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Delivering The Benefits of Chemical-Biological Integration in Computational Toxicology at the EPA

This presentation was given at the ACS Meeting in Philadelphia in August 2016.

Delivering The Benefits of Chemical-Biological Integration in Computational Toxicology at the EPA

Researchers at the EPA’s National Center for Computational Toxicology integrate advances in biology, chemistry, and computer science to examine the toxicity of chemicals and help prioritize chemicals for further research based on potential human health risks. The intention of this research program is to quickly evaluate thousands of chemicals for potential risk but with much-reduced cost relative to historical approaches. This work involves computational and data-driven approaches including high-throughput screening, modeling, text mining and the integration of chemistry, exposure and biological data. We have developed a number of databases and applications that are delivering on the vision of developing a deeper understanding of chemicals and their effects on exposure and biological processes that are supporting a large community of scientists in their research efforts. This presentation will provide an overview of our work to bring together diverse large scale data from the chemical and biological domains, our approaches to integrate and disseminate these data, and the delivery of models supporting computational toxicology. This abstract does not reflect U.S. EPA policy.

 

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Zika Virus and a hypothesis regarding the impact of Pyriproxyfen

I have been interested in the Zika Virus ever since I heard about it while visiting Brazil last year to give a talk at the Brazilian Natural Products conference. What I did not expect was the incredible surge in worldwide attention that Zika would attract. I am grateful to have been included in the work led by Sean Ekins (@collabchem) in the perspective “Open Drug Discovery for the Zika Virus” recently published on F1000Research. Up until last week the hypothesis was that Zika was a mosquito-borne disease but now the suggestion is that the disease may be related to a larvicide.

The chemical in question that is being named as the offending agent is Pyriproxyfen. I had never even heard of this chemical until a couple of days ago. At that time there was nothing on Wikipedia but, of course, it has since been updated with this

“In 2014, pyriproxifen was put into Brazilian water supplies to fight the proliferation of mosquito larvae.[2] Some Brazilian doctors have hypothesized that pyriproxyfen, not the Zika virus, is the cause of the 2015-2016 microcephaly epidemic in Brazil. [3]

Consequently, in 2016, the Brazilian state of Rio Grande do Sul suspended pyriproxyfen’s use. The Health Minister of Brazil, Marcelo Castro, criticized this step, noting that the claim is “a rumor lacking logic and sense. It has no basis.” They also noted that the insecticide is approved by the National Sanitary Monitoring Agency and “all regulatory agencies in the whole world”. The manufacturer of the insecticide, Sumitomo Chemical, stated “”there is no scientific basis for such a claim” and also referred to the approval of pyriproxyfen by the World Health Organization since 2004 and the United States Environmental Protection Agency since 2001.[4]

Noted skeptic David Gorski discussed the claim and pointed out that anti-vaccine proponents had also claimed that the Tdap vaccine was the cause of the microcephaly epidemic, due to its introduction in 2014, along with adding “One can’t help but wonder what else the Brazilian Ministry of Health did in 2014 that cranks can blame microcephaly on.” Gorski also pointed out the extensive physiochemical understanding of pyriproxyfen that the WHO has, which concluded in a past evaluation that the insecticide is not genotoxic, and that the doctor organization making the claim has been advocating against all pesticides since 2010, complicating their reliability.[2][5]

Because we live in a time of Open Data, and at a time when there is soooooo much information available on open databases, I thought I would go after any evidence-based identification of the chemical as a potential contributor to the explosion in Microcephaly.

PubChem exposes a LOT of useful data under the Safety and Hazards tab. The long-term exposure points to issues with blood and liver. FIFRA requirements are listed on PubChem and toxicity data is also available here. Reproductive toxicity is limited to reports in animals that reports

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In /a/ developmental study in rats, a maternal NOAEL/LOAEL were determined to be 100 mg/kg/day and 300 mg/kg/day, respectively. These findings were based on increased incidences in mortality and clinical signs at 1,000 mg/kg/day with decreased in food consumption, body weight, and body weight gain together with increases in water consumption at 300 and 1,000 mg/kg/day. The developmental NOAEL /and/ /LOAEL were 100 mg/kg/day and 300 mg/kg/day /respectively/ based on the incr of skeletal variations at 300 mg/kg/day and above.

64 FR 56681 (10/21/99). Available from, as of April 28, 2003: http://www.epa.gov/EPA-PEST/1999/October/Day-21/p27398.htm
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In /a/ developmental study in rabbits, the maternal NOAEL/LOAEL for maternal toxicity were 100 and 300 mg/kg/day based on premature delivery/abortions, soft stools, emaciation, decreased activity and bradypnea. The developmental NOAEL was determined to be 300 mg/kg/day and developmental LOAEL was /not/ … determined; no dose related anomalies occurred in the four remaining litters studied at 1,000 mg/kg/day.

64 FR 56681 (10/21/99). Available from, as of April 28, 2003: http://www.epa.gov/EPA-PEST/1999/October/Day-21/p27398.htm
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a 2-generation reproduction study in rats, the systemic NOAEL was 1,000 ppm (87 mg/kg/day). The LOAEL for systemic toxicity was 5,000 ppm (453 mg/kg/day). Effects were based on decreased body weight, weight gain and food consumption in both sexes and both generations, and increased liver weights in both sexes associated with liver and kidney histopathology in males. The reproductive NOAEL was 5,000 ppm. A reproductive LOAEL was not established.

64 FR 56681 (10/21/99). Available from, as of April 28, 2003: http://www.epa.gov/EPA-PEST/1999/October/Day-21/p27398.htm
Just to point out that this information, and it is valuable, is sourced from HSDB.
Pyriproxyfen reports on PubMed doesn’t seem to turn up anything about birth defects that I can find.
There is no evidence, yet, for the potential impact of this chemical on the incidence of microcephaly but the hypothesis is now out there and it will be interesting to see what happens as investigations are pursued. As yet I have no opinion….but will be watching with interest to see what comes out.

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Transform Tox Testing Challenge – Innovating for Metabolism

Scientists from EPA, NTP and NCATS have used high-throughput screening (HTS) assays to evaluate the potential health effects of thousands of chemicals. The Transform Tox Testing Challenge: Innovating for Metabolism is calling on innovative thinkers to find new ways to incorporate physiological levels of chemical metabolism into HTS assays. Since current HTS assays do not fully incorporate chemical metabolism, they may miss chemicals that are metabolized to a more toxic form. Adding metabolic competence to HTS assays will help researchers more accurately assess chemical effects and better protect human health.

Details can be found here 

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Molecular Microscopy Takes the Next Step – Monitoring a Reaction One Molecule at a Time

A new paper hit Nature Chemistry today “Reversible Bergman cyclization by atomic manipulation” (The paper will be featured on the cover of the March Issue). I have so much appreciation for what these scientists are doing. Selfishly I want to continue to applaud them for the breakthrough science that they continue to produce. I have never met the “IBM molecular microscopy” team (my chosen label) but I have had a chance to work with them on two separate occasions. One high profile one was on Olympicene, a fun story reminisced here: Olympicene From Concept to Completion. It was a lot of fun to work with scientists who found the work interesting and in reality it is NOT just a marketing story for RSC as some people mocked at the time, including some of my own colleagues! In fact, if you look at the number of articles that I have now linked (and continue to add to) on my Kudos page you will see a LOT of publications came out of the work (Kudos’ed Olympicene article plus linked articles) so not just “fun science”. In reality science is fun and real utility and understanding can come out of researching fun science, clearly.

The other chance I had to work with the team was on one of my personal interests: Structure Elucidation by NMR and the applications of Computer-Assisted Structure Elucidation (CASE) software/algorithms. The work “A Combined Atomic Force Microscopy and Computational Approach for the Structural Elucidation of Breitfussin A and B: Highly Modified Halogenated Dipeptides from Thuiaria breitfussi” combined CASE-based approaches with single molecule microscopy to elucidate new structures.

Now the team is demonstrates a reversible Bergman cyclization for the first time using atomic manipulation and verification of the products by non-contact atomic force microscopy with atomic resolution. I will let the movie below tell the story and reference you to the original paper. FASCINATING WORK. Congrats to all. How many reactions will now come under the scrutiny and validation of the team now? We will see…

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Integrating Cheminformatics and Spectroscopy to Elucidate the Structures of Natural Products

This is a talk I gave at the 5th Brazilian Conference on Natural Products as part of my “spare time” activities and to remain engaged with my passion of NMR, structure elucidation and computational spectroscopy applications

Integrating Cheminformatics and Spectroscopy to Elucidate the Structures of Natural Products

The structure elucidation of natural product structures from analytical data, specifically NMR and MS, remains a major challenge. With an enormous palette of NMR experiments to choose from, and supported by breakthrough technologies in hardware, the generation of high quality data to enable even the most complex of natural product structures to be determined is no longer the major hurdle. The challenge is in the analysis of the data. We are in a new era in terms of approaches to structure elucidation: one where computers, databases, and a synergy between scientists and algorithms can offer an accelerated path forward. Software tools are capable of digesting spectroscopic data to elucidate extremely complex natural products. Scientists can now elucidate chemical structures utilizing multinuclear chemical shift data, correlation data from an array of 2D NMR experiments and utilize existing data sets for the purpose of dereplication and computer-assisted structure elucidation. With the explosion of online data especially, in public databases such as PubChem and ChemSpider, many tens of millions of chemical structures are available to seed fragment databases to include in the elucidation process. This presentation will provide an overview of how cheminformatics and chemical databases have been brought together to assist in the identification of natural products. It will include an examination of the state-of-the-art developments in Computer-Assisted Structure Elucidation.

 

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Beyond the Paper CV (or how to build an online profile as a scientist)

Beyond the Paper CV (or how to build an online profile as a scientist)

This presentation was given at the UKICRS meeting (http://www.ukicrs.org/2015-symposium.html) on April 16th 2015 at the University of Nottingham. This presentation was in a workshop and focused on trying to inform attendees in the postgraduate phases of their careers how to use online tools to start building a reputation and profile in their field. It was good to get positive feedback from some of the attendees. Generally the comments were in regards to the number of different online tools they could use that I highlighted as well as them getting an understanding that they must take responsibility for their reputation and do it soon…there are benefits to starting early!

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My Spoiler Alert about Netflix and the House of Cards

This is NOT about chemistry. If you are expecting chemistry stop here and move on. If you are a watcher of House of Cards on Netflix I may ruin your enjoyment of the show if you read further. You choose…

I work a lot of hours. I generally start my day at around 6am, work a 8-9 hour day during normal working hours and then when my boys are in bed (or on the days I don’t have them)  I commonly get back in front of my computer between 8pm-midnight/1am. Doing this I have an opportunity to get involved outside of my normal work acitivities to work with collaborators to do some exciting science (specifically with people like Sean Ekins, Alex Clark and Gary E. Martin). I also spend a lot of time looking at what is going on with social networking tools and data sharing platforms that may be of value to scientists.

While I am working at night I consume a lot of movies and series via Netflix and Amazon Prime. I have cut off cable TV to the house, put up a digital antenna (well, my very skilled friend did) and use cable internet almost exclusively for entertainment now.

Both Netflix and Amazon now have specific programming that doesn’t make it to general TV channels. For example Orange is the New Black and House of Cards on Netflix and Alpha House and Bosch on Amazon Prime. I have enjoyed them all. Amusing, intelligent, edgy and shocking covers the general flavor of what these programs have as entertainment value.

It took me a couple of episodes of House of Cards to really get into it but with Season 3 just around the corner I am excited to see whether or not my interpretation of many scenes, acts and  breadcrumb clues throughout the show are right. The relationship between Frank and Claire Underwood is really what this show is about…everything else around it, the manipulations, the espionage, the nastiness and the supposed harsh realities of Washington pale in comparison to the farce that is the relationship between Frank and Claire. And it makes for addictive TV for sure.

I am not going to drag out why I have come to this conclusion as there are sooooooooo many clues. I may be totally off base here but here’s throwing out my judgement of the shocker that will show up one day for House of Cards…and I find no evidence that this is suggested anywhere on the internet.

Frank and Claire are brother and sister (or at least family)

Think about all their “rendezvous” with partners outside of their marriage, and even one with their security man/driver. But notice they never rendezvous with each other…EVER (that I recall). They definitely love and respect each other, they are both hungry for power and for what it brings, and there are lots of stories about their history but with no evidence for how they met, their backgrounds etc. I think they are working together to get to ultimate power…and the Presidency is that for sure.

I am either way off base but it would be a great ending to a show…or maybe I applied my analytical skills in a good way. Time will tell..I love a good puzzler, a good story and a shocking ending. It happens in some of the science I do occasionally! Always fun.

 

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Amazon and the management of my Author Profile

I have authored or co-authored a number of book chapters with friends and collaborators over the years and have been privileged to do so (see the book chapter section in my CV). I have also been involved with authoring or editing a number of books and one is presently in press and two will hopefully be finished by end of year. They are listed below.

IN PRESS Computer-based Structure Elucidation from Spectral Data: The Art of Solving Problems with ACD/Structure Elucidator, Mikhail E. Elyashberg, Antony J. Williams, Springer Link

Modern NMR Approaches for the Structure Elucidation of Natural Products PART 1 by Gary E. Martin, David Rovnyak and Antony J. Williams, in preparation, Royal Society of Chemistry Link

Applications of Modern NMR Approaches to the Structure Elucidation of Natural Products PART 2 by Gary E. Martin, David Rovnyak and Antony J. Williams, in preparation, Royal Society of Chemistry Link

I really like the Amazon Author Page for keeping all of this information integrated. My page is here: http://www.amazon.com/Antony-J.-Williams/e/B004YRPRV2 and I update it with book chapters and books as they come out.

Yesterday I commented on the issues of poor name searching related to the Chemtrove article published recently. When I added the Springer book to my profile today I took a look at the capabilities of Amazon assuming that things would likely be a lot better. In order to do this I found the Springer book here: http://www.amazon.com/Computer-Based-Structure-Elucidation-Spectral-Data/dp/3662464012/

and clicked on the name Antony J. Williams listed as shown here:

Click on the name Antony J. Williams to find related books

Click on the name Antony J. Williams to find related books

The result set is shown here. Only two of these books are mine, the rest are shown below and yes, the one entitled “I Hate Sex” remains on my list. I did NOT write it! I couldn’t see why the Granular Materials book is listed against me until I looked at all 30 editors/contributors for the book here and saw that Antony and Williams (very much separated) were shown in the list. The All Hallows book makes more sense as it has David Williams, Antony Oldknow, but the last one about dinoflagellates has the same issue as the granular materials book…Antony and Williams in the list of authors.

Four of the books found searching against Antony J. Williams

Four of the books found searching against Antony J. Williams

Having added the book to my profile however made a dramatic difference as it now links to my author page and lists all of my books rather than performing a loose search. This is a good overall solution but DID need my participation to claim my book. To date the evidence suggests that Google really have their act together in terms of being able to automatically associate articles with my profile but for other platforms such as Kudos, ORCID and Amazon Author Pages the author is best to stay involved with CLAIMing their articles to ensure good association and high quality data.

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Hosting public domain chemicals data online for the community – the challenges of handling materials

This is the presentation I gave at the Opportunities in Material Informatics meeting in Madison, Wisconsin.

Hosting public domain chemicals data online for the community – the challenges of handling materials

The Royal Society of Chemistry hosts one of the worlds’ richest collections of online chemistry data that is free-to-access for the community. ChemSpider presently hosts over 30 million unique chemical compounds together with associated data and accessible via a number of search techniques. With almost 50,000 unique users per day from around the world the site offers scientists the ability to investigate the world of small molecules via property searches, analytical data and predictive models. The challenges associated with providing a similar platform for “materials” are manifold but, if they could be addressed, would offer a valuable service to the materials community. This presentation will provide an overview of how ChemSpider was built, our efforts to expand the capabilities to a more encompassing data repository and some of the challenges faced to embrace the diverse world of materials informatics and online data access.

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Speaking at “Opportunities in Materials Informatics” workshop

Those of you who have been following my blog over the years are likely very aware of some of the work that we have done working on ChemSpider, ChemSpider SyntheticPages, OpenPHACTS, PharmaSea and the Chemical Database Service. We have many years of investment in the ChemSpider projects of course but our primary focus now is working on the data repository project that we published an early outline of last year. The majority of projects that we have focused on have focused on small organic molecules primarily and, I judge, we have been successful in addressing many of the challenges around the informatics challenges…many, but certainly not all! For sure, when we started ChemSpider over 7 years ago we were not aware of some of the issues we would face as we developed ChemSpider and there has been so much learned in the process. For sure we have been able to spend time with, collaborate with and push forward with some of the best minds in cheminformatics…and to them we are grateful.

Tomorrow I will give an overview of our work in the field of building small molecule databases for the community – with a focus on ChemSpider of course but also knitting together many of the other areas I have been connected to. I am privileged to have been invited to participate in the “Opportunities in Materials Informatics” workshop in Madison, Wisconsin. There are many experts in the field attending (see list) and I am sure I will learn WAY MORE than I will be able to share in terms of wisdom! In some ways I will be out of my depth and hearing about some of the approaches people are taking to develop informatics platforms for materials data. I will put up my slide deck when it is finished in the usual place on Slideshare when its ready. Follow the twitterfeed for the workshop at #matinformatics2015.

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