Never send in a chimp when a human will do: assays in discovery research

What a day! Between the scintillating launch of the new blogs (really, I am all aquiver) and doing my best to be irksome in my actual day job, I am more than ready to knock back a dry vodka (Grey Goose, preferably) martini at my favored watering hole in Einsteinville.

Part of my job is to pass judgment on protein targets gearing up for screening campaigns. "Screening" refers to high throughput screening which is the bread and butter of discovery research in Big Bad Pharma. It's an automated process in which the general idea is to increase that needle in the haystack factor. This is accomplished by assaying huge numbers of compounds (typically 1 million plus) against an enzyme or receptor target of therapeutic interest.

Just as the saying goes in techno lingo, garbage in, garbage out. To obtain hits (those compounds which affect the enzyme's or receptor's activity) which follow through nicely in secondary analyses, the assay must be good, and not merely adequate. A foible of the local corporate culture I have encountered here is the rush to get an assay in place for screening so that deadlines in a given therapeutic area can be met.

Well, good science can't be rushed in such a slovenly manner. If it's to be performed with efficiency and accuracy, then the folks involved need to know what they're doing. And there's the rub. Everyone and his/her freakin' cat believe they can develop robust assays. Thus, we have biologists who are otherwise quite talented with things cellular, pharmacological and organismal, who really don't have a good grasp of assay design. They don't check out linearity of assay response with time, protein concentration, influence of buffer components, the identity of small molecule and protein co-factors, etc. At some point along the line, they discover something isn't right, and my group, the biochemists (we focus on mechanistic studies), are called in for consultation. Ideally, we'd be there in all the exploratory trenches setting up the assays ourselves, but we're a small group and well, we just can't support everything and everyone. Therefore, we are sometimes doomed to consult. Shudder. So here I was consulting this afternoon.

The issue was an enzyme which, in my much vaunted opinion, is FUBAR . Its specific activity is sucktacular at best, and the Km of a key substrate is so far off the mark as to be in orbit around Jupiter. Yet, the therapeutic area wants to get this into screening ASAP, and one of the guys in the screening group is hesitant to tell them "No f*cking way." My opinion was solicited. So it fell to me, biobitch extraordinaire, to carefully word an e-mail which, in the nicest possible terms, said "Your enzyme is crap. Time for a do over!" Additionally, since this enzyme will be brought into my department for detailed mechanistic analysis, I'd really like to have some good protein in hand.

I hit "send."

Mine will be an unpopular judgment to be sure so we'll see what falls out next week. However, the chemists are very concerned about spurious data emanating from this particluar protein. And I always want to keep the medicinal chemists happy even if I have to piss 'em off sometimes.

All righty then. I'm off for my martini and to contemplate the words of a former mentor (a rather brusque and opinionated fellow):

Any monkey with a cuvette and a Gilford can "do" enzyme kinetics. It takes a human to interpret the data.

More like this

While I might have made you swoon with mention of pharmacognosy, all this talk of assay linearity with time and substrate Km is making me all tingly!! Welcome to the corral/refuge along with all of us newbies!

Amazing to me there would be pressure to go to a HTS campaign with a scheit enzyme; good thing that someone had the sense to call in the biochemist.

This speaks to a larger issue that I saw discussed in the blogosphere re the WSJ article on Merck's Peter Kim yesterday: there are skills that may make one a Natl Acad of Sci academician but not a great leader in pharma. Conversely, there are skills not well-appreciated or valued in academia that are absolutely essential in pharma. Derek Lowe covers some of these things at In the Pipeline but I would love to learn your insights on what can be done in academia to better prepare scientists for a career in pharma. For example, how could those "biologists who are otherwise quite talented with things cellular, pharmacological and organismal" be better prepared for the biochemical rigor necessary to launch a HTS campaign? Or, is it better to have a team of experts in their narrow respective fields who have the sense to call upon one another for advice and, gasp, consultation?


So, substrate Km's and linearity with time make you all tingly? C'mere, baby, and let me whisper to you: "rapid equilibrium pong bi bi...primary isotope effect...commitment to catalysis...ooooooh!"

Fortunately, the rush to HTS with schmutzy protein isn't a universal approach at my place of employment.* I'm relieved that the biologists are reaching out to us. Also, there are some very sharp scientists in our lead discovery/hts division who quickly move to thwart bad proteins and to fix them. In this case, the HTS dude is less inclined to say "No way!" as some of his more assertive colleagues are.

Yes! I read Derek Lowe's piece on Peter Kim. The confluence of academia and pharma drug discovery can be a dicey one. Now it has been a while since I have talked to former colleagues who are now at Novartis in Cambridge, but I wonder how Mark Fishman, another academic transplated to big pharma, is faring? I haven't heard any major rumblings emanating from the old Necco Candy Co. facility. Also, at my former place of employment*, the individual who was the CSO when I first started working there was an academic and was really quite good in the CSO role. When this individual was promoted to president of the company, well, it wasn't such a great fit.

Re: preparation of young scientists in academia for careers in pharma. You have just provided me with fodder for a near future blog entry.

*"place of employment" - I need to come up with thinly, or thickly, veiled pseudonyms for these. Derek has already taken "The Wonder Drug Company."