Juniorprof reaches superstar blogger status…

… at least according to my preset standard. I am now on Derek Lowe’s blogroll. Now that’s an honor! It also explains the considerable uptick in traffic around here.

Somewhat cryptic reviews, any advice?

We just got the referee and editor comments back on a paper we’ve been trying to get out for some time now. We first aimed high with a glamor mag and got some very encouraging reviews back from the editor but they were ultimately asking us to do far more than we can reasonably do (essentially asking us for experiments that would require us to develop a collaboration because we have no expertise in the type of very technically challenging and error-prone experiments they asked for) so we decided to shoot a tad lower and go for a very nice but non-glamour mag journal. We just got revision comments back from that review and I’m a tad confused by the comments from the editor.

We had the standard 2 referee report. 1 referee is clearly on our side, in fact, she said “now acceptable for publication” in the review and also noted that we had appeased the comments of both referees. I was pretty happy about that. The other reviewer didn’t seem so happy and has asked us to do yet more experiments including several that they did not ask for the first time around (this frustrates me to no end, if you didn’t think of it the first time then don’t ask for it the second time). If we did all the experiments suggested by the reviewer we would end up with about 15 multi panel figures. This is obviously excessive. I should qualify that all the experiments suggested are very interesting and we would like to do them but at some point you have to consider that a paper can only be so long and can only fry so many fish.

The interesting thing was the comment from the reviewing editor. They state right up front that the manuscript is potentially acceptable for publication and that they want to see a revised manuscript soon but they use the words “major revisions”. They also say that they are going to carefully review the manuscript and the response to the reviewers suggesting that they are not going to send it back to the referees (one clearly said accept anyway). The language is a bit cryptic so while I don’t think they are going to send it back to the referee that we have not fully convinced I cannot be 100% certain. The language of the editors really suggests to me that they would like to see the paper in the journal.

We would be very happy to have this manuscript published in this journal so we don’t want to blow the opportunity by taking anything for granted. If we do all that the non-convinced reviewer has asked us to do we have 4-6 months of work ahead of us before we can get a revision in. This thought makes me sick to my stomach because we have advanced this work significantly into another area and we are almost ready to get that paper submitted too but it has to wait on this one. On the other hand, we can do a completely different experiment, which the reviewer has not asked for, that would very strongly support our contention but through a negative rather than positive result. That experiment would take less than a week. I am strongly inclined to do the fast experiment and make considerable text revisions and get this puppy back in. It does seem that the editors are on our side and a quick turn-around would hopefully catch them while they are still feeling good about what we have done.

So, dear reader, what do you think? Am I off my rocker or does this sound like a reasonable path to acceptance?

Rapid behavior-based identification of neuroactive small molecules in the zebrafish, Pharm 551A: Kokel et al., 2010

Today’s paper is a continuation of our discussion on screening compounds for drug discovery: Kokel et al, 2010 Rapid behavior-based identification of neuroactive small molecules in the zebrafish, Nature Chemical Biology [PMC]. Having just returned from the IASP meeting in Montreal I am really pressed for time today so this is going to be brief; however, don’t let my brevity stop you from delving into the details of the paper — its a really fascinating study with major implications for drug discovery.

The problem is a simple one: when screening compounds we typically work on the assumption that the target for the disease is known. This is required because a typical library screen is based on receptor or enzyme activity and not a relevant behavioral phenotype. While this is fine for disorders with well understood targets, this is often not the case for neurobiological disorders where we don’t necessarily know the target beforehand. Hence, a behavior-based screening mechanism that is done in a high throughput fashion/screen (HTS) would be optimal for identifying novel neuroactive compounds. The problem is that behavioral experiments and model organisms are generally not conducive to this sort of thing:

Unlike target-based approaches, phenotype-based screens can identify compounds that produce a desired phenotype without a priori assumptions about their targets. Phenotype-based screens in cultured cells and whole organisms have identified powerful new compounds with novel activities on unexpected targets in vivo. However, it has been difficult to combine chemical-screening paradigms with behavioral phenotyping, perhaps because many well studied behaviors are too variable or occur in animals that are too large for screening in multi-well format.

So how have the authors provided a solution to this problem?

And I’m off…

to Montreal! Having lived in Montreal for 3 years as a postdoc at McGill I’m about as excited as I can be to be headed back to my old stomping grounds for the International Association for the Study of Pain meeting. Mrs. JP and I will be there for a week and are both attending the conference. This will be Mrs. JP’s first time at the conference and our first time going to a conference together (the basic and clinical mix at this conference has provided the opportunity). Should be exciting!

This is the first IASP meeting on the new two year rotation (next one is in Japan 2012 and then to Argentina 2014). The schedule for this meeting is very strong (IASP is always good) but the growth in the field is readily evident from this year’s line-up of talks and posters. I may try to blog the conference but more likely I’ll be sending out tweets.

Pharm 551A class, there will be no posts this week for class content since I won’t be around.

Quantifying biogenic bias in screening libraries, Pharm 551A: Hert et al. 2009

Today’s paper [PMC] is Hert et al., (2009) Quantifying biogenic bias in screening libraries. At issue for todays class is a discussion about one of the first steps in drug discovery, compound library selection and generation. The authors of this paper pose a very interesting question: with the available chemical space (which is massive) how do high throughput screening (HTS) efforts for drug discovery ever succeed?

Chemical space—that is, all possible molecules—is estimated to be greater than 10^60 molecules with 30 or fewer heavy atoms; 10 ug of each would exceed the mass of the observable universe. This figure decreases if criteria for synthetic accessibility and drug likeness are taken into account and increases steeply if up to 35 heavy atoms (about 500 Da) are allowed. Positing even a modest specificity of proteins for their ligand, the odds of a hit in a random selection of 10^6 molecules from this space seem negligible.

So, based on this seemingly impossible complexity, how does HTS ever succeed to begin with. They have at least two hypotheses:

HTS nevertheless does return active molecules for many targets; how does it overcome the odds stacked against it? One might hazard two hypotheses. First, molecules that are formally chemically different can be degenerate to a target, and many derivatives of a chemotype may have little effect on affinity. This behavior, and the polypharmacology of small molecules, undoubtedly contributes to screening hit rates. Such chemical degeneracy seems unlikely, however, to overcome the long odds against screening. A second explanation is that screening libraries are far from random selections, but rather are biased toward molecules likely to be recognized by biological targets. This second hypothesis seems more plausible, as many accessible molecules are likely to resemble or derive from metabolites and natural products. Some of these will have been synthesized to resemble such biogenic molecules, while others will have used biogenic molecules as a starting material.

Pharm 551A: first day of class

Today was the first day of class for Pharm 551A. Not much to talk about other than a brief discussion of the construction of the class and expectations followed up by a quick run through of the basics of drug discovery to prep for the papers we’ll be doing over the next month. We’ll start the online continuation of paper discussion here after Thursday’s class.

If you’re coming over to check out the blog and are in the class here are some links to the pharma blogs I told you about this morning:
Derek Lowe’s In The Pipeline
Pharmalot
and another I forgot to mention: Pharma Conduct, although it may have gone dead because nothing has been posted in some time.

Also, here are some of my previous discussions on drug discovery on this blog, in case you’re interested:
Drug Discovery in Academia
Drug Discovery in Academia and NIH funding

Regular readers of my blog (DM and someone else I’m sure), this is the start of the incorporation of my class into the blog. Yes, its an experiment and, yes, the students agreed that it “might” be useful.

REPOST: Henry (Hank) Yamamura, 1940-2008

On the first day of class at UofA its a good time to re-commemorate one of the true giants in the history of pharmacology. Almost 2 years ago today Hank Yamamura passed away after a fight with lung cancer. Today, 2 PhD students started in our department funded by the Hank Yamamura Fellowship. The fellowship is a terrific way to remember a great scientist dedicated to understanding how drugs interact with receptors, training the next generation of scientists and mentoring junior faculty. He is one of my scientific heros and a dear friend and mentor. Here is what I had to say about Hank the day after he passed away.

Pharmacology has lost another giant. Hank Yamamura died last night after a long battle with cancer. It is hard to imagine that there is a pharmacologist alive today that is not familiar with the work of Dr. Yamamura. He is the author of nearly 500 papers, countless books and book chapters and a mentor to a generation of pharmacologists. Hank did his PhD at University of Washington and then headed to Sol Snyder’s lab for postdoctoral work. Hank played a major role in the original descriptions of muscarinic pharmacology while working with Snyder. In 1975 he moved to the University of Arizona where he eventual became a Regent’s Professor in the Department of Pharmacology. At the University of Arizona, Hank practically wrote the book on opioid receptor pharmacology with especially strong contributions to the area of delta-opioid peptides. Hank was an active and cherished member of the Department of Pharmacology from 1975 until the day of his passing.

I first learned about Hank Yamamura, like most pharmacology PhD students, from his book “Neurotransmitter Receptor Binding”. His contributions to cannabinoid pharmacology played an important role in my PhD work. For the past 9 months of my life I was lucky enough to work in the same Department with Hank. When I first arrived here he was one of the first to greet me. Hank made a point to come visit my office (which was in a separate building) at least once a week and he was always eager to hear about what we were working on. He read all of my grant applications and gave me incredibly detailed comments. He shared advice on navigating the varieties of channels at the University and we eventually developed a small collaboration (which will continue). In other words, in 9 short months Hank became one of the most important mentors I have ever had and became a dear friend. I am just one of hundreds of trainees and faculty who have been positively touched by Hank’s never-ending enthusiasm for science and boundless generosity. I think I can speak for the entire field in saying that we will all miss Hank.

Filing suit to block competition for federal funding?

This is almost unbelievable. Apparently a federal judge has blocked the Obama administration’s change to stem cell research policy.

There’s this gem of a paragraph at Forbes on the story:

A federal appeals court had ruled that two fellow plaintiffs – doctors who do research with adult stem cells, James Sherley of the Boston Biomedical Research Institute and Theresa Deisher of AVM Biotechnology – were entitled to sue over the new guidelines, prompting U.S. District Judge Royce Lamberth on Monday to reverse a decision he made in October when he dismissed the lawsuit.

Sherley and Deisher allege that the guidelines will result in increased competition for limited federal funding and will injure their ability to compete successfully for National Institutes of Health stem cell research money.

I almost fell over when I read that so went searching for confirmation and found this at USA Today:

Lamberth’s reversal follows a federal appeals court ruling that allowed two adult-stem-cell researchers to pursue a lawsuit, claiming that the new guidelines would increase competition for limited federal funds and that it violated federal law.

Lamberth said that the “injury” of increased competition that James Sherley of the Boston Biomedical Research Institute and Theresa Deisher of AVM Biotechnology would face “is not speculative. It is actual and imminent. Indeed, the guidelines threaten the very livelihood of plaintiffs Sherley and Deisher.”

I really don’t know what to say but this seems like a dangerous precedent to me from Judge Lamberth. There is obviously more to the ruling than the dangers of competition for NIH funding (seriously, I can’t believe this) as part of the ruling is based on anti stem cell interests but this NIH thing appears to have played a part. And, yes, if you think you recognize the name James Sherley from something else, you probably do.

UPDATE: In case you don’t go all the way down in the comments, look what DM found
UPDATE II:

A primary research paper has just changed my gym routine

My lab dabbles in mTOR work so I pretty regularly scan pubmed for new papers with mTOR in the title or abstract. Its a fast moving field so there’s lots to keep up with and usually 20-30 new papers out for each of my saturday morning mTOR searches. This morning I stumbled upon this little gem:
Burd et al., PLoS One Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men.
Now, I’m no exercise physiologist so I’m not going to go into details on the background of the work but I do know enough to know that stimulating protein synthesis in muscles through weight training is your goal. This builds muscle mass, makes you stronger/faster — all those reasons that we go to the gym in the first place. The question is how best to do that. mTOR, for those that don’t know, is a kinase involved in regulating protein synthesis. Its a complicated cascade but the basics are that stimulating mTOR in a cell type leads to more protein synthesis. If a specific type of exercise stimulates mTOR activity, this is probably a good thing to achieving results from your workout. In the paper they had young men do three types of exercise (on a leg extension machine): 1) low rep / high weight, 2) medium rep / medium weight and 3) low weight / high rep. In a nutshell, they found that low weight / high rep was the best way to go to stimulate mTOR in muscle fibers. So what does this mean?

Lilly… ouch!

Can this get any worse? On Monday this story on financials and drugs coming off patent vs. the pipeline for Lilly is in the NYTimes. Then, yesterday, this story comes out about Lilly’s failed gamma-secretase trial for Alzheimer’s. Derek Lowe has a nice run-down on this latest failure plus links to his previous musings about this up today. Doesn’t sound good for Lilly. And what does this mean for all the hype on the Alzheimer’s biomarkers last week? Looks like major turmoil ahead to me.