Trouble at CIHR continues

Looks like CIHR continues to have trouble with the Project Scheme Live Pilot. Applicants are waiting for results of the competition to release today, and by the sound of it there was an unintended early release for some applicants that included the names of their reviewers. The message from CIHR is below (emailed to applicants today):

ResearchNet funding decision release incident

This is to advise that at 21:30 on July 14, 2016, a system breakdown caused by a local power failure resulted in ResearchNet releasing funding decisions for the Project Competition prematurely. In addition reviewer names were accessible for a maximum of 49 applicants for 17 minutes. Corrective actions were immediately undertaken and the system was restored to normal operating status. Reviewer names can no longer be accessed. CIHR is in the process of advising each of the reviewers whose name could have been accessed.

At this time, competition results are being released as scheduled. CIHR sincerely regrets this situation and recognizes its significance given the importance of confidentiality in the peer review process. CIHR is currently assessing the technical cause of this incident with ResearchNet in order to ensure that it is not repeated. 

Canadian Institutes of Health Research

This is clearly a big issue for the integrity of the review process. Its good to hear it was caught early, but this is not an encouraging development for an already controversial process. The most recent developments have been covered by CBC and Science magazine.

Revised Glycan Nomenclature System

C&EN has highlighted the recent revision of the CFG (or “Essentials”) nomenclature for the structure of complex glycans. The revised nomenclature is posted on the NCBI site, which will be part of the upcoming third edition of Essentials of Glycobiology. The new nomenclature now includes a longer list of monosaccharides, which will be a welcome addition for anyone working on non-vertebrate glycans (especially bacteria or plants). There are also some changes to the use of color, with white symbols being reserved for unassigned monosaccharide stereochemistry (often the case with structures confirmed only by mass spectrometry). Colors are then reserved for specific stereochemistries of monosacharides, so a generic hexose is a white circle and Glc and Gal are blue and yellow, respectively. Many of these colors overlap with previous use in earlier nomenclature, so those that know the system for mammalian glycans should be able to read the revised system without much trouble.

If you need to draw your own glycans, the CFG site has a free tool for this: Glycoworkbench. Note that it still appears to use the 2nd edition nomenclature. The current link for that doesn’t seem to have an obvious link to the software, but you can find a version here.

NSERC-funded research open access policy

It looks like the earlier draft policy on open access for federal Tri-council funding in Canada has been made official. NSERC grants starting after May 1, 2015 will have to comply with the new policy. This seems similar to many other agencies, such as the NIH, which require access within 12 months of publication.

The “deposit elsewhere after publishing” model is usually referred to as “green” open access, and many journals now support this model after funding agencies have begun requiring it. This is usually a zero-cost option for the authors (which is a good thing.) “Gold” open access (where the authors pay a fee at the time of publication to allow immediate OA) costs grant money, and is not always an option when budgets are tight.

ACS journals allow users to deposit their work after 12 months in a repository, such as PubMedCentral, for NIH funded work. Presumably a similar policy will be developed for NSERC. RSC journals also allow OA archiving, as does Nature Publishing Group, Wiley, Elsevier, and others. Some of these (like Elsevier) are journal-specific, and may be worth reviewing before submitting a paper for review.

Open access repositories that NSERC funded chemists are likely to use include PubMedCentral, PubMedCentral Canada, and Institutional Repositories.

 

Posttranslational modifications – What are these things stuck to my protein?

If you took introductory biochemistry, you are probably familiar with the most common biopolymers: nucleic acids (DNA & RNA), proteins, and carbohydrates. The roles of the first two polymers are probably best encapsulated in what is known as the central dogma of molecular biology (coined by Prof. Crick).

Essentially, DNA stores the sequential coding information, it is transcribed into RNA which delivers specific fragments (as mRNA) which become translated into protein sequences. The proteins tend to be the functional molecules in the cell which catalyze chemical change or form essential structures in the cell (and generate the phenotype of the cell/organism). So what happens after translation (posttranslation, and the namesake of this blog)?

Posttranslational modifications (PTM) are chemical changes that happen to proteins after the coding sequence has been converted into a protein. By defenition, these changes are not encoded directly by genetic information. There are many examples, with glycosylation (attachment of a carbohydrate) and phosphorylation (attachment of a phosphate) being some of the more prevalent examples (here is an excellent review on the subject).

So, what do these modifications do? (The real answer is a long one – so I’ll just include some highlights.) A lot of these modifications change the function of the protein. As an example, some sulfotransferase enzymes are inactive as their primary sequence, but when the active site residues are modified (by an enzyme known as FGE) the enzyme becomes active. Some modifications actually control which proteins interact with each other, a mechanism that is essential in immune cell response (among many others.) PTM can also change the stability, shape, or flexibility of proteins.

One of the problems in this field is that PTM, since they aren’t directly encoded, aren’t easy to predict (i.e. things get messy). Think of it this way: if the genetic information stored in DNA is the blueprint of a house, PTM end up being the tweaks and changes that our builder might include that we didn’t specifically ask for (but might even be needed to make things work). This one feature, which leads to complexity and variability, is a large part of why we know a lot less about PTM than we do about, say, DNA. As a result, to study these modifications we have to go in and specifically see what modifications took place in a given cell or condition.

Sialidase NEU4 is involved in glioblastoma stem cell survival

Our group was recently part of a study that looked at the role of a specific enzyme, NEU4, in the survival of glioblastoma cells (a type of brain cancer.) I wanted to summarize some of the elements of the work here. Our group’s contribution was the provision of an essential reagent, which was used to test the hypothesis that this enzyme could be targeted with a small molecule drug. The bulk of the work was done by a group at the University of Milan, led by Profs. Venerando and Tringali.

First – what is NEU4? NEU4 is one of four different enzymes in humans known as a neuraminidases. You may know that neuraminidase enzymes are important in the pathology of influenza. The virus needs this enzyme to escape and reinfect host cells, and drugs like oseltamivir and zanamivir target the viral form of it. But human cells have their own use for NEU enzymes, and these four enzymes are ones that we are still learning a lot about. Neuraminidases are named for their substrate, neuraminic acid (also known as sialic acid – and the enzymes are alternatively called sialidases.) Neuraminic acids are carbohydrate residues that tend to be on the ends of complex glycoproteins. In fact, many pathogens (like influenza) use these groups as a handle to enter host cells. But in general, our cells are making glycoproteins (and other glycoconjugates) that contain neuraminic acid, and the NEU enzymes are there to remove those residues. Exactly what molecules are involved is still an area that is being studied. There are four human isoenzymes: NEU1, NEU2, NEU3, and NEU4; development of inhibitors for these enzymes is a relatively new area.

So why do we care about NEU4 specifically? It turns out that Prof. Tringali and coworkers had previously shown that the enzyme was over expressed in some glioblastoma cancers. Based on that, they had initiated studies to understand what the enzyme was doing. It was during those studies (summarized in the title paper) that my group approached them with the offer of an inhibitor that we had just found which we thought could target the enzyme specifically.

The story of that inhibitor is a bit interesting, and is a lesson in how research doesn’t always go as planned. We first made the compound as part of a study we published in 2010. At that time, we only had the assay for one isoenzyme, NEU3. When we tested this compound (and a few others) we found that they had moderate activity for NEU3, but they left a lot of room for improvement. A few years later, we had developed a panel of all four isoenzymes. We’ve used that panel to identify selective inhibitors for several of the isoenzymes already. However, the most notable were some compounds we reported in 2013 which were remarkably potent against just one of the isoenzymes: NEU4. Some of these were the same compounds we had tested back in 2010, and while they still had weaker activity for NEU3, they were very powerful inhibitors of NEU4 alone. The best of these, compound 6, was a 30 nM (nanomolar, or 10^-9 molar) inhibitor. Most importantly, compound 6 was selective, it was 500-times more active against NEU4 than the next best isoenzyme target.

Of course our hope in finding these compounds was that you could use them to determine the role of specific NEU enzymes. The glioblastoma example reported by the group in Milan was a perfect fit for our hypothesis: malignant cells that had unusually high levels of NEU4. In principle, our compound would turn off the action of that enzyme.

The overexpression of NEU4 in these cells resulted in some changes that could be detected, first the cells had increased growth (proliferation) and expressed specific stem cell markers. When NEU4 was ablated genetically, both of these reversed: cell growth slowed and the markers went away. Most exciting for us, when the cells were treated with compound 6, they found the same observations: cell proliferation was reduced and the markers returned to normal levels. These results provide the first evidence that targeting of specific human NEU isoenzymes could be a strategy for an anticancer therapeutic.

Of course there is still a lot of work to do before this is something that could be used for therapy. First and foremost, although our compound was very active in vitro, the cells were not as cooperative. Very high concentrations of the inhibitor were needed to see the effects observed in glioblastoma cells. This is most likely due to the compound just not penetrating into the cells, and might be something we could improve chemically. Another potential concern would be that we don’t know what this compound might do in other tissues – i.e. what could its side effects be? Although NEU4 is upregulated in these cancer cells, it probably does something in normal cells. Inhibition by compound 6 (or a related compound) could lead to other undesired side effects. Our hope is that by targeting just one isoenzyme, negative effects in normal cells will be minimal as the other isoenzymes could still compensate and minimize side effects – but that all remains to be tested.

Our group is continuing to work on identifying selective inhibitors for the other human NEU isoenzymes, and hopefully we will be able to use these in the future to look at the role of the enzymes in health and disease.

RSC takes Chemical Science open access

To follow up on the last post regarding open access journals in the chemistry space, it looks like Chemical Science will be going to a gold open access model. The most notable feature here is that the publisher says they will waive any publication charges “for at least two years.”

This seems like a serious move from RSC, and one hopes that other chemistry publishers will follow suite.

For comparison to other gold open access chemistry journals, some stats on Chemical Science (in 2013):

  • Chemical Science, $0 (until at least 2016), 596 articles (658 if you count front/back/cover material)

Open access publishing in Bio/Chemistry – Whatever happened to PLoS Chemistry?

I’ve been a fan of the open access (OA) movement for a while. However, I can’t say that I’ve voted with my feet: I typically publish in society/specialty journals that are not open access. Of course, some of these publishers now give you the option of paying them to make your paper OA, so they can argue that one can still publish in those venues and just pay to allow access to your work.

I’m not a fan of this model – having an essentially random sampling of papers does not make for a good presentation to the reader, nor does it address the idea that an open archive of research data and conclusions is a benefit to the community. I would argue that opting to pay OA charges at these closed journals is basically supplementing the journal’s advertising budget with your research grant. At the end of the day, if readers want full access they must get their libraries to pay for the rapidly growing cost of closed journal subscriptions.

Which brings me to the subject of this post: What are the best OA venues for chemists to publish their work right now? I’m specifically interested in “gold road” journals, those that make their content freely available immediately upon publication. Here’s the list I put together in an hour or two of searches, I was targeting Organic Chemistry, Chemical Biology, Biochemistry, and related fields. I doubt this is exhaustive, and I’d appreciate any suggestions from others. (Journals listed with current publication charge, and number of articles published in 2013):

Clearly PLoS One is the largest venue, Scientific reports seems to be growing (about a 3X increase from 2012-2013). I hadn’t realized until now that Molecules, Arkivoc, and the Bielstein journals were OA. Some of the ones low in the list may need some incubation time to reach critical mass. I ruled out some smaller journals if they were not indexed on Web of Science, PubMed, or SCOPUS. Any others that I’m missing?

There was once some talk of a PLoS Chemistry, but I can’t seem to find any indications that its happening. I don’t see many of these venues competing with premier society level journals without buy-in from leaders in the field. My impression is that this has allowed the PLoS brand to take off, with a few of those journals having become top-tier venues.

Its worth noting that archive servers are a mechanism for OA publishing. This is dominant in some field (but sadly lacking in Chemistry/Bio):

bioRxiv.org is the new kid on the block here, and it remains to be seen how readily preprint servers are become adopted in biomedical research.