Early last year, it was reported that Bexarotene (a Ligand product that was discovered when I worked there) cleared amyloid plaques from mice, prompting the hypothesis that the retinoid X receptors were somehow involved in Alzheimer’s disease.  I have to admit I have a soft spot for nuclear receptors in general and rexinoids in specific, having worked on them for so long.  However, this was mouse data and as I have pointed out here and in other places, a mouse is not a human.  So it wasn’t really that surprising that several research groups reported today that they can’t reproduce the experiments. Oh Snap! 

This would fall in to the category of things I find mildly disappointing, except for the fact that doctors have apparently prescribing Bexarotene to their Alzheimer’s patients off label.  Having been at Ligand for a good portion of its troubled history, I know that Bexarotene has some pretty nasty side effects.  Hyperlipidemia that is sufficiently elevated to cause pancreatitis.   I have very serious reservations about off label prescriptions, particularly based on one study.  I know that Alzheimer’s is a horrible disease, but remember our friend Hippocrates, first do no harm.  This clearly falls into the doing harm part of the equation.  

Let’s remember A MOUSE IS NOT A HUMAN.

Sorry for shouting. 

I have to admit I'm a bit cynical.  I'm a chemist, trained in theoretical organic chemistry, so it does come a bit with the territory.  I also have to say I hate self-help books.  Most particularly I hate those that purport to follow or survey successful, happy, or rich people and distill the secret of their success to some easily manageable number of traits you are urged to mimic.  Often you will hear such amazing insights as successful people think big. Or the unbelievably informative statistic all successful businesspeople think positively.  

I find it difficult to imagine that the unsuccessful among us somehow started a business thinking "I never want my business to ever make more than $25,000 a year and what's more, I will most likely fail anyway!"  Its nonsense, and this is where the statistics come in.  You need to take a large enough sample and rate the traits your  groups exhibits and at a minimum compute a p value for the hypothesis that trait A, let’s say positive thinking, distinguishes populations X and Y.  No one ever does anything remotely like this.  So despite the rather silly premise that you can think yourself rich, they don't even bother to try to test their hypotheses. 

The fact of the matter is that randomness plays a much higher role in people’s lives than they want to admit. Let’s take the example of new restaurants.  You often hear the statistic that 90% of new restaurants fail.  It's actually closer to 67%, but that still isn't very good odds.  So what is the differentiator? The successful new eateries are usually started as 2ed or 3rd establishments by an already successful chef.  The 90% failure rate applies to people who knew nothing about the restaurant business before venturing out into the mean streets. 

So is positive thinking what made the restaurants successful?  No it was understanding the business.  What made the 10% of newbies succeed? Chance.  

I'm pretty good at building homology models and using them for virtual screening.  I usually listen to Baroque opera while building them.  Therefore should you, gentle reader, rush out and purchase a selection of Lully, Campra and Rameau before your next homology modeling exercise?  Yes! Not because it will help you build models, but because the music is wonderful and will elevate your spirit.  To be successful at the homology modeling game.  Build a lot of homology models and learn from your mistakes.  Trial and error, not positive thinking is the secret of success.

I’m sure you are all familiar with the Black Death. You may not be aware that in the 6th Century, in the reign of the Emperor Justinian I, a plague of immense proportions spread across the Mediterranean and kill ~1/3 of the population.  This plague is generally identified along with the Black Death as being bubonic plague, caused by the particularly nasty bacteria, Yersinia pestis.

Interestingly enough, there is still a raging debate on what was the causative organism of this plague.  The consensus has always been on Y. pestis; however, there have always been intrepid contrarians arguing that descriptions of the symptoms aren’t accurate enough to really identify the disease as bubonic plague. Some putting forth anthrax, others some yet unknown filovirus.

A paper appearing in PLOS Pathogens by a German group have confirmed Y pestis in DNA extracted from the teeth of bodies found in a 6th century cemetery in Bavaria.  The extra steps taken to use independent labs and prevent modern DNA contamination have pretty much put paid to the notion of an alternate cause to the Plague of Justinian.  I never really had any doubt.  I’m glad this controversy is finally over. 

I've noticed that most companies in the start-up to small company range don't have in house computational chemistry or a laboratory informatics  system.  The former is somewhat understandable.  The latter is inexcusable.  

This paper in PLOS ONE shows a disturbing lack of correlation between IC50’s for the Ephrin type-B receptor 4 (EphB4) when the compounds were dispensed by conventional disposable pipet tips and acoustic dispensing.  The R2 was 0.25.  Also catalyst pharmacophores developed with the two datasets were visible different, which isn’t surprising when you consider the lack of correlation between the two dispensing methods.  The really disturbing part is that when one takes receptor pharmacophores generated from the kinase’s ligand/enzyme complex crystal structures, they agree with the acoustic dispensing data pharmacophore, and are different than the disposable tip generated data. 

I think we have all been aware of the issues with compounds liking to stick to plastics, but this paper suggests a reason why all the data we have been generating and trying to model is so lacking in predictive value.  I personally wonder how many times models I have used to try to help drive a project were doomed before I began working on the project, because the data was contaminated with sticky plastic tips.  This adds one more factor to check when one is building models. A very important factor.  I hope we can see more studies like this and determine if a mass flight from disposable tips to acoustic dispensing is necessary. 

A recent paper in eLife, samples bacterial from the foreheads, palms/paws, stools tongues and the right palm of human household partners.  It showed that the phylotypes of bacteria between human and dog we more similar than between other humans and others dogs.  We are truly symbiotic with our dogs and considering that the correlation between toxoplasmosis and schizophrenia leading some to theorize there may be a physiological basis for the crazy cat person stereotype, it’s likely our homes are our own personal microenvironments.  The next time your dog wants to lick your face, just give up.  You already share all your bacteria with your best friend.

This post is slightly off the beaten path for a drug discovery consultancy, but these two articles were just too juicy to pass up. One paper in PNAS claims to have identified “ultra-conserved words” in a study of Eurasian languages.  It used a statistical analysis to propose a superfamily to all Eurasian languages that evolved ~15,000 YBP. The implications to this are that if you met a hunter-gatherer from that time, you would be able to speak the sentences: “You, hear me! Give this fire to that old man. Pull the black worm off the bark and give it to the mother. And no spitting in the ashes!” and they would at least have some idea of what you were saying. I know the “lumpers” in the historical linguistic camp have a bad rap because of Joseph Greenberg’s disciple Merritt Ruhlen’s claim the proto-human word for the number one was ‘dik’. I actually sort of buy into the hypothesis.  I have to admit one of my hobbies is reconstructing Proto-Indo-European roots, so I am biased.

The second article in Nature, does a convincing job in showing through evolutionary bioinformatics (something I again admit to practicing as a hobby, in the spirit of full disclosure) that the hepatitis B virus entered eukaryotes ~83 million years ago.  The oldest viral relic in a genome is the 99% conserved sequence for avian Hep-B in Zebra Finches.  Chickens don’t have a relic of Hep-B.  Since their oldest common ancestor lived ~82 million years ago, the virus must have entered the genome before that time. Bob’s your uncle!

Read both papers.  They are entertaining as well as quite possibly true.

Following a trail from Gizmodo to Live Science to Nature, I felt like Ponce de Leon.  I was promised that"science" has discovered the "fountain of youth".  Considering the resveratrol debacle that still continues to unfold, megadoses of vitamins, the supplement du jour, and assorted other concoctions of floor sweepings and lawn clippings, my expectations were, shall we say, not very high. It's basically a study of how NF-κB is a key regulatory element for apoptosis in hypothalamic neurons in mice. If you began reading this post hoping you would know how to live longer, the punch line is that when NF-κB is blocked in mice, they live 20% longer. 

If you are new to pharmaceutical research, let me leave you with one key learning:  A mouse is not a human. If you look at all the pathways that have an effect on aging in mice, when you examine them in humans, they are all pretty maxed out.  The take home message is do not try this at home.  If you want to live longer, the biggest single factor is your genetics.  You can exercise, eat healthy and avoid all potential toxins and mutagens and you probably won't live that much longer.  You may feel better, which is nothing to sneeze at, mind you, but eternal youth, well if it's not in your genes, it's not in your future.  Sorry.