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Sunday, April 16, 2017

GenX spill, national coverage, but where is the data

First (I have never blogged much about risk and hazard), I am not an toxicological expert nor a regulator. I have deepest respect for both, as these studies are one of the most complex ones I am aware off. It makes rocket science look dull. However, I have quite some experience in the relation chemical structure to properties and with knowledge integration, which is a prerequisite for understanding that relation. Anything I do does not say what the right course of action is. Any new piece of knowledge (or technology) has pros and cons. It is science that provides the evidence to support finding the right balance. It is science I focus on.

The case
The AD national newspaper reported spilling of the compound with the name GenX in the environment and reaching drinking water. This was picked up by other newspapers, like de VK. The chemistry news outlet C2W commented on the latter on Twitter:


Translated, the tweet reports that we do not know if the compound is dangerous. Now, to me, there are then two things: first, any spilling should not happen (I know this is controversial, as people are more than happy to repeatedly pollute the environment, just because of self-interest and/or laziness); second, what do we know about the compound? In fact, what is GenX even? It certainly won't be "generation X", though we don't actually know the hazard of that either. (We have IUPAC names, but just like with the ACS disclosures, companies like to make up cryptic names.)

But having working on predictive toxicology and data integration projects around toxicology, and for just having a chemical interest, I started out searching what we know about this compound.

Of course, I need an open notebook for my science, but I tend to be sloppy and mix up blog posts like this, with source code repositories, and public repositories. For new chemicals, as you could read earlier this weekend, Wikidata is one of my favorites (see also doi:10.3897/rio.1.e7573). Using the same approach as for the disclosures, I checked if Wikidata had entries for the ammonium salt and the "active" ingredient FRD-903 (fairly, chemically they are different, and so may their hazard and risk profiles). Neither existed, so I added them using Bioclipse and QuickStatements (a wonderful tool by Magnus Manke): GenX and FRD-903. So, a seed of knowledge was planted.
    A side topic... if you have not looked at hypothes.is yet, please do. It allows you to annotate (yes, there are more tools that allow that, but I like this one), which I have done for the VK article:


I had a look around on the web for information, and there is not a lot. A Wikidata page with further identifiers then helps tracking your steps. Antony Williams, previous of ChemSpider fame, now working on the EPA CompTox Dashboard, added the DTX substance IDs, but the entries in the dashboard will not show up for another bit of time. For FRD-903 I found growth inhibition data in ChEMBL.

But Nina Jeliazkova pointed me to her LRI AMBIT database (poster abstract doi:10.1016/j.toxlet.2016.06.1469, PDF links) that makes (public) data from ECHA available from REACH dossiers in a machine readable way (see this ECHA press release), using their AMBIT software (doi:10.1186/1758-2946-3-18). (BTW, this makes the legal hassle Hartung had last year even more interesting, see doi:10.1038/nature.2016.19365). After creation of a free login, you can find a full (public) dossier with information about the toxicology of the compound (toxicity, ecotoxicity, environmental fate, and more):


I reported this slide, as they worry seems to be about drinking water, so, oral toxicity seems appropriate (note, this is only acute toxicity). The LD50 is the median lethal dose, but is only measured for mouse and rat (these are models for human toxicity, but only models, as humans are just not rats; well, not literally, anyway). Also, >1 gram per kilogram body weight ("kg bw"; assumption) seems pretty high. In my naive understand, the rat may be the canary in the coal mine. But let me refrain from making any conclusions. I leave that to the experts on risk management!

Experts like those from the Dutch RIVM, which wrote up this report. One of the information they say is missing is that of biodistribution: "waar het zich ophoopt", or in English, where the compound accumulates.

Friday, April 14, 2017

The ACS Spring disclosures of 2017 #2: some history

Bethany Halford adds some history about the sessions (see part #1):
    I believe Stu Borman was the first to cover the Division of Medicinal Chemistry’s First Time Disclosures symposium for C&EN, but it was Carmen Drahl who began the practice of hand-drawing and tweeting the clinical candidates as they were disclosed in real time. This seems like an oddball practice to folks who aren’t at the meeting. Why not just take a picture of the relevant slide? Well, that’s against the rules: There are signs all over the ACS National Meeting stating that photos, video, and audio recording of presentations are strictly prohibited. In San Francisco, symposium organizer Jacob Schwarz repeatedly reminded attendees that this was the case. Carmen’s brilliant idea to get around this rule was to simply draw the structures as they were presented, snap a photo, and then tweet it out.

    I’ve inherited the task since Carmen left the magazine a couple of years ago. I find it incredibly stressful. For an even that’s billed as a disclosure, the actual disclosing is fairly fleeting. The structures are often not on the screen for very long, and I’m never confident that I’ve got it 100% right. Last year in San Diego I tweeted out one structure and I heard the following day from Anthony Melvin Crasto, a chemist in India, that based on the patent literature he thought I had an atom wrong. I was certain that I had written this structure correctly, so I contacted the presenting scientist. He had disclosed the wrong structure!

    I agree that there should be some sort of database established afterwards, and I think you all have done great work on that front. I think you’ll find the pharmaceutical companies reluctant to help you out in any way. They guard these compounds so fiercely that it often makes we wonder why we have this symposium to begin with.

The ACS Spring disclosures of 2017 #1

At the American Chemical Society meetings drug companies disclose recent new drugs to the world. Normally, the chemical structures are already out in the open, often as part of patents. But because these patents commonly discuss many compounds, the disclosures are a big thing.

Now, these disclosure meetings are weird. You will not get InChIKeys (see doi:10.1186/s13321-015-0068-4) or something similar. No, people sit down with paper, manually redraw the structure. Like Carmen Drahl has done in the past. And Bethany Halford has taken over that role at some point. Great work from both! The Chemical & Engineering News has aggregated the tweets into this overview.

Of course, a drug structure disclosure is not complete if it does not lead to deposition in databases. The first thing is to convert the drawings into something machine readable. And thanks to the great work from John May on the Chemistry Development Kit and the OpenSMILES team, I'm happy with this being SMILES. So, we (Chris Southan and me) started a Google Spreadsheet with CCZero data:



I drew the structures in Bioclipse 2.6.2 (which has CDK 1.5.13) and copy-pasted the SMILES and InChIKey into the spreadsheet. Of course, it is essential to get the stereochemistry right. The stereochemistry of the compounds was discussed on Twitter, and we think we got it right. But we cannot be 100% sure. For that, it would have been hugely helpful if the disclosures included the InChIKeys!

As I wrote before, I see Wikidata as a central resource in a web of linked chemical data. So, using the same code I used previously to add disclosures to Wikidata, I created Wikidata items for these compounds, except for one that was already in the database (see the right image). The code also fetches PubChem compound IDs, which are also listed in this spreadsheet.

The Wikidata IDs link to the SQID interface, giving a friendly GUI, one that I actually brought up before too. That said, until people add more information, it may be a bit sparsely populated:


But others are working on this series of disclosures too, and keep an eye on this blog post, as others may follow up with further information!

Saturday, April 01, 2017

Closed access book chapters, Bookmetrix, and job creations

Enjoying my Saturday morning (you'll can actually track down that I write more blog posts then, than any other time of the week) with a coffee (no, not beer, Christoph). Wanted to complete my Scholia profile (gree work by Finn, arxiv:1703.04222, happy to have contributes ideas and small patches) a bit more (or perhaps that of the Journal of Cheminformatics), as that relaxes me, and nicely complements rerunning some Bioclipse scripts to add metabolite/compound data to Wikidata (e.g. this post). Because this afternoon I want to do some serious work, like write up outlines for a few cool grant applications. And if lucky, I may be able to do a bit of work on this below-the-radar project.

So, I started updating a full work available at for a peer-reviewed IEEE paper (doi:10.1109/BIBM.2014.6999367), as it is not old Open Access, and I have to rely on green Open Access. Then I headed over to my ImpactStory profile and ran into a closed Open Access book chapter with Tony, Sean, and Ola (doi:10.1007/978-1-62703-050-2_10). But I have no idea if I can put online a green Open Access version of this book chapter.

Now, why I am blogging this (and meanwhile, adding four new DTXSIDs to Wikidata), is two observiations. First, I had not blogged about Bookmetrix yet, a cool project that reports the impact of book chapters. The ROI on writing book chapters I always considered as not so high, but then I saw the #altmetrics for this chapter:


Five citations is not that lot, but considering I do not cite book chapter much either. But look at that number of downloads, 2.39 thousand! Wow!

But there is another angle to that. We regularly report our societal impact, nowadays. It's part of the Dutch Standard Evaluation Protocol, or at least selected by our research institute as something to assess researchers on. Hang on, no, citations is not part of that category. But this is: the paper is sold for about 50 euro. Seriously? Yes, seriously. And apparently 2.39K people bought this chapter. I am not sure if I need to assume that this is mostly people buying the full book, which means the chapter is a lot cheaper. But the full book reports download numbers of above 50 thousand, so it seems not. Now, let's assume that a good part of the bought copies is via package deals and the average payment is half. That may sound high, but we ignore the 50k download for the full book to compensate for that.

Doing that math means that our joint book chapter contributed 60k euro to the European market. That's a full job the four of us created with this single book chapter. I'm impressed.