Nov
12

Giving and taking my own advice on starting a company

I have a tendency to agree to other peoples good ideas to do things and then it catches up with me. You know that feeling of massive over commitment.

Well I started to say NO a lot more frequently. I say no to all manner of requests to answer questionnaires, review for journals from publishers I never heard of, present at different kinds of unrelated conferences in China (although I really would like to go one day). I still say yes to anyone asking me questions, whether its students wanting career advice, friends needing references, strangers wanting reprints etc. Rare disease parent advocates are the top of my YES list. I have plenty of time for them because they have immense challenges to raise funds and convince other scientists to do the research that one day may help their child. Their approach has been a revelation to me to the extent that I have had to put aside other academic pursuits. I have let 2 book proposals languish, along with several papers I have always wanted to work on. Well I hope I have time in the future to get back to these projects. My focus, if I have any, is rare and neglected diseases. the latter because they are killing millions needlessly and the former because there are so many of them with huge gaps in our knowledge and both severely lack funding.

A few months a go Jim Radke at Rare Disease Reports asked if I would like to blog for them on occasion. Now I have a lot of time for Jim because he is very generous at highlighting all different groups involved in rare diseases and the website has a wealth of info. He is also a super nice fellow who told me I should do more of what I do on rare diseases. So I said yes, signed the contract and got on with my work. I also pledged to give any royalties to the rare disease foundations I work with. In the back of my mind for the past few months, all I could think about was writing on something I really am not an expert on but which might help others, by presenting the famous ‘Ekins naive perspective’ on a topic.

That blog topic was released today, a burst of writing after breakfast (not usually peak creativity time for me) and I put together a draft on giving advice and then taking that advice on starting a rare disease company. I am not a classic entrepreneur, no MBA, no business training, never started anything in my life and I do not drool after others’ business advice. Talk is cheap. 3 years ago I dispensed a little advice to Jill Wood, she listened, and she went off and started a company. It took 2.5 years to fund and we have a very long way to go before we will likely have anything to show for it.  Although with rare disease parents and devoted scientists like those involved, that could change very quickly. I dispensed advice but really I was probably telling myself to do the same. I had a huge moment of inertia to overcome, a family, 2 children and several part time consulting jobs that paid for the fun projects. Helping rare disease groups has become a bigger part in my life. You meet the rare disease children, the parents, the families, the scientists and that has a big impact too. Whatever I can offer is pretty insignificant, but ideas and experience at funding work through grants is totally translatable. A positive outlook when all the odds are against you helps in some small way. We will never start a major pharma but then we do not have to. Small is great. One scientist, one parent or patient is enough. The straw that broke the camels back was meeting another rare disease parent a few weeks ago, she told me of the treatment that might help her daughter that was languishing in a lab. I resolved then that I had to use the experiences gained from starting one rare disease company to start another for those unable to do what Jill did, because they have a full time job looking after the child with a debilitating disease.

At coffee with a good friend a few days later I mentioned my need to start this New Company and my severe inability to actually do it. I went off and wrote a 1 pager because that is what I generally do, write something. My friend then put me in touch with an accountant and the ball was rolling.  A couple of weeks later on and I had no reason why I could not write todays blog, I had given advice 3 years ago and it it took me that long to take it myself. Better late than never. My incorporation papers came through today.

 

Nov
04

App exposure

It is the little things in life that make it all worthwhile – perhaps. I have noticed a definite uptick in interest in the science apps we developed over the last few years. For example I was recently contacted by a science writer who wanted to write about the open drug discovery teams app. This is all very flattering, so we will see how that translates to an article. Simultaneously I noticed that Derek Lowe over at the In The Pipeline blog mentioned Android mobile apps and TB Mobile got a mention . Of course these free apps have been around on iOS for several years now. The Android version of TB Mobile is version 1, while TB Mobile 2 on iOS has built in machine learning algorithms and many more features.

There is a definite lag time between building something novel for science like a mobile app, getting some visibility for it and even publishing papers on it. Finally to get more general interest, and well by then you have perhaps moved on to something new. A post mobile app world anyone. Yes, the fact that so much technology can be crammed into these chemistry apps by the likes of Alex Clark is truly incredible. The fact that chemists are only now realizing the potential of mobile apps is astounding. I am a late adopter of technology, but chemists and pharma in general seem even later adopters. Imagine if these apps had been around 5 years ago. Of course it does make you wonder how many apps will survive and live on in one form or another as the software and mobile device tastes change. It would be a shame to lose some of the innovation just when its getting real traction and credibility.  A discussion of the legacy of the data and algorithms created in these apps needs to be going on to prevent someone else in the future repeating what has already been created.

Oct
31

Rare disease collection

The last few months I have been putting some rare disease related ideas out into publications, and now they are starting to see the light of day.

First there is an editorial that highlights some of the challenges in finding out about the 700o or so rare diseases. The editorial also has some artwork from a couple of children with rare diseases in the hope this can raise a bit more awareness. This is followed by an opinion piece with collaborators Nadia Litterman, Michele Rhee and David Swinney in which the idea of a centralized rare disease institute is raised as well as discussing topics such as how to connect with others interested in rare diseases and how to foster collaborations.

Hopefully these articles will be followed in the rare disease collection at F1000Research by submissions from other scientists and rare disease advocates.

Oct
23

Underwhelming big pharma response to Ebola – I urge more collaboration

A few weeks ago I asked where are the big pharma companies who have been largely surprisingly quiet during the Ebola epidemic. Today I see a press release announcing J&J will have their vaccine next year and GSK later this year. Possibly other companies will be involved at the WHO’s urging. What took so long? This has been all over the press for months and these companies are just now waking up from their stupor or pulling themselves away from playing Angry Birds or the “who can we buy out next” game! And why oh why is there no mention of trying small molecule drugs? Where are all those big pharma’s the Merck’s, Pfizer, Sanofi, Novartis etc?

Lets not forget that in the second world war many drug companies ‘collaborated’ to manufacture penicillin – what was the commercial gain then if any? What is the difference between then and now? The big pharma companies have largely lost their direction, perhaps even their moral compass in some senses. Where are the visionary leaders? I can bet if Paul Janssen was still around he would have been all over Ebola.

There are patients dying in Africa and elsewhere, get out of those meetings and do something, send your drugs to USAMRIID, get them tested vs Ebola and then if they are useful crank up the manufacturing and ship them out. Now there is a strategy. Stop talking about doing something with WHO and actually DO SOMETHING.

Oct
20

In response to the NIH director

I just found a post by Dr. Antony Fauci and Dr. Francis Collins on Ebola. So I have added my 2 cents – lets see if it gets accepted and a response from some moderator (..Tax dollars well spent – who would want that job responding to folks like me). There are plenty of smart people in the world and I am not seeing anyone using the great human assets that are out there to identify treatments for ebola.

Dear Dr’s Fauci and Collins,

A full 2 weeks before this post I searched the NIH’s own Pubmed (anyone can do this) and found a study from last year that DTRA funded to screen FDA approved drugs (http://www.ncbi.nlm.nih.gov/pubmed/23577127)-.. Several drugs (Amodiaquine, Chloroquine, etc ..) were found active and with promising data in mouse models. A Dr. in Haiti then alerted me to another paper with additional compounds (http://www.ncbi.nlm.nih.gov/pubmed/23785035). It appears there are no shortage of FDA approved drugs that have activity in vitro and in vivo in mouse etc.. there is even a common pharmacophore which I put in the public domain (http://www.collabchem.com/2014/10/02/a-pharmacophore-for-compounds-active-against-ebola/).

It would not take much for any of these drugs to be explored further. I am amazed that all the discussion is on a vaccine / biologics and yet there has been considerable efforts to fund screens of small molecule drugs and they have been largely ignored. I am also saddened by the lack of big pharma response (http://www.collabchem.com/2014/10/08/where-is-the-big-pharma-knight-riding-in-to-slay-ebola/).

We have known about the disease for 40 years and yet we did not have a plan for when it went beyond one village in Africa? That is very surprising to me as a scientist.
There are many questions that someone should answer, like why was the funding for small molecule screening and exploration of the hits/ leads stopped? Why was there no exhaustive effort to screen every FDA approved drug? Why are the existing drugs already on the shelf in Africa not being used? Why is nobody looking at those that are not getting Ebola, is it because they are already taking a medicine that is protecting them?

Food for thought.

 

Oct
16

How the experiment may impact the data

Here’s one to file under “I am still trying to get my head around it”.

Back in April at the CDD community meeting Christopher (Chris) Lipinski presented some slides looking at kinase selectivity and the relationship with ligand efficiency. There seemed to be a general trend that more selective compounds had a better ligand efficiency. My colleagues at CDD have been digging deeper into this and will present a webinar Wed, Oct 22 from 2-3pm ET at which Chris and Matt Soellner will debate Entropic and Enthalpic Propensities Inherent in SBDD and HTS.

Now my involvement has been pretty limited to thinking of some interesting datasets to compare. Obviously my personal bias is towards the neglected diseases and anything that is in the public databases. For one I was interested to see how the >1000 whole cell Mycobacterium tuberculosis (Mtb) hits coming out of high throughput screens compared with ligands from structure based drug design studies (SBDD) for which there are examples in the PDB. A measure of enthalpy of the SBDD hits suggested it was higher than for the HTS hits. Because several datasets have been released on antimalarial HTS hits we can do the same comparison with SBDD hits.

Without trying to give too much away I would say some of the slides I have previewed were very interesting. Of course most will want to hear about the kinase data but lets think about what other questions could we ask. SBDD by its nature is trying to optimize the fit of compounds into a target, simplistically it is trying to get good interactions. Phenotypic HTS is not bothered about that, key determinants of activity are getting the molecule into the cell and then shutting down some target/s. So hydrophobicity is predominantly driving whole cell activity for Mtb, as we see many of the hits have a higher calculated logP (using whatever method you decide), although other properties may also be key.

So fundamentally depending on what kind of experimental approach we use to get Mtb active compounds we are biasing towards compounds with different physicochemical properties. We have come full circle. Target based approaches to antibacterial drug discovery have been a failure because one they found few hits and two the few hits did not have whole cell activity. It seems obvious now but target based drug discovery is really finding a needle in a haystack, trying to get very specific interactions while whole cell approaches ‘just’ need to get the compound in and perhaps have OKish affinity for one or more targets. Maybe the latter represents more of a complete system effect (more targets to interact with vs a single target).

So what does this say about our efforts using computational approaches to find compounds active against Mtb? Will they also have some of the same issues inherent in HTS and SBDD? For example docking molecules in a crystal structure as part of SBDD is going to drive towards very specific interactions, and if the method and scoring functions are poor then the hit rate will be very low. Machine learning methods are going to learn from just the mass of data you give them. So if you feed in whole cell data all you are going to do is basically replicate the physicochemical properties that allow you to get compounds into Mtb and hit a whole array of potential targets. Is there some middle ground here, a hybrid approach?

Perhaps running compounds through whole cell assays and just feeding those hits into SBDD as starting points? Then followed by feeding the resulting SBDD designs/hits into whole cell assays to ensure that there is a balance between specificity and ability to get into the cell. Perhaps this iterative approach would be more efficient computationally as a pipeline where the known whole cell hits are fed into docking against as many Mtb structures in the PDB as possible and those that have good scores would serve as a starting point for design.

Another question you could perhaps ask is are the compounds that we want to avoid in HTS (like PAINS) different in some way? Would they stand out from real HTS hits and real SBDD hits. Is a PAIN found by docking more useful than a PAIN found by HTS? Do they have different enthalpy scores?

Well I am sure the webinar will have others asking questions too. Its certainly got me thinking.

 

 

Oct
08

Where is the big Pharma Knight riding in to slay Ebola?

In full disclosure my better half works for a big pharma, this is not going to hold me back from writing what I am sure everyone is thinking. It saddens me as someone who worked for big pharma (until 2001) to have to write this.

We are months into the rapidly escalating catastrophe that is Ebola. We have experimental therapeutics that are depleted, and we now have patients in Europe and the US that are critically ill. Thousands have died in Africa. The latest news is that a US patient is taking an experimental broad spectrum antiviral (read not FDA approved) from a small biotech.

But the people who have been incredibly silent are the big pharma companies? Where are they? I cannot think of one article I have read, one news item that even mentions them offering something. I am sure they are, have or are thinking about it. If there was one opportunity to right all those wrongs that seem to get press such as the latest allegation of corruption, Ebola is it.

We hear about the times companies do something for malaria , TB and other neglected diseases – such as: screen their vast compound libraries, dump the thousands of hits into the public domain, open up their patents etc.. But why are they not throwing their compounds at the CDC, the army or whoever can test them against Ebola? Why are the big pharma vaccine makers like GSK and Novartis who have been paid by the government to provide vaccines for Flu pandemics and more not responding quicker? Let me repeat, we knew this was likely not just another small scale Ebola outbreak months ago.

What would it take to organize some effort from the pharma side to show they were responding. Namely we could get drugs and compounds off the shelf from pharmas and test them. The compounds big pharma offered to NCATS for example might be a place to start? Maybe this is happening but the NIH have not communicated this.

I have already highlighted in multiple places what must seem the most astute science ever done that was funded by the government. Namely two studies that independently screened FDA drugs against Ebola in 2013. And yet even this published work is being ignored and the data from screening is not publically accessible. PLOSONE somehow overlooked this. Now if only the data from the FDA approved drugs screens was publically accessible, it could be used for machine learning models to help identify possibly better compounds. Has not a single journalist looked in Pubmed? If there was a time to highlight the need for open data this is it. What about using the various computational approaches out there that could search through the huge corpus of knowledge and suggest compounds to test, or dock compounds into targets for Ebola?

So are big pharma just moving so slowly because that is the way they operate? Or are they caught deer in the headlights like? Could they put something out there via PhRMA (even a small press release) so the general public has some idea they are responding to Ebola in some small way and not waiting for it to go away on its own? Big Pharma may be scared of putting their drugs out there and them having no impact, they may see it as a double hit, the market is small and the publicity around failure might cripple their share prices. Perhaps government could offer some reassurance that this could be done anonymously to avoid any bad publicity.

Who will be the knight that rides into slay the dragon that is Ebola? Will it be a small biotech that has nothing to lose and everything to gain, it will likely not be an NGO or the WHO. If big pharma could find the knight to lead them this could be a battle they might win by marshaling their cumulative brainpower, resources and then perhaps the public will have a new faith in this industry.

This is not a dream, Ebola is the worst nightmare we could imagine. Its going to take big pharma to get involved to end it. Please someone wake them up.

 

Oct
07

The most expensive data set I have modeled – dont blink (over $500M)

The cost of data generated in science is probably not something many people ponder. When I look back over some of the datasets I have looked at over the years its interesting to speculate on the costs of the underlying data. Working for pharmaceutical companies, data from specialist tests for toxicities (e.g. hERG) probably ran from the tens to hundreds of thousands of dollars for 10s to 100s of compounds of interest (back when the assays were low throughput and contracted out). Even high throughput screens performed inside companies probably had similar costs.  But the prize for the most expensive data set I have worked on surely goes to the recent analysis of over 300 NIH funded chemical probes. 

By conservative estimates this project and therefore the data derived from it likely cost well in excess of $500M (as quoted in 2010) . If there are any bean counters out there with an updated value please let me know. To date the countless grants have funded hundreds of screens. The result a little over 300 probes so far. So each probe compound is worth well over $1M ! OK I am NOT exaggerating, this is by FAR the most expensive dataset I have had the opportunity to model. Lets put this in some perspective, it cost over $3B to fund the human genome project. When I think of potential for impact on healthcare etc, somehow this dataset does not register even close to the human genome. Thats not to discount it, but what will it lead to? Probably you could say the same for the human genome but many would argue its propelled many insights, projects and products in science (almost like the billions sunk in the space race in the 60′s).

So what does this all mean? Well the analysis we recently published suggested that over 20% of the probes were undesirable based on the experience (40 yrs) of a medicinal chemist. That suggests 20% of the > $500M may have been a complete wast of time. Thats over $100M down the drain (conservatively). This of course is just small change for an agency that has an annual budget of $30.15 billion . $100M could make a significant impact on rare disease research, it could be used productively for Ebola research as well as many other diseases. But you may argue this project is past tense. The various research groups took their hefty chunk of overhead, and there were costs that were sunk in equipment and staffing etc. But the data lives on and resides in PubChem.. half a billion dollars of data just sat there.

We used all the data to try to model the medicinal chemists decision using machine learning methods. This suggests that perhaps we can use such models to prioritize compounds before we invest more time and resources in them. Literally the $500M machine learning model exists ! This might never have happened but for a discussion with Christopher Lipinski and Nadia Litterman back in April to see if a model could be created to emulate his decision making in some way. So while I am amazed at the costs to generate this data, without this we would not have been able to do the analysis we did. Is this the end of it? Probably not. This is not really BIG DATA but it took BIG MONEY.

If anyone has examples of more expensive datasets of molecules and screening data please point them my way.

 

 

 

 

 

Oct
02

A pharmacophore for compounds active against Ebola

I was looking through Pubmed yesterday looking for repurposing efforts applied to Ebola and found the paper by Madrid et al. This described many hits, including chloroquine and amodiaquine. Then I was tweeting with@DokteCoffee last night and she suggested another paper by Johansen et al., which described SERMs such as clomifene and  toremifene. Interestingly Madrid et al., had also found toremifene as active but did not test viral replication.

I have generated a common feature pharmacophore with these compounds and posted it on figshare. To narrow down the number of hits when screening libraries I added the van der Waals surface of amodiaquine. Interestingly the pharmacophore has multiple hydrophobic features and a single hydrogen bond acceptor feature. If anyone wants the Discovery Studio files  please let me know and I will email them out. I have posted the searches as csv. files on figshare for the CDD library and microsource library. There may be additional compounds that have not been screened in vitro that could be worth looking at.

Estradiol maps very well to the pharmacophore and although Madrid showed no viral replication activity in vitro, this compound would be interesting to test in vivo.

 

Sep
19

Promoting younger scientists to editorial boards of journals

Today I realized I am in the fortunate position to be on the editorial boards of several journals and that I have a “voice”. Then I realized I am no longer a young scientist, I am 44..What about those that are doing their postdocs in their mid 20′s when do they get a voice in the say of journals? I look at even the new journals that keep starting, (and another was in my in box today), and their editors are closer to my demographic mid to late 40s or beyond. Yes experience is important but what about listening to those that are doing science now, not science 20 years ago. I am not saying that we are past it as scientists, I am just proposing that editorial boards of journals with those in their 40s- 50s-60s is probably not ideal or representative of the population at major conferences. Just go to an ACS, AAPS, SLAS, etc.. there are thousands of young scientists.

So I tweeted a bit about this today.

Tweet 1 = Just thinking – isn’t it time publishers put a journal together that has a “younger scientist” focused ed. board that addresses needs (1/2)

Tweet 2 = (2/2) Younger scientist journal, needs ultra fast turnaround, transparent reviews and reviewers, free & open, open to new ideas & feedback

Tweet 3 = perhaps some much younger scientists could chime in on my comments.. I feel less relevant as I am > 40 but all journals focus on experienced

I have also sent the following to the editors of the 4 boards I am on, namely Pharmaceutical Research, Drug Discovery Today, Mutation Research Reviews and The Journal of Pharmacological and Toxicological Methods. These are by far not huge journals but they are with Springer and Elsevier and I do think its time the big publishers were more responsive to younger scientists.  Just look at the editorial boards.

Here is the text I sent to each journal editor: I was thinking today – is there a way we could get some “younger scientists” on the editorial board.. I look at myself and I am 44, I am no longer a “young scientist”. I think it might be important to get some input from those under 40 and possibly in the early 30s because things are moving quite fast in the publishing world e.g. F1000Research, PeerJ etc.. and we may risk seeing competition from these types of journals that may attract younger scientists.”

Yes I do realize that this comment may get me kicked off these journals, and hopefully replaced by someone younger.

 

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