy making use of time-lapse microscopy, the authors followed the growth of individual cells and traced their history and lineage in microcolonies. Sporulation took place in two successive rounds, allowing a better use of resources. More surprising was the observation that the fate of many cells was already determined at the end of the exponential growth, long before any sporulation-related events could be detected.

B. subtilis microcolony development, from Figure 1 of PNAS article. Click for a larger view.To assess which determinants were responsible for the sporulation decision, Veening et al. initially analysed cell aging (a process previously reported for other bacteria such as Caulobacter crescentus and Escherichia coli). Although they demonstrated that B. subtilis indeed suffered aging during growth, no correlation was found between cell age and spore formation. The authors studied other cell cycle-related physiological parameters but could not identify any relationships to the sporulation decision.

Inheritance in the decision to sporulate, from Fig. 4 of PNAS articleNevertheless, spore formation did show certain lineage dependence ― i.e., families of cells were more likely to “agree” in their determination to become a spore or to stay as a vegetative cell. To visualize early events in the sporulation process, the authors examined recombinant B. subtilis strains that expressed green fluorescent protein (GFP) in response to active (phosphorylated) Spo0A. The latter protein is a key transcriptional regulator, directly responsible for the initiation of sporulation. In the reporter strains, GFP expression was highly lineage-dependent and could often be traced back for more than four generations. Therefore, the signal to activate Spo0A was apparently received from an ancestor, not as a message encoded in a DNA sequence but as an epigenetic inheritance. It is suggested that the sporulation signal is probably “memorized” by the autostimulatory architecture of the Spo0A regulatory cascade, which includes a number of kinases whose transcription is activated by phosphorylated Spo0A.

Epigenetic memory in bacteria can be a property of a genetic regulatory network (as in the reported example), but it can also be mediated by DNA methylation patterns. These mechanisms may play an important role in pathogenesis and the formation of socially organized structures such as biofilms and fruiting bodies.


Original article (open access):
Veening, J., Stewart, E.J., Berngruber, T.W., Taddei, F., Kuipers, O.P., Hamoen, L.W. (2008). Bet-hedging and epigenetic inheritance in bacterial cell development. Proceedings of the National Academy of Sciences USA, 105(11), 4393-4398. DOI: 10.1073/pnas.0700463105


Image sources:
First image from Wikipedia.
Second and third images from the PNAS original article (Copyright © 2008 by the National Academy of Sciences).

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May 19, 2008

Paul Ewald: Can we domesticate germs?

TED (Technology, Entertainment, Design) is a group of conferences that "brings together the world's most fascinating thinkers and doers, who are challenged to give the talk of their lives (in 18 minutes)." The following video corresponds to a talk by Paul Ewald, director of the program in Evolutionary Medicine at the Biology Department of the University of Louisville; he has written popular news articles, academic papers, and two books. In his conference, Ewald reasons that, for the control of infectious diseases, alternative strategies should be privileged over the never-ending development of more new drugs. The central idea consists of creating conditions that favor the less virulent variants of pathogenic microbes — in contrast to the present rise in drug-resistant strains due to the overuse of anti-infective medicines.



Link for the video at TED (filmed on March 2007): Paul Ewald: Can we domesticate germs?.
Or view it at YouTube.

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May 14, 2008

Neglected diseases in the news

Trypanosoma forms in blood smear from patient with African trypanosomiasisThe so-called neglected diseases comprise a number of parasitic and bacterial infections which are the most common afflictions of humankind. So, how can these diseases be "neglected"? When you get sick, you don't ignore your illness, do you? But we all can ignore a disease... as long as we ourselves don't suffer it.

Neglected diseases are especially endemic in low-income populations in developing regions of Africa, Asia, and the Americas. They mostly affect the poorest people, living in remote rural areas, urban slums or conflict zones. In the meantime, the rest of humankind just "neglect" those pains, as exemplified by the poor coverage on news media.

(If you already know about these diseases, just jump to the paragraph starting with "An interesting study...")

According to the Global Network For Neglected Tropical Disease Control, the most prevalent neglected tropical diseases are:



























DiseaseCausative agents
Affected people
Soil-transmitted helminthiasesSeveral nematodes: roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), hookworms (Ancylostoma duodenale, Necator americanus)Over 2 billion infected; over 70,000 deaths/year
Lymphatic filariasis (elephantiasis)Several nematodes: Wuchereria bancrofti, Brugia malayi, B. timoriOver 120 million infected; 40 million with clinical symptoms
River blindness (onchocerciasis)A nematode (Onchocerca volvulus)37 million infected; 500,000 visually impaired; 270,000 blind
Schistosomiasis (bilharzia)Several flukes (trematodes) of the Schistosoma genus200 million infected; over 200,000 deaths/year
TrachomaA bacterium (Chlamydia trachomatis)84 million infected; 8 million visually impaired or irreversibly blind



But, unfortunately, the list of neglected diseases is much longer, including:
[disease name, causative agent]

Wow, if you are still reading this, you must be really interested. Or you've just jumped over all those boring, unpronounceable words. That's OK. But the title of the post said "in the news", so let's go.


ResearchBlogging.orgAn interesting study has just been published on the open-access journal PLoS Neglected Tropical Diseases, showing that these diseases rarely make the headlines... Oh, wait, we already knew that. True —but this report seems to be the first one trying to analyze, in a quantitative manner, the international media coverage of neglected diseases, as a support for future advocacy work.

The authors searched the archives of 11 English-language media, from January 2003 to June 2007, including 6 newspapers (The New York Times, Los Angeles Times, Washington Post, The Guardian, The Daily Telegraph, The Financial Times), BBC Online, CNN.com, Agence France Presse (AFP), and two news magazines (Time and The Economist). They analyzed coverage of "neglected diseases" in general, with a focus on African trypanosomiasis, leishmaniasis and Chagas' disease (probably not the most neglected). The researchers also interviewed leading health journalists, highlighting factors influencing reporting.

During the study period, they found only 113 articles on neglected diseases. In comparison, there were over 1000 articles on HIV/AIDS in the AFP database alone during the same period. There was wide disparity in coverage between the various media: the BBC had the highest coverage (20 articles), while CNN had the least coverage (only 1 article). Coverage of global health issues was particularly poor in the American media.

As the authors recognize, it would be useful to expand the analysis, including more international media and languages other than English. However, the selected media may be considered a useful sample, and some patterns emerged:
" For example, the penchant for a local angle was even parochial at times. Stories get written about leishmaniasis in pets before humans, as was seen in The Daily Telegraph. "
In the interviews, journalists explained that the main obstacles for reporting on these issues were: a lack of real news development, the drive to cater to domestic audiences, and competing health interests.
" “Poor people dying from an illness is not news,” unless there is some change or development, one producer from an international broadcaster said. But HIV/AIDS was widely reported on “because it sells stories” and has the funding and attention of policymakers. "
That's perfectly understandable: news media need to make a living, and only "newsworthy" stories get the attention. Here, the role of health agencies (either public or private) is essential: all journalists said health agencies were not communicating adequately about the burden of neglected tropical diseases. Some organizations (World Health Organization, Bill & Melinda Gates Foundation) were criticized for the difficulty in reaching officials for comment, while non-governmental organizations such as Médecins Sans Frontières (MSF) were cited as good sources for stories.

News coverage was also difficult due to the lack of powerful "human" stories from the field (including interviews with patients).
" The “human element” was powerful, but few journalists were able to get such stories first-hand from the field. This represented a real constraint for coverage. One communications advisor (consulting for DNDi) said health agencies needed to present stories featuring “real people” rather than “experts in their ivory towers” and the “yuck” factor about these diseases needed to be played up to “grab the public imagination” rather than facts about the lifecycle of the parasite. "
Remarkably, journalists who did cover these diseases were often personally motivated. Andrew Jack (Financial Times), who authored the largest number of articles detected in the study, said his reporting was “100%” driven by his interest.

In other words, a single individual can make a difference.


Original article (open access):
Balasegaram, M., Balasegaram, S., Malvy, D., Millet, P., Hotez, P.J. (2008). Neglected Diseases in the News: A Content Analysis of Recent International Media Coverage Focussing on Leishmaniasis and Trypanosomiasis. PLoS Neglected Tropical Diseases, 2(5), e234. DOI: 10.1371/journal.pntd.0000234



Related links:


Image credits:
Trypanosoma forms in blood smear from patient with African trypanosomiasis. Source: Public Health Image Library (PHIL). Content provider: CDC/Dr. Myron G. Schultz.

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May 9, 2008

Big bacteria with lots of DNA

Thiomargarita
Size matters.

That's why there are no insects as big as horses [*], or bacteria as large as to be seen without the use of a microscope. Well, actually, the latter is not true —although a typical bacterial cell is not longer than 5 micrometers, a few species such as Thiomargarita namibiensis (left image) and Epulopiscium fishelsoni may reach a length of over 0.5 millimeters (500 micrometers); enough to become visible to the naked eye.

Big bacteria enjoy some advantages; for instance, they can not be swallowed by most predators (such as ciliates) that feed on smaller cells. But they also face important problems, especially those related to diffusion limitation. In general, bacteria obtain their food molecules by diffusion; for this reason, their cells need to maintain a high surface-to-volume ratio. Thiomargarita solves this problem by creating a huge central vacuole that fills about 98% of the cell volume, leaving only a thin layer of cytoplasm lining the cell wall. However, Epulopiscium appears to have a low surface-to-volume ratio (despite the presence of many invaginations of its cell membrane). This anomaly might be partially explained by the fact that Epulopiscium lives in the gut of a tropical fish, presumably a very rich medium (that is, a high concentration of nutrients may compensate their poor diffusion into a big cell). Additionally, this bacterium has some peculiarities that may be related to this issue: it reproduces by forming internal daughter cells (see figure below), and most of its DNA is arranged around the periphery of the cytoplasm.

Life cycle of Epulopiscium
ResearchBlogging.orgRemarkably, a recent article published on PNAS reports that each Epulopiscium cell has tens of thousands of copies of the genome. Because so far nobody has been able to culture Epulopiscium, the authors had to collect some tropical fishes (Naso tonganus, a unicorn fish) on reefs around Lizard Island, Australia. Then, they extracted the intestinal contents, and handpicked thousands of individual Epulopiscium cells with the aid of a microscope and a micropipettor (an automated device for pipetting microliter volumes). Finally, the researchers used quantitative PCR (Polymerase Chain Reaction) to enumerate the copy number of certain genes on individual cells and in DNA obtained from populations of cells. Epulopiscium large cells contained about 250 picograms (pg) of DNA (compare to 6 pg of DNA in a human diploid cell!), corresponding to several tens of thousands of copies of a ≈3.8 megabase genome.

Such an extraordinarily high number of genome copies per cell could be related to Epulopiscium evolution in a number of interesting ways. Given the biased distribution of DNA within the cytoplasm, these big cells might possess a functional compartmentalization. In the authors' words:

"In this way, a large bacterium could function like a microcolony, with different regions of the cell independently responding to local stimuli, which would alleviate some of the pressure to remain small for the sake of rapid intracellular diffusive transport."
The article ends with:
"The enormous, polyploid Epulopiscium cell has converged on the advantages of social microbes but with additional benefits (exceptional motility, enhanced resistance to predation) normally found in large eukaryotic microbes or multicellular organisms."
Epulopiscium: another fascinating microbe!


Original article:
Mendell, J.E., Clements, K.D., Choat, J.H., Angert, E.R. (2008). Extreme polyploidy in a large bacterium. Proceedings of the National Academy of Sciences USA, 105(18), 6730-6734. DOI: 10.1073/pnas.0707522105


Related links:

[*] Giant insects might reign if only there was more oxygen in the air, EurekAlert.


+++++++++++++++++++++++++++++++++++++++++++++++++++++++
Etymology of species names:

Epulopiscium
= “guest at a fish's banquet”
(Latin epulo [sumptuous food, banquet] + piscium [of a fish])

fishelsoni
= "of Fishelson"
(in honor of Lev Fishelson [Tel Aviv University, Israel], one of the discoverers of Epulopiscium)

Thiomargarita
= "sulfur pearl"
(Greek thio [sulfur] + margarita [pearl])

namibiensis
= "from Namibia"

(Please correct me if I'm wrong)
+++++++++++++++++++++++++++++++++++++++++++++++++++++++


Image sources:
Thiomargarita, at the cover of Science (April 16, 1999). The photomicrograph shows three cells under polarized light (middle cell is ~0.2 mm in diameter), and the small yellow spheres are sulfur globules that are restricted to the thin outer layer of the cell. Image: Ferran Garcia-Pichel.
● Life cycle of Epulopiscium. Reprinted by permission from Macmillan Publishers Ltd: Nature Rev. Microbiol. 3, 214-224 (2005). Copyright 2005.

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May 5, 2008

Charlton Heston: the connection

Charlton Heston in The Ten CommandmentsNow I am explaining the connection between Charlton Heston and actinomycetes. It is indeed a very simple link, as you will see.

As a boy, Charlton Heston was not Charlton Heston —not yet— but John Charles Heston and, under this name, he attended New Trier High School at Winnetka, a northern suburb of Chicago. There he might have met some students who later became famous, such as actor Rock Hudson (then still known as Roy Harold Scherer, Jr. [*]) and Nobel laureate Jack Steinberg (a physicist, donated his Nobel medal to New Trier High School). However, perhaps the three boys never met, because of their differences in age: Heston was born in 1923, "future Hudson" in 1925, and Steinberg in 1921. You know, two years may be seen as a generational barrier by teenagers, even (or especially) if attending the same school.
Rock Hudson and Jack Steinberger attended New Trier High SchoolHave a look at the New Trier High School's logo: it shows the Porta Nigra (Black Gate) built by the Romans around 180-200 AD in Augusta Treverorum —now Trier, Germany. The reason is that Winnetka is one of the villages in the New Trier Township, Illinois; the township was established in 1850, and its name was most likely chosen by a German settler. Trier claims to be the oldest city in Germany, founded in or before 16 BC. In addition to possessing a remarkable set of Roman and medieval buildings, Trier is known as the birthplace of philosopher Karl Marx (1818-1883).

But... am I digressing? Then, I will finish the explanation in a new post.


Image sources:
Heston as Moses in The Ten Commandments: Wikipedia.
Hudson, New Trier Highschool's logo, and Steinberger: Wikipedia (1, 2, 3).

[*] The name "Rock Hudson" is a combination of the Rock of Gibraltar and the Hudson River (!)


Clipart from Clipartheaven.comA year has passed since my first post on this blog.
Happy birthday, Twisted Bacteria!

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Creative Commons License Except where otherwise noted, blog posts by Cesar Sanchez in Twisted Bacteria are licensed under a Creative Commons Attribution 3.0 Unported License. Please let me know if any quotes or images on this blog are improperly credited. E-mail: TwistedBacteria AT gmail DOT com . Social media icons by Oliver Twardowski and AddThis.