ACS 2015, chemistry talks, posters and Tattoo!

I am just back from a very busy trip to Boston for the ACS. It was great to meet up with many people I see only rarely, at these meetings as well as meet new people including one with a molecule tattoo that got a lot of interest on Twitter .

I gave 5 talks on a diverse array of topics from Chagas disease to big data,  including one in the #CINF Careers session organized by Rachelle Bienstock. I have posted these on F1000Research in addition I gave 2 posters and these are also on F1000Research. (As of 21st Aug I have them on Slideshare too)

So a big thanks to all the chairs of sessions and those in the audience for asking great questions and stimulating lots of thoughts on further experiements etc. It was also an honor to be part of the very first JC-Bradley session Chaired by Antony Williams and Andrew Lang on data openness. I tried my best to formulate the complete soup to nuts history of my involvement in the Ebola story that is still in process.  This meeting also marked the first time I attended the small chemical business sessions and I was pleasantly surprised and inspired! I made some great contacts and had chance to chat with entrepreneurs including Dr’s Harry Mandeville and George Whitesides who had started a drug company (GelTex) in the 90s and sold it for $1.3bn to Genzyme.

OK now back to the task of working on grants to see if we can put all this productivity into funding some more research. Back on the treadmill.


A needle in a haystack

A busy day before going to the ACS. We have put a couple of similar posts (here and here) out in an attempt to try to identify some Sanfilippo type D (MPS IIID) patients or at the very least to get their families to register in the registry .

This is like finding a needle in a haystack. Looking through the literature there are so few case reports and certainly nothing recently, which calls out for an update. If you are reading this and know of any, please point them our way and we can let them know there is work ongoing to develop an enzyme replacement.

I would certainly welcome any ideas of how we could find these families.



My updated schedule for the ACS Boston meeting

Well next week it is the ACS in Boston and of course I leave it to the week before to pull everything together. I initially put up here my listing of abstracts titles etc back in May. This has now been updated a bit to include additional talk and poster showings as well as times and locations. I am looking forward to the careers panel on Sunday morning, that is a new one for me. I will also be giving a talk at the Broad on Tue morning  hosted by Patrick McCarren on the Tuberculosis work also, so its going to be a bit busy! I hope to see you there.
Sunday Am
Careers in Chemical Information and Cheminformatics
Panel Discussion & Brunch
9:00 to 11:00 AM, Boston Convention Center, Room 52AB

PAPER ID: 2246123
PAPER TITLE: Applying cheminformatics and bioinformatics approaches to neglected tropical disease big data (final paper number: CINF 10)

DIVISION: Division of Chemical Information
SESSION: The Growing Impact of Big Data in the World of Chemical Information
SESSION TIME: 8:30 AM – 11:50 AM

DAY & TIME OF PRESENTATION: Sunday, August, 16, 2015 from 10:05 AM – 10:30 AM
ROOM & LOCATION: Room 104B – Boston Convention & Exhibition Center

PAPER ID: 2248989
PAPER TITLE: Starting small companies focused on rare diseases (final paper number: SCHB 4)

DIVISION: Division of Small Chemical Businesses
SESSION: Entrepreneurs’ Poster Session
SESSION TIME: 11:00 AM – 1:00 PM

DAY & TIME OF PRESENTATION: Sunday, August, 16, 2015, 11:00 AM – 1:00 PM
ROOM & LOCATION: Galleria – Westin Boston Waterfront

PAPER ID: 2249028
PAPER TITLE: Development and sharing of ADME/Tox and drug discovery machine learning models (final paper number: COMP 104)

DIVISION: Division of Computers in Chemistry
SESSION: Emerging Technologies in Computational Chemistry
SESSION TIME: 8:30 AM – 11:45 AM

DAY & TIME OF PRESENTATION: Monday, August, 17, 2015 from 9:00 AM – 9:30 AM
ROOM & LOCATION: Room 157C – Boston Convention & Exhibition Center

PAPER ID: 2248973
PAPER TITLE: Making it open: Putting cheminformatics to use against the Ebola virus (final paper number: CINF 79)

DIVISION: Division of Chemical Information
SESSION: The Growing Impact of Openness in Chemistry: A Symposium in Honor of JC Bradley
SESSION TIME: 1:00 PM – 5:50 PM

DAY & TIME OF PRESENTATION: Monday, August, 17, 2015 from 1:25 PM – 1:45 PM
ROOM & LOCATION: Room 103 – Boston Convention & Exhibition Center

PAPER ID: 2248989
PAPER TITLE: “Starting small companies focused on rare diseases”
DIVISION: SCHB: Division of Small Chemical Businesses
SESSION TIME: August 17, 2015 from 8:00 PM to 10:00 PM

DAY & TIME OF PRESENTATION: August 17, 2015 from 8:00 PM to 10:00 PM
ROOM & LOCATION: Hall C (Boston Convention & Exhibition Center)

PAPER ID: 2248999
PAPER TITLE: Mobile apps for transporter drug-drug interaction prediction: A tool of the future, now (final paper number: TOXI 48)

DIVISION: Division of Chemical Toxicology
SESSION: General Poster Session
SESSION TIME: 6:30 PM – 8:00 PM

DAY & TIME OF PRESENTATION: Tuesday, August, 18, 2015, 6:30 PM – 8:00 PM
ROOM & LOCATION: Grand Blrm A – Westin Boston Waterfront

PAPER ID: 2248982
PAPER TITLE: Mining big datasets to create and validate machine learning models (final paper number: CINF 159)

DIVISION: Division of Chemical Information
SESSION: Computational Toxicology: From QSAR Models to Adverse Outcome Pathways
SESSION TIME: 1:30 PM – 5:10 PM

DAY & TIME OF PRESENTATION: Wednesday, August, 19, 2015 from 2:35 PM – 2:55 PM
ROOM & LOCATION: Room 103 – Boston Convention & Exhibition Center


My experience of submitting another manuscript to PLOSONE

Its been several years since I last submitted to PLOSONE . Since then we embarked on a Phase II grant working on tuberculosis and after much work by many labs at Rutgers and SRI we are now submitting the work today. So we decided to give PLOSONE a second chance. In the interim I have published in PLOS Computational Biology and PLOS Neglected Tropical Diseases.

So one of the challenges of having a large collaboration is the number of co-authors, this one has 13. Using Editorial Manager just adding author details alone took nearly 1h. They do not make it easy to enter addresses for people from the same group either. Then there are the picky figure resolution and image file formats to deal with that create hours of work for the non graphic designers out there. After trying to get images of the right resolution and size  etc. I have probably re-uploaded at least 10 times, waiting to read the figure quality report only to see the word fail. I have become far too familiar with a graphics program called GIMP and the removal of the “alpha channel”. Frankly I do not want to be spending my time working as a graphic artist just to publish in PLOS, I am beyond tired of their requirements. Compared to other journals like ACS, Springer, F1000Reports etc, submitting to PLOS ones are time consuming in my opinion. After spending 5.5hrs working to submit the manuscript, 4 figures and 5 supplemental files, I am wondering why anyone would want to do this again. Lets see how it does in review.



Wearing many hats

I wear a few different hats and yesterday I was CEO, working on the commercialization plan for a phase II grant for a rare disease. To this point the big selling point was getting a Rare Pediatric Disease Priority Review Voucher but this is a challenge because its unclear if there will be more of these in the future. This lead me to write a post for the good people at Rare Disease Report (any fees will be donated to rare disease foundations).

Today is another day and I am wearing another hat, working on grants for a different company with different challenges.


Targeted Drug Development : The FDA perspective – A more approachable regulator?

As I am slowly catching up on my reading and I came across this new white paper type doc from the FDA which came out a few weeks ago called Targeted Drug Development: Why are Many Diseases Lagging Behind?

It makes for an interesting read and of course conjures up images of diseases on a race track.. but should it? Tortoise and hare each being different diseases, Alzheimers and Hepatitis C perhaps in this analogy. 

I did get a sense of the FDA throwing down a challenge and saying that discovery and testing had not kept up, the regulatory side was doing just fine thanks, but that’s just my take.

The diseases chosen were those which billions of dollars / euros have been invested, cancer, diabetes, Alzheimers, HIV/AIDS and Hepatitis C. And then there is a little mention of rare diseases, which appear to be the Cinderella here, they are generally poorly funded, have few patients and have to be creative to make their mark.

Take home messages –

These were the need and use of surrogate endpoints in clinical trials. Flexible trial designs were also mentioned and this could mean many things such as adaptive trials, or anything that veers away from the gold standard randomized placebo controlled trial. The need for the FDA to work closely (collaborate) with companies, academia and patient organizations was also touted as important.

Is this a sign of a more approachable (read warmer and cuddlier) FDA as they push the US as leading the world in the introduction of novel drugs?

Personally I think a 13 page PDF is a bit much, it could have been boiled down to one page. My summary is that even if you spend billions on a big disease over decades you still may not have what it takes to find a treatment. Focus on what clearly matters to the FDA, come up with a good surrogate endpoint, plan a flexible trial, collaborate and voila you should be able to succeed. According to this document it sounds like the FDA has development covered and it is a shot across the bows to discovery to clean up their act and get with the program. Not so fast you might say – I can bet coming soon is a comparable doc from the NIH saying we need more funding to improve the discovery situation. So is this all posturing ready for the next president you might ask? Well I will let you decide, but frankly I wished the FDA would just focus on getting more drugs approved and leave white papers to others.



Wiki, Wiki, Wiki – for chemical probes

Sorry for the cheap title (for those born after the mid 80’s its a reference to a song by a funk band called Newcleus).

A very interesting commentary published today in Nature Chemical Biology by Arrowsmith et al and its all about chemical probes. Go check it out and note that it took over 50 people to put this together. I am not an expert on these things but at a guess it could have been written by a handful of authors…how many of these authors are tacked on for show?

I found out about it yesterday and was asked to comment on it for Chemistry World – I would have much preferred to have reviewed it for Nature Chemical Biology and then perhaps this would have ended up in a journal that is more appropriate based on the results it contains.

The results are a Wiki.. and so far the Wiki contains only 7 chemical probes. Yes I had to look a few times to make sure I had not gone to the wrong address today when it published – when I looked yesterday all I could find was a GoDaddy site. With over 50 authors from very distinguished labs I would have expected them to push out (or their students) a grand total of more than 7 probes. Dare I mention how many $millions these labs pull in from the tax payer to work on finding chemical probes..naming no specific names. And then there are the big pharma folks, pretty sure they have wasted a good few $billion pursuing avenues of research based on duff probes..they could have chipped in a few that actually work. Why not add them to the commentary for good measure? Yes Wiki’s take lots of effort but based on this, the wiki was an afterthought, the commentary came first. I would hazard a wild guess that there will be less than 50 people submitting probes to this wiki (outside of the authors). I hope WellcomeTrust do not look at what they have funded anytime soon – they may want to wait until the number of probes at least reaches double figures. And with that they should have published when there was something substantial to show.

I do not mean to come across as cynical because a few of the authors are widely admired (by me at least for their consistent efforts in exposing crummy molecules, probes and drugs)..Some of the authors are admired for other things that generally do not involve chemical probes or developing wiki’s.

My actual email to the reporter from Chemistry World is below – you can see how just one line was chosen out of several choice quotes – IMHO producing a database would have been ideal that is at least structure searchable (we are dealing with molecules here after all) and contained all the probes out there (good and bad).. And how can you totally ignore the massively funded NIH chemical probes effort when one of the authors is from the NIH? Why did this have to come from the Structural Genomics Consortium? The more I read it and think about it, the more questions.


Dear Ida,

I am happy to provide some comment on reading this paper. Thank you for bringing it to my attention.

My first comment is does it really need 53 authors to preach to the choir on this topic? Or does this journal only accept mega-author papers
Many of these groups are either responsible for putting probes out there / funded to the total tune of over $500M by the NIH over the past decade, they should have thought about the consequences of what they were doing at the outset and planned a database of probes and information.

Is it me or has the definition of a probe and requirement continually shifted with each publication?

A chemical probes portal – a great idea but the url appeared to fail – did the reviewers of the article test it –(I get a godaddy site!)
Most people would write a paper after they had done something useful, perhaps it would have helped if they created the wiki first, made sure it was functional, then publish a paper on it?
No idea if such a portal would actually be searchable by structure – that was not suggested in the paper by the authors!

Most people would probably come across the probes with issues on “in the pipeline” blog – Derek Lowe does a good job of alerting the community anyway.

The authors did not cite our recent summary of issues with chemical probes – which is unfortunate, I know at least one of the 53 authors read it- Parallel worlds of public and commercial bioactive chemistry data. – PubMed – NCBI 

Hope that helps.







What’s needed for TB: A critical analysis of the drug discovery pipeline and efforts

After attending the Gordon conference on Tuberculosis (TB) drug discovery (without breaking the rules on describing what was presented) I think I can safely make a few general comments which were already in my mind before the meeting. This week what stood out for me was the lack of knowledge of all the efforts that are going on globally in TB. No single person has attempted to summarize the various global initiatives, the multigroup collaborations, the consortia of all shapes and sizes and at all stages. When you ask colleagues you know or those you meet for the first time, they do not have a complete picture. Most of the TB initiatives are under the radar to most. Frankly if we are to make the case for more funding there needs to be an unbiased and transparent assessment of the preclinical and clinical efforts, the funding situation in each country has to also undergo some scrutiny and any non essential duplication could be avoided.
How could this be remedied. A team needs to be formed that can cover the biology and chemistry as well as some of the funding elements and write it up succinctly. While there are pipelines for drugs, there is no definitive source of all the preclinical hits or leads. There is no summary table of all the consortia or major funded collaborations in TB. It’s not clear what consortia are open or closed to others not in them. It’s not even clear what efforts are being made to learn from the data that has been generated historically or is being generated (e.g. all the screening data). For what targets is there duplication of effort, which have failed, or considered most or less valuable?  What libraries have been missed? What chemical space has been covered and what should be done next (most do not truly understand the drug discovery process)? This kind of analysis probably happens frequently in many other diseases but I think it is sorely needed for TB. Is there anyone willing to help do this?


Waging war on infectious diseases

While I am at the Gordon Conference on Tuberculosis (TB) Drug Discovery and Development this week I cannot live Tweet due to their policy. I do however have some thoughts based on my observations.

This is not a war fought by soldiers armed with guns and artillery against an enemy similarly armed, this is a long war in which each side has evolved its weapons. The enemy is infectious diseases, they mutate, they morph, they resist our weapon of choice the drug. Fortunately through technology advances our drugs also change, we identify new chemistry, we find new targets and we combine our weapons to make them lethal.

These soldiers do not get recognition, their battlefield is the laboratory and their enemy is contained within plastic plates or mice infected with the disease. This practice battleground prepares them for the real battle in countries around the globe, the billions affected and the millions of casualties every year.

What scars do our soldiers show, the years of research against a microscopic foe. Their brains the real arsenal, combine and collaborate. But do they suffer too? We take for granted our scientists and the mental anguish they face. Take a disease like TB which has existed for millennia, humans have battled for just as long. Only in the past 70 years have we fought back, and now we are at status quo, our drugs are losing their bite, our funding is diminishing in the west. Are we losing our way? Where are our leaders and what are our new heavy artillery to put in the front line?

As I speak to young scientists focused on the disease its pretty clear they plan to devote their whole career to this disease, their goal is to find a cure. The pipeline looks dire whichever one you pick (1, 2), we therefore have to look in new places for ideas. I think we have to invest in the new generation of scientists as we look to the future. This war will not be won by refusing to fund R&D, it will not be won by continuing to do the same old approaches. I look forward to openly sharing my ideas this week.



Observations on big and small collaborations

Its been a pretty hectic year to date with several grants coming to their conclusion and the need for writing up final reports and manuscripts. In addition it has provided just a little time for reflection. Pretty much everything I am involved in is a collaboration of some sort so I am just a tiny piece of a pretty complex puzzle. Some of the collaborations are small scale (one or two labs) while others are much bigger (MM4TB ~20 labs). In the latter case I have noticed as we got further into the project the sense of collaboration really took off. Which likely suggests that funding a group for 5 years is really too short because just as they get into their stride the project will end. I think this is probably natural as it takes a while for researchers to get to know each other and the more moving parts, the longer this takes. Initially within such a collaboration groups likely self organize with those they know already or feel comfortable with. But how do you get a big team to address a complex set of objectives, to think as one? Does this also suggest there is some optimal group size for collaboration? Possibly. What do you need as a core team for a drug discovery collaboration? Obviously it may depend on the disease to some extent. Take TB. You have in vitro screening, molecular biology, structural biology, medicinal chemistry, computational chemistry, ADME screening, in vivo testing skill sets / components. How many people are needed for each component? Do you need duplication of resources to verify what is seen in multiple labs or cover for illness or problems with experiments not progressing etc? There are a lot of questions. Ideally in a collaboration / project everyone should know each other before the start and be comfortable with your colleagues and this may mean understanding everyones strengths and weaknesses. It is also likely you need at least 2 of everything so this would suggest about 10 labs. This is much closer to the NIH ‘center grant’ type model. Too many groups and collaboration may only happen in small clusters, too few groups and everyone is overwhelmed.

If I was to do something like another large scale collaboration (e.g. MM4TB, which has been an amazing and productive experience to be involved in) I would probably tackle TB from my personally biased direction. Namely, use all the TB knowledge we have accumulated and use the computational models to identify new in vivo active compounds (start with in vivo and not in vitro). I would also combine with some structure based work, docking known in vitro whole cell actives into TB targets as a way to de-orphan compounds. There are literally thousands of HTS screening hits from whole cell screening but there have been minimal efforts to identify which of these have in vivo activity. For all the faults in the old in vivo TB literature data I would use it as a resource from the beginning. There would also be very tight loops between prediction and testing and then updating models. So future collaborations in TB should have a bigger computational and modeling component to compliment medicinal chemistry and biology aspects. While I think smaller scale collaborations do a better job of balancing the experimental and computational aspect, they often lack the breadth of the team you get in a big collaboration. You miss out on that accumulated knowledge. It will be interesting to see if any of these ideas are addressed at next weeks TB Gordon conference. Of course the team size pretty much depends on the grant source. STTR and SBIR funds will dictate small scale collaborations while bigger center grants and the past FP7 funding from the EC has lead to the larger scale TB collaborations. I am still learning from exposure to these kinds of projects and time will tell which will have long term impact. Either way, we need to focus training students to work well in collaborations.

It also occurred to me perhaps these observations could be useful for other diseases and drug discovery. For example in PubMed there are similar numbers of references on drug discovery for TB as for bigger diseases that we think of such as cancer, depression etc (see the rough figure). While admittedly much of my recent work has been on more neglected or rare diseases (Charcot-Marie-Tooth, Ebola, Chagas disease etc) , could the general ideas for a collaborative drug discovery team gleaned from TB be applicable to smaller and bigger diseases? This has implications because it may point to ways in which we can equalize out the effort to spread more resources to the thousands of rare diseases.  Perhaps young researchers will self organize and work on the rare and neglected diseases, but there has to be funding there for small molecule drug discovery. We cannot pull the money from such collaborations as we are seeing in Europe. This perhaps is something that could be expanded as a future topic. How do we learn the best ways to collaborate and pass these skills on to the next generation, and make sure that all diseases benefit from these efforts.

diseases fig


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