Djerassi, spring break and mass spectrometry
Find out a bit about why Carl Djerassi is such a big deal and also why mass spectrometry means so much to life sciences generally and drug discovery and development as well
In the last class before our spring break, I asked my drug development students if they’d heard of Carl Djerassi and knew why this pioneer drug developer had a huge impact on the week they were about to experience. Not one of these students knew of Carl or his many contributions. How fleeting is the reputation of those who advance science. I’ve recently collected obits for Djerassi, given his passing from cancer at 91 this past January. Prof. Djerassi was a renaissance man with notable credits in academic science (>1,200 papers), industry (R&D and management), and the arts (literary and visual). He was not a “modest man with much to be modest about” as the famous Churchill quote goes, but rather “an immodest man with much to be immodest about.” Several described him to me as sitting in the center of a perfectly reflecting sphere. I knew his reputation when we first met 40 years ago. He was not one of those academic derelicts who imagine their brilliance. The guy delivered. A guy that smart would not have missed this valid truth.
While birth control is still debated by some as an illegitimate use of pharmaceuticals, I heartily endorse it. In fact, we could use a lot more of it given current demographics. My students well understood the implications for the university spring break and asked when all this started. I recounted that this began with FDA approval 35 years before they were born; in a decade even more troubled than this one. Djerassi’s work began over a decade before that. Along with the birds and bees, spring also brings thoughts of mass spectrometry to the aging bioanalytical chemist. Each year, the American Society for Mass Spectrometry (ASMS) holds its annual meeting. Meet me in St. Louis, Louie; meet me at the fair. Here again the name Djerassi plays a role. In 1964, he published a book with two of his postdoctoral associates at Stanford [Budzikiewicz, Herbert; Djerassi, Carl; Williams, Dudley H. Mass spectrometry of organic compounds, Holden-Day, San Francisco]. This book was highly influential as mass spectrometry transitioned from a curiosity of physics and physical chemistry, to a tool for petroleum chemists, a detector for gas chromatography and more generally as a structural tool for organic and natural products chemists. Given the introduction of the Varian A60 NMR and benchtop IRs in the same decade, organic chemists never looked back to deducing structures by how they reacted.
Mass spectrometry was greatly facilitated then by light beam recording galvanometers, replacing glass photo plates and later, by minicomputers with data systems replacing physical recorders. During my introduction to mass spectrometry in 1966, the heights of peaks at each m/z were measured with a stainless ruler on rolls of light sensitive paper. This was laborious. In solution-phase electrochemistry we could at least snap Polaroid pictures with a camera bolted on a storage oscilloscope. Either way, I liked ions and still do.
Today, mass spectrometry is most frequently used as a quantitative tool, while its partnerships with NMR, IR, Raman, UV and X-ray continue to grow, particularly in the life sciences where there are plenty of unmet challenges with proteins, lipids, carbohydrates and combinations such as glycoproteins and antibody-drug conjugates. We are far from done with structure explication.
There remain a number of challenges with quantitative work as well. I see three big ones. First, there are many nonlinearities whereby variable components of no interest in complex mixtures influence the desired analyte response. Many users do not understand this aspect and its impact on method validation. Second, mass spectrometry technology is still not yet competitive for random access, allowing for rapid examination of different analytes in each of a series of samples with a single instrument. This is especially impactful for intensive care clinical applications where turnaround time can be critical. On the other hand, when samples are numerous (1,000 +/-) there is no better performance for a price. Third, most worrisome today is the difficulty feeding our instruments with well-collected and well-characterized samples from carefully controlled biology. Sampling matters. Every bio sample comes with a set of attributes which too often are incomplete. This realization, the will to do better and the money to do better are not generally available. It’s time to fix that. To stimulate debate, let me say there are too many innovators and not enough validators. In academia, this means groups with too many Ph.D. students and inadequate support from skilled technicians. I look forward to learning more in St. Louis and hope to see you there. Mass spectrometry momentum is alive and well. The maturity experienced by other chemical instrumentation is still far in the future. The fierce competition among the few leading suppliers is driving innovation in an ecosystem with academics and small suppliers fast on their feet. You have to play to win.
Peter T. Kissinger (who can be reached at firstname.lastname@example.org) is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.