Readers of a certain age may fondly remember the interviews with Dr. Noitall that used to enliven the pages of Science. Sadly, he died a few years back. But his cousin, Dr. Saysno, is still very much alive. Practical Fragments caught up with him at a recent conference in Shutka.
Practical Fragments (PF): Dr. Saysno, you've stated that experts should never be trusted.
Dr. Saysno (DS): Niels Bohr defined an expert as a person who has made all the mistakes that can be made in a very narrow field. If someone has made every possible mistake, how could you possibly trust them?
PF: But don't you think they may have learned from their mistakes?
DS: Balderdash! Hegel was right: the only thing we learn from history is that we learn nothing from history.
PF: What's your opinion of ligand efficiency (LE)?
DS: Ligand efficiency is an abomination! It's mathematically invalid!
Worse, determining the free energy of binding from a dissociation constant is not even wrong: if you change your definition of standard state, you can make ΔG° any positive or negative number you want. Just how relevant do you think your definition of standard state is on the surface of Venus? Or Pluto?
For the same reason, pH is utterly meaningless. You really ought to throw out your pH paper, not to mention your pH meters, since they all assume an arbitrary reference state.
PF: But what about all the researchers who find pH and LE useful?
DS: Usefulness is the last refuge of the scoundrel!
Look, many of the best selling drugs on the market are antibodies, and when you calculate their ligand efficiencies, they are close to zero. How can you have a metric that doesn't work on some of the most important drugs out there?
I only believe in equations that are universal and apply in all situations, unsullied by the physical world. Anything that involves standard states is just mumbo-jumbo.
PF: What do you think of pan-assay interference compounds, or PAINS?
DS: Now that’s a topic that really gets my blood boiling! PAINS were defined on the basis of just six assays. Six assays I tell you!!! [DS vigorously pounds his shoe on the desk.] Just because something hits six assays – or six hundred for that matter – doesn’t mean it will hit the six hundred and first!
PF: But aren't there some chemical substructures that are so generically reactive they should never be used in probes?
DS: Nothing is universal! All molecules are unique, like little snowflakes. If a compound comes up as a hit in your assay, by all means publish it as a chemical probe in the best possible journal, and try to encourage suppliers to start selling it so other people can use and cite your brilliant discovery.
No one has a right to criticize your molecule unless they test it against every single protein in the human body and show that it hits all of them.
When the revolution comes, the imperialist PAINS stooges will be swept into the dustbin of history along with the lackeys of ligand efficiency!
PF: So if you don't trust experts, you don't like metrics, and you can't make generalizations, how can we move forward in science short of deriving every result ourselves from first principles?
DS: That's simple: just ask me!