On any given week, readers of Derek Lowe’s “In the Pipeline” blog are likely to find posts detailing new layoffs, downsizing, shutting down of whole research groups by big pharma. Why is this happening? The short answer is that useful new drugs aren’t being found. The long answer is that to find a drug, you ought to know what it is that you want the drug to do. The longer answer is that we don’t understand what’s going on inside cells and organisms well enough to even know what we want a drug to target.
I’ve always been impressed with how little we know about what’s going inside our cells, let alone what’s going on between them, despite unbridled biochemical and molecular biological hubris to the contrary. Remember nonCoding RNA — it codes all right, just not for protein. Remember Junk DNA — since we didn’t know what it did, it received the name, despite the fact that over 50% and probably all our DNA is transcribed into RNA.
Over the years, I’ve written lots of posts about our ignorance about these matters. This is exactly why finding new and better drugs is so hard. I’ve collected them into a new category “Aargh! Big pharma sheds chemists. Why?” They all assume that you know your chemistry (as do all the posts on this blog). How much molecular and cellular biology readers know is unclear. However all the background a chemist should need to read this is found in another category “Molecular Biology Survival Guide (for the chemist)” which contains 5 background articles.
Here’s a brief heads up about what each article in the category contains and a link to it. Note that they don’t appear in an particular logical sequence, just in the order they were written, newest first. More will be added.
1. https://luysii.wordpress.com/2011/11/20/life-may-not-be-like-a-well-but-control-of-events-in-the-cell-is-like-a-box-spring-mattress/ concerns feedback, and how it obliterates the simple minded notion of control.
2. https://luysii.wordpress.com/2011/10/20/more-troubles-for-the-poor-pharmacologist/ — concerns Miraculin, a molecule which acts as an agonist in some situations and an antagonist in others. How many of our drugs might act like this.
3. https://luysii.wordpress.com/2011/07/17/weve-found-the-mutation-causing-your-disease-not-so-fast-says-this-paper/ — Very disturbing work — showing that mutations thought to cause epilepsy don’t always do so (depending on genetic background). By implication this is true for other diseases as well, and makes it unlikely that we will ever uncover ‘the’ cause of many diseases.
4. https://luysii.wordpress.com/2011/03/02/we-dont-know-all-the-players-which-is-why-finding-good-drugs-is-so-hard/ — This is the real reason drug discovery is so hard. This work describes some newly found players which determine how much protein actually gets made by a given cell.
5. https://luysii.wordpress.com/2011/02/02/medicinal-chemists-do-you-know-where-your-drug-is-and-what-it-is-doing/ This describes a paper which shows that amitryptyline, a drug we thought we understood, has a radically different action, and in cystic fibrosis of all things. Hint: it involves ceramide a newly discovered second messenger inside the cell.
6. https://luysii.wordpress.com/2010/12/29/tidings-of-great-joy-for-synthetic-organic-chemists-anyway/ — Shows had all sorts of small (under 1000 Dalton) molecules of intermediary metabolism bind to cellular proteins (not necessarily on their active sites) and affect their function. Checking this out gives us a whole new group of druggable targets — again assuming we know everything the protein is doing.
7. https://luysii.wordpress.com/2010/11/14/protein-mutation-the-view-from-the-bedside-and-the-lab/ — discusses two different views of proteins — that of the clinician, for whom even a single mutation causes disease, and that of the population geneticist who shows that in a given population each proteins contain tons of them which have no significant effects at all.
8. https://luysii.wordpress.com/2010/09/08/positive-allosteric-modifiers-exciting-and-humbling/ — discusses allosteric modifiers of protein function, and how hard it will be to find them, since our understanding of all the conformations a protein can assume and how to shift from one to the other is so sketchy.
9. https://luysii.wordpress.com/2010/08/12/2-new-kinds-of-genes-who-knew-we-didnt/ One is about genes coding for multiple very small peptides — which essentially have been ignored, since one way of looking for protein coding genes, it to search DNA for sequences lacking stop codons.
10. https://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/ — Concerns this nebulous disease and the fact that most kids with it have a genetic defect peculiar to that family. Given that, how do you find a single drug to treat it (assuming treatment is needed — something contentious at this point).
11. https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/ How a pseudogene for a tumor suppressor determines the actual level of the tumor suppressor. The first inkling of what turns out to be a year later a very widespread phenomenon (ceRNA –aka competitive endogenous RNA) – a future post will discuss how this introduces a whole new layer of control in the cell.
12. https://luysii.wordpress.com/2010/07/01/why-linearity-is-not-enough/ Essentially #1 all over again — I plagiarized myself.
13. https://luysii.wordpress.com/2010/06/16/bad-news-on-the-cancer-front/ A mere 50,000 single nucleotide changes between normal tissue and one highly sequenced adenocarcinoma of the lung. Doubtless, not all are causative, and doubtless that different tumors will have different mutations, but it’s hard to see a generalized drug for cancer.
14. https://luysii.wordpress.com/2010/02/17/organic-chemistry-under-assault-ii/ Why even knowing 6 genetic causes of a well understood disease (Parkinsonism — due to a deficiency of dopamine) doesn’t really give you a clue as to a way to treat it.
15. https://luysii.wordpress.com/2010/02/14/organic-chemistry-under-assault/ A mystery — figuring out how a well known toxin does what it does
16. https://luysii.wordpress.com/2009/11/09/some-humility-is-in-order/ Despite having studied hemoglobin and sickle hemoglobin out the gazoo for 60 years, we still don’t have a small molecule inhibitor of hemoglobin sickling, showing how paltry our understanding of protein dynamics actually is.
17. https://luysii.wordpress.com/2009/10/20/vegetarians-are-wimps-science-now-tells-us-why/ A fun post showing how even something ‘natural’ has unexpected effects inside our bodies.
18. https://luysii.wordpress.com/2009/09/25/are-biochemists-looking-under-the-lamppost/ — Explores the possibility that side chains of proteins can chemically interact with each other to form new and exciting compounds. The example is green fluorescent proteins, but see a recent comment, about 5 home grown cofactors that proteins make for themselves. Iss more of this going on in our cells. We won’t know until we look.
19. Added 12 Jan ’12 – https://luysii.wordpress.com/2012/01/12/why-drug-discovery-is-so-hard-reason-19-ribosomal-profiling/. More than half of 5000 proteins studied in a mouse embryonic stem cell have multiple variants due to synthesis initiation at multiple sites on the mRNA. This is distinct from splice variants (which also occur).
2o. Added 29 Jan ’12 – http://luysii.wordpress.com/2012/01/29/why-drug-discovery-is-so-hard-reason-20-competitive-endogenous-rnas/. How mRNAs for one protein act as sponges, sopping up microRNAs which might otherwise be decreasing the levels of another protein.
21. Added 7 Mar ’12 – https://luysii.wordpress.com/2012/03/07/why-drug-discovery-is-so-hard-reason-21-rna-sequences-wont-help-you-determine-function/. RNAs with almost no sequence similarity can have very similar functions. Using human lincRNAs to cure developmental defects in Zebrafish
22. Added 18 Mar ’12 – https://luysii.wordpress.com/2012/03/18/why-drug-discovery-is-so-hard-reason-22-drugs-arent-doing-what-we-think-they-are/. Hallucinogens don’t excite your brain, they put parts of it to sleep. Who knew?