Category Archives: Science Article

The latest hardware for biology

As part of the synbio revolution lab-as-a-service providers such as Transcriptic and Emerald cloud labs are popping up, enabling researchers to perform experiments remotely. On the other hand, locally deployed low-cost setups are also gaining ground. An example is a paper published last year in Nature Biotechnology by the Riedel-Kruse lab. The authors developed a microscope coupled to a small flow chamber to observe Euglena swimming around. Via a web interface LEDs that surround the flow chamber can be turned on, so you can actually remotely control the movement of the Euglena (as they like to move to the light). The whole setup only costs $1000 a year, so an low-cost and accessible option for the educational field. The project seems a follow-up on a previous educational device from the same group called the LudusScope, a Gameboy like smartphone microscope.

In 2015 the TU Delft iGEM team won the grand prize with their biolink 3D printer. Last month a write up of an improved version was published in ACS Synthetic Biology. Instead of building a 3D printer from K’nex (as the iGEM team did), this version is a modification of the CoLiDo DIY 3D printer. Structures can be build by dissolving bacteria together with alginate and depositing this ‘bioink’ on a buildplate containing calcium. The combination of alginate and calcium triggers a cross-linking process leading to solidification of the extruded mixture. Using the technology a 14-layer high structure (of around 2 mm) containing two different bacterial strains was printed in various shapes.

Bacterial 3D printing based on the modified CoLiDo DIY framework, right a close up of the extruder head. (Source: http://pubs.acs.org/doi/abs/10.1021/acssynbio.6b00395 CC-BY-NC-ND)

Bacterial 3D printing based on the modified CoLiDo DIY framework, right a close up of the extruder head. (Source: 10.1021/acssynbio.6b00395 CC-BY-NC-ND)

The Maerkl lab published a preprint on bioRxiv last month on a microfluidic biodisplay with 768 programmable biopixels. Of this biodisplay each individual compartment (or pixel) can be inoculated with a different strain. As a proof-of-concept the pixels were loaded with previously developed arsinicum sensing strains. The WHO states a maximum of 10 μg/L of arsenite in tap water, so water spiked with various amounts of arsine were flown over the biodisplay. After 10 hours a skull-and-cross-bones symbol is visible using a microscope when as little as 20 μg/L arsinite spiked water is flow over the biodisplay. As there is room for 768 different strains, this setup can actually be used to do some pretty powerful analysis.

Response of the biodisplay to tap water after 24 hours of induction with 100 µg/l of sodium-arsenite. (Source: http://biorxiv.org/content/early/2017/02/27/112110, CC-BY 4.0)

Response of the biodisplay to tap water after 24 hours of induction with 100 µg/l of sodium-arsenite. (Source: 10.1101/112110, CC-BY 4.0)

In the Journal of Laboratory Automation an article describes an open source (although the article itself is not open access) peptide synthesizer named Pepsy. Peptide synthesizers often cost  more than $20.000, whereas Pepsy can be assembled for  less than $4000. The author put the complete  Fmoc solid phase peptide synthesis process under the control of an Arduino (an open source prototyping platform). As an example, a ten residue peptide was synthesized that can be used as a contrast agent for nuclear medicine. The source code for Pepsy is available here on Github.

The fully assembled PepSy system with the reaction syringe in the middle. Courtesy of Dr. Gali

The fully assembled PepSy system with the reaction syringe in the middle. Courtesy of Dr. Gali

Do you have more exciting examples? Let me know!

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How many new drugs does the FDA approve?

Recently a question was floated on Twitter as to how many drug approvals the FDA has done. Quickly a few answers came in where it heavily depends on what one counts as a ‘new drug’, is a registered generic molecule also a new drug or is this not innovative enough?

For the sake of doing statistics on these numbers I’ve extracted the datapoints of a few data resources. First from the FDA itself, they have a funky table showing the number of new drug application (NDA) approved, received and the number of new molecular entities. I’ve extracted the data and plotted this below from 1944-2011 and can be downloaded here.

FDA NDA Approvals & Receipts from 1944-2011 (data)

Another interesting categorisation is the source of the molecules. In 2009 John Vederas published a highly cited article on the origin of the FDA approved drugs between 1981 -2007. Unfortunately the raw data behind this plot is not available so I’ve interpolated the numbers from this article figure and plotted the data below, again can be downloaded here. It is pretty clear that the number of natural (derived) molecules is declining.

 Number of drugs approved in the US split up by source from 1981 to 2007 interpolated from Vederas et al. (data)

feature in Drug Discovery Today  by Kinch et al. shows extensive analysis of new molecular entities as well as the ones one paid for the R&D. As a commenter notes on PubMed Commons it is too bad the underlying data is not available. Therefor the graph shown below is an interpolation of their figure.

Number of new molecular entities (NME) approved by the FDA from  1930-2013  interpolated from Kinch et al. (data)

A quick comparison shows that the FDA NME numbers and the numbers by Kinch et al. are in the same ballpark, deviations can be due to my interpolation or a difference in counting NMEs, for example Kinch et al. are  “excluding imaging and diagnostic agents.

Comparison of new molecular entities as reported by the FDA and  Kinch et al. 

If anyone has a more comprehensive article or publicly available numbers that would greatly be appreciated.

 

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A step closer in culturing “unculturable” bacteria?

MicroBio_img_006Last week the first real novel antibiotic since the ’90 saw the light. The authors made the discovery by diluting a soil sample in agar and casting this in a matrix with tiny holes. Next this matrix chamber (called iChip) was sealed with a semi-permeable membrane and placed back in the soil. After a month colonies were picked and after co-culturing with S. aureus the authors found the new antibiotic. The compound, teixobactin is produced by a large biosynthetic gene cluster of the previously uncharacterized bacteria Eleftheria terrae. The new antibiotic is functional against S. aureus but also against M. tuberculosis and probably a whole range of other Gram positives. Back to the culturing, with the iChip the authors claim to show the growth recovery “approaches 50%, as compared to 1% of cells from soil that will grow on a nutrient Petri dish10.”

iChip in action  (Photo: Slava Epstein / Northeastern University)

iChip in action (Photo: Slava Epstein / Northeastern University)

It is thus encouraging to see that by reconstituting the environmental cues (by placing the iChip back in the soil) a bigger fraction of the microorganisms is able to grow. This back-to-nature approach has a parallel with in vitro culturing techniques of eukaryotic cells where supplementing with fecal calf serum is used to reintroduces as many growth stimulating cues as possible. The question remains whether the limit of this method has been hit or if the recovery rate can be even further ramped up.

Another paper published last month in Applied and Environmental Microbiology ramped up growth in a different way. The authors systematically investigated the role of autoclaving phosphate buffer together (which is currently the practice in most labs) or separately with agar. It turns out that separately autoclaving the components is a difference of day and night with regard to the amount of cells that grow on the plates. Figure 3 in the paper shows about 8*107 CFU/g of soil when phosphate and agar were not autoclaved together compared to 3*107 CFU/g of soil when they were autoclaved together. In other words a ~2.5 fold increase in colony formation. In the conclusion the authors’ even report at 50-fold increase in CFU. The reason for this difference lies in the formation of hydrogen peroxide in the agar when it is autoclaved together with the phosphate buffer. The authors include a figure that indeed shows a correlation between an increase in H2O2 and phosphate buffer.

What can be learned from these two articles? First of all that it remains very challenging to culture a large fraction of the microbes out there and second the process is, after 100 years of cell culturing, still being improved.

Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature (2015). doi:10.1038/nature14098 [$]

Tanaka, T. et al. A hidden pitfall in agar media preparation undermines cultivability of microorganisms. Appl. Environ. Microbiol. 80, 7659–7666 (2014). [$]

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What do a TIM barrel and flavodoxin have in common?

4q37_bio_r_250Last month Birte Höcker, an experimental and theoretical protein scientist form the Max Planck Institute for Developmental Biology published an interesting article in Nature Chemical Biology.  The general challenge described is that sequences that look different on first inspection can give rise to very similar 3D structures. It also shows a nice combination of bioinformatics complemented with experimental work. Central in this case are the two folds (Figure 1, blue and green):

  • TIM barrel also known as the (βα)8-barrel  consisting of 8 β-strands in the core and 8 α-helixes around
  • Flavodoxin  which folds with 2 α-helixes on the outside sandwiching 5 βstrands in the core.

So the common theme: they both have αhelixes on the outside, sheets on the inside.

The underlaying question here is: How is one fold converted to the other?

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The 9 reads for Christmas

logosA selection of some interesting papers of the past period. Unfortunately some are only accessible for subscribers. Some topics covered; protein folding and design, antibiotic resistance genes, RNA polymerase complex and a paper on choosing the right color for your data.

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On promoters and operators, which combination is the best?

DNA helix artistPromoters and (their often forgotten partner-in-crime) operators are two key elements in the transcription of a protein sequence. A promoter sequence recruits the RNA polymerase and the status of the operator determines whether or not the adjunctive protein sequence gets translated (Figure 1). So far, biochemistry 101. Far more interesting is the diversity in promoter/operator complexes currently employed in the biotech industry and their associated efficiency rates. Not a lot of quantitative and  real comparable research had been done on this topic, until March 2013…

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Happy DNA day!

DNAsnapshotToday it is exactly 60 years ago (April 25, 1953) J.D. Watson and F.H.C Crick published their famous DNA structure paper in Nature. You can  read the original article at Nature website here for free. In 1962  James Watson, Francis Crick and Maurice Wilkins were awarded the Nobel Prize in Physiology or Medicine for their discovery. As of 2003 the 25th of April is celebrated as DNA day.

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Boiling ubiquitin results in a new landmark in protein folding

antonThis week David Shaw set another milestone in the protein-folding field. Two years ago he was the first to show how twelve “fast folding” proteins fold. Now he is the first to show how a “slow” protein folds. As test case he used the well-studied ubiquitin protein. The main goal was to prove the folding rules they found for “fast folders” is also applicable to “slow folding” proteins.

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The simple wonders of nature: a niffy enzyme

acidianus

Transmishion electron microscope (TEM) image of a Acidianus archaeon by George Rice

Now and then you stumble upon a straightforward self-explaining stereotypical paper. In this case it bears the clear name “Evolution of a new enzyme for carbon disulphide conversion by an acidothermophilic archaeon”(Smeulders et al., 2011) and written by the Microbiology department of Radboud University Nijmegen in The Netherlands. It extensively describes how a hydrolase (which converts CS2 to H2S and CO2) was likely to be evolved from a β-carbonic anhydrase (which converts CO2 in HCO3). But the work preceding this conclusion and the enzyme itself are actually much more interesting…

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