Apr
19

Another tragedy – BIA 10-2474 – yes its toxic after 600hrs of committee deliberations

Wow what an anticlimax.. Months after the tragic death in January of a clinical trial volunteer, the medical experts (CSST) in France have declared BIA 10-2474, the experimental drug administered was the problem. It has to to be read to be believed.

I bet you could have picked anyone off the street and presented with the evidence they would have come to the same conclusion and yet it has taken months for these EXPERTS to the same and they have virtually absolved everyone. Again LeFigaro in their assessment, pulls no punches. The CRO Biotrial comes out roughed up by the CSST compared to the company Bial whose drug it was and it seems the regulator (ANSM) is of course is blameless. This is a travesty, if this happened anywhere else I could imagine the regulator’s job would be on the line. The Google translate of the LeFigaro article which roughly translates as “blame the molecule and not the people that should have ensured this molecule went nowhere near a human”.

The preclinical toxicity data is ignored, the irreversible nature of the drug is ignored – the real tragedy is that the manufacturer did not do more preclinical work to consider how the compound was causing the animal toxicity. A little digging usually results in some answers. I can bet LeFigaro will chase this further. I eagerly await reading the full report when it is translated.

** Google translate of the LeFigaro article from today – its not perfect but you get the idea **

clinical trial Rennes cleared the agency accused Biotrial
Keywords: Clinical trial in Rennes, ANSM AGENCY OF DRUGS, Biotrial, Bial, CSST
By Anne Jouan – the 04.19.2016
The twelve experts commissioned by the drug agency come to make their conclusions. According to them, the agency has not sinned by validating the clinical trial in Rennes, but Biotrial, the investigator was not careful.

January 25, Dominique Martin, head of the French drug agency (ANSM) appointed a Scientific Committee Specialized Temporary (CSST) to study the causes of the deadly clinical trial in Rennes. On 17 January, for the first time in Europe, a man was killed during a clinical trial and five others were hospitalized with neurological disorders. After this accident, ANSM as the Portuguese Bial laboratory entrenched themselves behind the industrial and medical confidentiality not to disclose to a stunned international community, testing documents.

The CSST therefore delivers its final conclusions after several weeks of work, corresponding, in his words, by “a significant amount of work (estimated at more than 600 hours in total).” Nothing new compared to the intermediate report end of March. What about the responsibility of the French Agency which has validated this test? The SSTC still not say. “It was not within the powers of the CSST (unlike the two inspections in progress, that of the General Inspectorate of saociales business and the judicial inquiry, Ed) to rule on the validity of the authorization of the test by ANSM after consulting the Brest Patient Protection Committee “. We are reassured. How experts – including more than half work for the arrangement could they speak ill while subsidies they receive depend on this agency?
One of the volunteers had already had a stroke before the test

Regarding pre-clinical studies now conducted on animals. The CSST confirmed that Le Figaro wrote, that “rats and mice, brain damage, especially at the seahorses” in three animals treated with very high doses. But for the CSST curiously, “these attacks (…) seem quite frequently observed in rodents in studies of this type and were not a priori capable of generating a signal that such attacks do not seem to have been observed with other inhibitors of FAAH “. And to conclude this chapter, that nothing in the data that the CSST has studied “constituted a kind of signal to indicate a passage against-humans”. The ANSM therefore not wrong to validate the protocol.

If the agency is unharmed, it does not hold true for Biotrial. The critical CSST and age healthy volunteers, “the dispersion of volunteers recruited ages (18 to 55) is high, some being relatively old compared to what is generally observed in Phase 1 studies” . Experts instructed by the Agency also criticized the inclusion of volunteers not so healthy. They note as well: “We note, in addition, the inclusion of several volunteers that can be considered as a potential risk factor vis-à-vis certain adverse drug reactions.” According to our information, one of the volunteers had done well before the start of the trial strokes, without the date of the accident can be given with certainty. But this stroke made it more vulnerable especially for a voluntary molecule targeting the central nervous system. “One can only wonder, especially in the case of a molecule acting through the central nervous system, the balance provided for selection, inclusion and tracking of volunteers did not include a neuropsychological evaluation with maintenance clinical and cognitive tests, “notes besides the CSST.
transmission request of the internal investigation to justice

The lawyer for the family of the deceased volunteer, Jean-Christophe Coubris reacted to this report. “Consider that preclinical trials show no toxicity of the product is in total contradiction with the information disclosed by the Figaro and Mediapart,” alluding to a confidential internal survey carried out on 18 January. “This rating refers to the concern of a scientific assessor to the existence of toxic effects on the central nervous system of dogs, mice, rats and monkeys have been subjected to pre extra clinical trials referred. A priori, the Medicines Agency has ignored this warning. ” And the lawyer added: “We ask that the internal and confidential note be forwarded to the relevant authorities as soon as possible so that we can make informed in the interest of the manifestation of the truth.”

But the CSST experts do not leave count. They thus conclude: “The occurrence of circumstances, the stereotypical character and the evolving profile of neurological involvement strongly suggests the responsibility of the product tested.” Palice sleep quietly.

 

 

Apr
13

BIA 10-2474 saga continues – who knew what and when – and nobody comes out a winner

Apologies, recovering from some bug and my head is a bit fuzzier than usual so I hope this all makes sense. A day that started surreal and just kept going.

Straight out of the gate this morning I had an email from a journalist Damien Mascret from Le Figaro. I had never been in contact with this French newspaper before so to get an email was a complete surprise. The contents were odd. He sent me the copy of a Fax received anonymously regarding BIA 10-2474, (the compound that was in a clinical trial tragedy earlier in the year) and asked me to interpret it. It contained some sketched molecules and no explanation. I had a quick Skype call with Chris Southan who probably knows more about the lineage of these molecules than anyone in the world based on patents etc. So I theorized a bit and sent Damien links to the exhaustive digging from Chris Southan and posts herein. (Perhaps as this unfolds it will become clearer as to what it means.)

And then I thought nothing more until I looked at Le Figaro online tonight…Its the headline or at least it was at the time of writing.

I have tried to Google translate the article (see bottom of page), its probably not perfect but from what I can gather – bottom line the French medicines agency ANSM allegedly swept aside knowledge that there was an issue with the compound from preclinical studies and then Biotrial allegedly ignored side effects (neurological) seen in the clinic. Le Figaro have a massive scoop in getting to the bottom of this tragedy. Or is it really the bottom yet? I am hoping for a better translation of the article at some point but coming back to the fax that Le Figaro received really does make you question whats going on. Why is a national newspaper able to find out whats going on when it appears  the official commission cannot? Why are people in this day and age still faxing documents – is it really anonymous? This is certainly not some whodunit  but as this unfolds no one is coming out smelling of roses, not Bial, not Biotrial, not ANSM and especially not the official commission that supposedly is digging into this or at least has come to no conclusion, infact this would appear to now be contradicted.

I am pretty sure one day a book will be written about this.

 

***Google translate of Le Figaro article – this may not be a perfect translation***

Clinical trial: the document that overwhelms and Biotrial ANSM
INFO LE FIGARO – The confidential investigation report of the Medicines Agency is much more severe than that given by the official commission.

It is a document which will not help Biotrial. The company realized on behalf of the Portuguese Bial laboratory, the now infamous fatal clinical trial in Rennes. On 10 January, Guillaume Molinet, voluntary 2508 was admitted to the emergency. He died seven days later. Five others were also hospitalized, and some of them still have neurologic sequelae. This accident is the most serious ever happened in Europe in the context of a clinical trial.

In this context, on 18 January the National Drug Safety Agency (ANSM) prepare a confidential internal investigation report signed by the Director of Evaluation, Cécile Delval. This document seen by Le Figaro is overwhelming to the trial sponsor, Biotrial but for ANSM who authorized. Among the most troublesome issues for the agency include that on his clinical assessment of the drug to be tested. This is to replay and approval of the Portuguese laboratory protocol before its establishment in Rennes, in which involved two reviewers (clinical and non-clinical). The internal investigation and noted that “the non-clinical evaluator submitted its report (…) alerting the evaluator on a central nervous system neuro-effect” particularly because of the lesions observed in dogs, mice, rats and monkeys. Alas, this alert did not prevent the clinical evaluation ANSM concluded that “patient safety is ensured in this study.”

Worse, “the clinical evaluation report does not include the signals of the non-clinical evaluator of neurological effects observed in animals,” soberly notes the Director of Evaluation. Finally, the clinical report highlights that this is a first-in-man, but said “it is not a question of a product at risk.” A widely disputed today analysis.
Side effects

Another very embarrassing spot – this time for Biotrial – the occurrence of adverse effects at lower doses than that which led the volunteer died in hospital. These side effects were identified, at least blurred vision, by the temporary specialized scientific committee (CSST, mandated by the ANSM) in early March, but they were gone unnoticed. Thus, two volunteers (cohort MAD) who took 10 mg of the molecule presented on two occasions, blurred vision and diplopia (double vision). To volunteer in 2308, unrest occurred twice, each time 5:15 after taking the product. For voluntary 2305 diplopia occurred respectively 5:35 ET 8:35 after taking. Four episodes that each time lasted between 1 and 2 h 30. But “this finding was not considered relevant event by the investigator and the monitoring committee and, in fact, has not been found in volunteers of the 20 mg cohort, “yet concludes the CSST.

Other adverse reactions suspected to alert also observed at 10 mg, headaches. First in the volunteer 2303. Again, the CSST report only mentions that “cases of dizziness or mild headache.” Without specifying, unlike the internal investigation report Cécile Delval, that headache lasted … almost 29 hours. And this time, the effect is still observed at 20 mg, in another patient (the number 2404) for 47 hours. In total, four different volunteers (groups who ingested 10 mg and 20) who have submitted unusual side effects without worry Biotrial. Contacted by Le Figaro, the Rennes business, through his counsel, ensures that “signs that happen in life and who are neither widespread nor repeated” are not worrisome.

This explains the statement “no serious adverse events had been reported” before hospitalization and death of the volunteer who received 50 mg. A neurologist interviewed by Le Figaro is surprised that “lightness” of Biotrial “If, in a study of the central nervous system, signals such as blurred vision or headaches are not regarded as effects side, we walk on the head. ”
Include cannabis smokers

Moreover, the people Protection Committee (PPC, responsible for ensuring that each biomedical research project on human beings by the rules) has accepted the request of Biotrial include smoking cannabis or marijuana at height of two cigarettes a day, four times a week during the six months preceding the test. “This could be a confounding factor, but not necessarily dangerous,” notes Professor Danielle Piomelli, professor of neurobiology but also pharmacology and biological chemistry at the University of California at Irvine. His judgment is, however, much more severe as the transition to high doses. “The real problem with BIA 102474 (the test molecule, Ed) is that the very high cumulative dose reached in the Phase 1 trial has produced what we call an effect off target. Why now she has tested as high a dose? It is not very clear, he explained to Le Figaro. They knew that a much lower dose of the compound completely blocked FAAH (the “target”) in 3 days in humans. ”

He added: “They can answer it is normal to increase the dose in a Phase 1 to ensure that a compound is safe. This is true, but only up to a point. The exposure levels (blood and tissue) they wanted to achieve no sense based on the pharmacology of the compound. “One point obviously misunderstood by the CSST right note in his report of 15 February: “the increase of the doses administered, although of a type sometimes practiced in phase 1, appears problematic as too brutal end of progression while the opposite would have been expected.” and if the escalating problem dose was not his brutality, but its uselessness? Quite simply.

 

 

 

 

Apr
07

20 years in America – from brain drain to scientific immigrant

If my memory serves me well it is 20 years this week since I came to America as a Postdoc at Eli Lilly in 1996. The pharma industry was not looking great in the UK and I figured getting some experience in another country was worth a shot. I had not planned to be here longer than a couple of years to do some in vitro work on CYP2B6, but then I ran across computational chemistry approaches and that lead to a career direction change.

The 20 years have continued in that vein with job changes every few years initially, slight direction changes until finding something of niche in the modeling, software, drug discovery world. Its hard to predict what will be next but I have gained some valuable life experiences along the way in no particular order.

  1. Collaborate broadly, inside field, outside field
  2. If its not working move on, don’t ever look back
  3. Write, talk and get your ideas out there
  4. Be positive, connect others
  5. If its interesting do it, if its not kindly decline
  6. Bring along others and encourage them
  7. Don’t be afraid to get out of your field of expertise frequently
  8. Embrace technology and look for new applications
  9. If anyone asks for help that may lead to the next career move
  10. Connect the dots, because you might be the only one doing it

The pharma industry has changed in these 20 years and in a way many of my projects and jobs have illustrated this, I have been fortunate to meet and work with people who have been responsible for some of these efforts.  In recent years the shift to work on rare diseases and be inside organizations that are patient or parent lead, to me represents the next logical step.

It just remains for me to thank my colleagues at Eli Lilly in 1996 that made America so welcoming (Dr Steven Wrighton and Jim Wikel who were brilliant mentors) and all my collaborators and clients since then.

Apr
05

How close were we in our predictions on the Zika structure?

Perhaps you missed it but late last week the 3.8Å resolution structure of the mature Zika virus as determined by cryo-electron microscopy was published in Science by groups at Purdue University and NIAID.

I knew it was coming since I emailed Dr. Rossman Feb 24 with our ‘homology models’ paper submitted to F1000Research and had a reply on the 26th to the effect of .. ‘we are working on it.’

Sadly our models did not get a citation even though we 1. correctly predicted a single glycosylation site at Asn154 using freely available software which they experimentally confirm and  2. we correctly predicted that the virion would closely resemble Dengue virus on the surface. Perhaps this is an oversight in the rush to get published but anyone can go to F1000Research or to our Figshare collection and compare the files and what we had written over a month earlier. Perhaps the authors can add one reference after the fact because they definitely were aware of the work based on the email. I think our little computational experiment with Zika virus may suggest that actually such approaches can do a pretty good job when all we have to work on is a sequence! That will be very useful for the next virus of interest when we know we have at least a month to wait before a cryo-EM surfaces. A month can make a big difference if you have to quickly find a potential therapeutic.

Perhaps what was missing from the Science paper was discussion of the surface charge pattern on the virus and perhaps more detail that could be gleaned from it compared to other flaviviruses. While the Science paper made little or no reference to drug discovery, certainly it will also be interesting to see how this low resolution structure compares to the homology models for glycoprotein E for docking etc. For sure there is plenty to be done as the cryo-EM structures below show immature flavivuses look similar to other immature flavivirues and mature viruses look similar to other mature flaviviruses but the devil is in the details at the molecular level and that suggests the need for unique vaccines and probably drugs too for each virus. Plenty of work ahead.

This little project so far was also a wake up call, that it does not matter how open you are, people will still not cite work you are involved with! Am I right to call this out, you decide. Moving on..

flaviviruses

Mar
26

Whats holding back biopharmaceutical research in the USA?

Wow what a week.. If you were a fly on my wall in my virtual science office you would be blown away. My email has seen it all, my phone conferences have been blistering. But I am about to join the dots – and please give me some leeway, I may have stumbled on to why biopharmaceutical research is in such sad shape in the USA. Its a combination of people, facilities and money.

So the names and affiliations have been totally removed to avoid any red faces. Here are the  observations from a week when I have spent 5 x 15 hr days writing grants, working on paper resubmissions and just generally trying to clear the backlog after a week at the ACS in San Diego. Here goes:

First off when you spend 2+ years working with terrific world class academic collaborators on a project which you are the PI, wrote some of the 2 NIH grants, wrote all the commercialization documents, general champion, wrote the first draft of the provisional…. Do not at any point expect an external set of patent lawyers to assume that you or any of the inventors are actual inventors.  But that is not all, they missed off the key researcher from the lab who did the biology… Do not expect the collaborating tech transfer office to even have any rational sense to disbelieve the said patent lawyers when they completely decide on an incomplete set of inventors. I am using the term loosely. A poor job was done and it took 3 months and at what cost. After many emails and one phone call things might get put right. No promises here because this legal team has no clue.

Second you collaborate over a year with another set of terrific collaborators, clinicians, with no lab space of their own. They have a brilliant idea to do drug discovery you help them find some new molecules that work on a horrific disease that affects millions. They unsuccessfully apply to their institute for seed funding. They then obtain funding from an outside foundation and do the in vitro work to show the idea works. Can they get internal support to file a provisional  ? Not a sure thing. We decide to write an STTR to put the molecules in animal models before going to the clinic..we need to have an internal champion, we need a lab, no support from the institute is provided. In fact they almost shut down our attempts to put the grant together. What next, do we remove them from the equation and just outsource? And here comes the rub.

Three, outsourcing preclinical animal models in the USA is not cheap. Outsourcing anything here either ends up in Europe or China and that’s a problem because NIH grants will not fund this work abroad. Doh. So if you do not have the facilities to do the work, e.g. a lab of your own, how on earth do you get the work done. If the institute of the collaborators’ does not support them with space while adding on a hefty overhead, what gives? You are stuck and that my friend is one of the many reasons why the innovators in biopharma will continue to struggle.

This reminds me of my interactions with a major University / hospital on the east coast. Again a long term collaboration with a bright young researcher who works tirelessly and is underappreciated by said university. I am fortunate to consult on a grant and get to invoice for my relatively small check. I have to wait six months for them to pay me. No apology. I was made to feel as though I should be happy I was paid at all. I am a self employed consultant. One year on, the second time I invoice I remind them how long it took the first time. Three months pass by after many reminders, no check. I decide to email the president of the University. Within 1 hr a senior finance figure calls and says a check is in the mail. It arrives in a day. Now if I really needed the money what would happen, I would still be waiting. This is a university with gazillions in federal funding which clearly is a sorry bureaucratic mess and just swimming in a massive amount of overhead. Scientists & research clinicians are losing out because the bean counters are running the show and doing so badly.

So whats needed? As a small company trying to translate some of the ideas you come up with alongside collaborators, call them inventions.. well its an uphill battle to just go beyond the idea, when you actually make progress you get slapped by some patent lawyer or tech transfer group, or you hit the administrators that want their favorite people as co-investigators on your grant “to ensure success”.  I would say quite honestly this smacks of corruption. An old boys network comes into play. I could not make this stuff up. HBO will be making a drama out of this next. Game of Biopharma.

I get to collaborate 24/7 and everywhere I see the same thing, it does not matter if its a big university or a small research institute. You can work with the scientists but ultimately they are being held back by the very fabric which should be giving them the support needed to make discoveries, to cure disease, to invent and to patent. Its sad to see for all the billions the NIH puts into these institutes, a great percentage is being thrown away.

The only ray of light I have seen in this is the fact that there are some very small foundations that are willing to give out $10K here or $30K there to researchers or clinicians with a great idea to help get it off the ground. We need more walk up or flexible lab space where scientists or clinicians can actually do experiments that could serve as a foundation for something bigger. Whats needed after that are US based CROs that can do the preclinical work well and at a fair price, and not ship it off to China. Beyond that there needs to be better ways that the NIH can directly fund the scientists without overhead  going to the bricks and morter- just ban it, let these administrators work to earn their money instead of riding on the backs of the fortunate grantees. There needs to be better help for patenting and generally translating and helping when an outside group comes in and is willing to write grants to fund the research. We should not be holding back the ideas, we should be testing them and making sure if they work they reach the patient.

 

 

 

Mar
18

10 more years of the Pediatric rare disease priority review voucher

I just saw an email from Nancy Goodman and The Kids v Cancer Team describing the passing of legislation that will lead to the extension of the pediatric rare disease priority review voucher. This is a topic I have covered here and most recently in our recent publication with Jill Wood. In full disclosure I am CEO of a couple of small rare disease companies, so this is huge for groups like ours. It provides a potential return on investment even for diseases where there might be just a handful of patients. It gives us at least 10 years to get there. Alright now lets go develop those drugs! A big thank you to Nancy and her team as well as all the families and groups supporting this legislation. I am pretty sure it will be the topic of a lot more discussion to come. UPDATE – STILL HAS TO MAKE IT TO FLOOR.
Advancing Hope Act, S. 1878, passes the Senate Health, Education, Labor and Pensions Committee
 
 
We are very happy to announce that last week, the Senate HELP Committee passed the Advancing Hope Act to reauthorize the Creating Hope Act pediatric priority review voucher program in a strong showing of bipartisanship, by 18 to 2.
In a  Manager’s Amendment to the Advancing Hope Act, the Senate HELP Committee extended the program almost 10 years — with a 2022 sunset, and an extension until 2027 for drugs and biologics that receive a rare pediatric disease designation by 2022.
We look forward to supporting the Senate’s effort to bring the Advancing Hope Act to the Senate floor as part of the Senate’s Innovations for Healthier Americans Act.
We thank our Senate sponsors, Senator Casey and Senator Isakson.  In addition, we thank the leadership of Chairman Alexander and Ranking Member Murray.  And as always, we are grateful for the continued support of Representative McCaul, Representative Butterfield and Representative Van Hollen.
Sincerely,
Nancy Goodman and The Kids v Cancer Team

Mar
16

Why this may be my last ACS

For many the ACS is the one meeting they go to year in year out. Me too. On and off over approximately 16 years I have attended with a poster or given talks and even done booth duty. But the current meeting in San Diego may well be my last.

Monday I gave a couple of talks in the division of small chemical businesses in a small room with a handful in the audience. I met a couple of the fellow speakers who were very interesting as were their talks. And yet we were speaking to ourselves, preaching to the converted. Over the years I have done the same thing in various CINF sessions. I see the same kinds of things recycled, I try to give something different each talk and this takes quite a toll in preparing etc. I have been happy to do this because each presentation in a way is like a mini publication and it helps put ideas together for future papers.

But enough, I am done. My next talk is on Thursday, on “using machine learning models based on phenotypic data to discover new molecules for neglected diseases” in the multidisciplinary program planning group. I have had a couple of days to mull this over. 4 days in one place to give 3 talks. I imagine the audience again will be small tomorrow.

I have been spending my downtime connecting with collaborators and friends in the area as well as keeping on top of emails, paper submissions, grants etc. I could have been so much more productive if this meeting had been virtual and I could have just connected when I needed too. I enjoyed doing the ACS virtual conference last year and frankly that was a good time investment. Plus by not attending this meeting I would have saved my money. Sure the face to face discussions are priceless and there are the chance discussions.  The exhibition room is fun to see new technology and load up on freebies. But is that really justification?

No hard feelings ACS, I have done my bit. I need some space. I have other meetings I can go to. I like smaller meetings also, ~1000 is a good size.. or Gordon confs. I think the ACS national meeting system needs a refresh as its so 20th century, the format has barely changed in the time I have been attending. So no Philly trip for me unless I have a  massive change of heart. I will miss the familiar faces but I am sure we will cross paths elsewhere. Consider this voting with my feet.

 

Mar
07

Zika – front page news

This morning The Wall Street Journal had the Zika virus vaccine efforts on the front page with comments suggesting a vaccine is 18 months away. In section B the headline was “hunt is on for a Zika Vaccine”. About 90% of the space was dedicated to describing all the companies chasing vaccines. Then almost as a PS they add that the NIAID and the Scripps Research Institute are searching for drugs. This is interesting as remember back in January when I contacted NIAID they were waiting for someone to bring them an assay. So this is interesting and frankly I am wondering whether everyone is starting from scratch because of public pressure and the race is on. I wonder if we could get there faster by using all the protein models we have now put in the public domain.   The 2 year wait for a vaccine I think is just a number plucked out of nowhere. As stated before – we still are waiting for HIV, TB, malaria and Ebola vaccines. So lets just not promise any delivery dates and get hopes up.

What is needed is collaboration. I think we need to also try to do as much as openly as we can and be realistic in how long it is going to take.

Feb
24

Illustrating and Homology Modeling the Proteins of the Zika Virus

After a busy few weeks of using every bit of spare time and engaging some great and very generous collaborators we now have the latest installment in the #ZikaOpen project submitted to F1000Research. The preprint is also posted on Figshare. The project kicked off after the illustrator John Liebler got in touch as he wanted to illustrate the Zika virus. This really nudged me – or more politely kicked me in the rear, because if we could model the glycoprotein E on the surface of the virion then why not do all the rest of the proteins. It took a weekend of heavy SWISS-MODEL use (summarized here) to produce the files and some further effort to analyze the structures. Again what started as a very simple idea of a ‘research note’ around the Zika virus models expanded to comparing the virions of flaviviruses and predicting glycosylation sites. We used GoogleDocs again to draft the paper over a week or so and as different collaborators connected I would share the draft. This was supplemented with tweets, direct messages, emails, phone calls and Skypes with different team members. Yesterday was the big push and it was polished up this morning. Hopefully this is a significant contribution that others can take and use for docking and screening etc. A MASSIVE thank you to all the contributors especially Carolina Andrade and Bruno Junior Neves in Brazil, as well as all the people who have been acknowledged for supporting this nascent effort. Which brings me to the question – what can we do next? Certainly docking into the valid structures is a priority but if others would like to get in touch please email, tweet, phone etc. John’s Email lead to this you could push us in new directions! Perhaps some funding would help (and that for us is a priority in order to fund the testing of compounds etc) and it is encouraging that several funding agencies have issued Zika virus targeted announcements.  But again the process is likely not fast enough.

Citizen scientists can get involved – but as I found doing the homology modeling not all of the NIH and NSF funded tools and papers are readily accessible unless you have an academic email / affiliation and library access. For me this has to change. Here we are putting our free time into this effort and we have to dig to find the few tools that are accessible. Fortunately I have access also to some commercial software and access to a university library which I am grateful! But still these are important challenges.

I think the big take away here is that you can do quite a bit with a small team contributing in a distributed manner. I am excited and also humbled to be around such great people!

Feb
19

Zika Virus- insights from old papers when you can get them

Hunting for information on the Zika virus has revealed several insights for me, both of them point to areas that are obvious. 1. Researchers may have missed out by not reading anything older than a few years old and 2. for all the pronouncements on data sharing and open access, still publishers have not opened up old papers.

Searching Google scholar for papers on ‘Zika virus and in vitro’ and ‘Zika virus and in vivo‘ retrieved a few papers of note. Some of which were behind a paywall (e.g. Elsevier’s journals like Antiviral Research for example). One interesting paper from 2003 by Crance et al., described interferon, ribavirin, 6-azauridine and glycyrrhizin tested against 11 flaviviruses in vero cells. As far as I can make out this is one of the few papers I have found to date that lists anything tested against Zika virus in vitro. I have access to a university library account so I was able to get this and save  $35.95. Which raises the issue, shouldn’t there be some freeing up of papers on Zika? A recent paper by Hamel et al., from 2015 also showed interferon inhibited Zika virus replication in primary skin fibroblasts, but did not cite the earlier work from 12 years earlier. So could interferons be a viable treatment for those with the virus?

The linkage between Zika virus and microcephaly was recently further cemented with a case study. But had there been any earlier signs of this possibility I wondered? Fortunately Springer made a paper by Bell, Field and Narang freely available on the ‘Zika virus infection of the central nervous system in mice‘ from 1971. This paper is telling in that inoculation of 1 day old and 5 week old mice with the virus went on to show enlargement of astroglial cells, destruction of pyriform cells of Ammons horn and clear replication of the virus occuring in neurons and astroglial cells as observed by histopathology. So for over 45 years it has been known that Zika virus could have profound CNS effects. While this study did not look at mouse fetus, it does raise concern for young infants that might be infected with the virus, could it have the same effect on the CNS as in mice? Why has this work not been highlighted earlier, it it had I think there would have been a greater urgency to develop treatments for this disease knowing that it could have developmental effects. Perhaps part of the challenge is finding this information you might say? Well there is so little literature on the virus and a few minutes spent searching can retrieve likely important papers. The challenge is still accessibility and discoverability.

 

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