Learning from the Uncontrollable

It was 1974, and at the age of 25, I was working on the control of the cell cycle in fission yeast, one year into my post-doc with Murdoch Mitchison in Edinburgh. Hugely impressed by papers from Lee Hartwell, which described the isolation of cell division cycle (cdc) mutants in budding yeast, I started isolating cdcmutants in the rod-shaped fission yeast. These mutants could not divide but could still grow and thus became highly elongated. Screening for them was a laborious and slow business—only about 1 in 10,000 of the original mutagenized cells yielded a cdcmutant. As a consequence, it took the best part of a year to identify enough mutants to define just 30 cdc genes (we now know that there are 400–500 cell-cycle genes). To reduce the tedious workload of random visual screening, I needed a selection procedure and so hit on the idea of centrifuging cells after mutagenesis through a gradient to enrich for enlarged cells, then examining the micro-colonies formed from these cells under a microscope and micro-manipulating away elongated cells as potential cdc mutants. This was not such a bright idea, however, because mutagen-damaged DNA blocks onset of the subsequent mitosis, resulting in elongated cells not due to a specific gene defect but because of non-specific DNA damage, which affects many cells in the population. I struggled with this procedure for a couple of weeks, unfortunately finding fewer cdc mutants than by my normal