The domino effect

30.9 turning 513

24/9/04

5:41 pm

Page 513

essay turning points

The domino effect When taking a risk proved a wise choice for one postdoc. Jamshed Tata

ob security is a rare luxury for postdocs. But early in my scientific career, I turned down a secure position to follow a challenge from a senior scientist. My gamble paid off, and a quick succession of unexpected results enabled me to return to a secure career path. When doing my second postdoc in 1959 at the National Institute for Medical Research (NIMR) in London, I attended a joint meeting of the British and Scandinavian biochemical societies in Turku,Finland. There, I listened to Lars (Lasse) Ernster from the Wenner-Gren Institute of Stockholm University talk about the uncoupling of oxidative phosphorylation by L-thyroxine — the precursor to active thyroid hormone — when added in large amounts to isolated mitochondria. Thyroid hormone was known to increase the basal metabolic rate (BMR), the rate at which a warm-blooded animal consumes oxygen and other fuels at rest. At that time, Ernster and many others believed that thyroid hormone’s physiological action could be explained by these in vitro experiments, which showed that the hormone uncoupled the consumption of oxygen from energy (ATP) production.After I told him — with some chutzpah — that I was not convinced that is how the hormone would work in vivo, he responded, “if that is so, come and prove it in my laboratory”. This challenge was enticing,but put me in a dilemma. I had been offered a rare Senior Beit Fellowship to continue at NIMR. Turning down this offer and accepting Ernster’s would be risky.What if I turned out to be wrong? But taking a gamble, I took up Ernster’s offer and arrived in Sweden a year later. Luckily, the very first experiment indicated that I was on the right track.We soon demonstrated that under physiological conditions, triiodo-L-thyronine (T3) — the active form of thyroid hormone — regulated the amount of ATP made by mitochondria in liver and skeletal muscle in strict proportion to their rate of respiration (that is, respiration and energy production remained coupled). The result was in stark contrast to the uncoupling previously obtained by the Wenner-Gren and other groups with highly toxic doses of the hormone in vivo or in vitro. The next set of experiments most gratifyingly explained why. T3 caused a net, tissue-specific increase in the content of mitochondrial enzymes, particularly dehydrogenases (the first step of fuel burning for energy production) and membrane proteins

J

The author (left) meets Fritz Lipmann.

involved in oxidative phosphorylation. Then I had more luck — I was able to demonstrate the marked effect of T3 on protein synthesis by ribosomes and microsomes that had been isolated simultaneously with mitochondria from the same tissues. More importantly, this was manifest with a reduced latent period for the enhancement of mitochondrial respiration, which was significant as inhibition of protein synthesis blocked the stimulation of mitochondrial respiration and BMR by T3. In a paper in Nature, followed by a more detailed account in the Biochemical Journal, we dismissed the uncoupling hypothesis and proposed that thyroid hormone regulated the body’s BMR by a selective control of the synthesis of key mitochondrial enzymes and proteins. Ernster not only graciously accepted this conclusion and co-authored these and subsequent publications, but also wrote about my findings to several proponents of the uncoupling hypothesis, urging them to listen to my arguments against it when I visited the United States the next year. In 1961, I toured the United States explaining our results, with varying degrees of success, to eminent groups that championed the uncoupling hypothesis, such as those of Albert Lehninger and Henry Lardy. My last port of call was The Rockefeller University, New York, where — to my great surprise and joy — Fritz Lipmann, one of the first proponents of the uncoupling of oxidative phosphorylation, encouraged me by generously sharing some unpublished lab notes from the mid-1950s that described a stimulatory effect of thyroxine on protein synthesis. Back in Stockholm, I met Peter

NATURE | VOL 431 | 30 SEPTEMBER 2004 | www.nature.com/nature

Medawar at a reception at the Karolinska Institute on the day after his Nobel prize award. He was soon to take up the directorship of NIMR, and invited me to return there to continue the work I had started in Sweden. The year 1961 was truly eventful, not just for my future career — our third child was born just before the stroke of midnight on New Year’s Day, and I escaped a fatal air accident when on my United States tour! I went back to NIMR as a junior member of the staff on a three-year contract at a time when biochemistry and molecular biology were rapidly moving forward. Although attempting to determine if the latency in the response of protein synthesis to T3 came after stimulation of transcriptional activity, Chris Widnell (my first graduate student) and I unexpectedly stumbled on the multiplicity of eukaryotic RNA polymerases, one synthesizing ribosomal RNA (rRNA) and the other messenger RNA (mRNA). Our paper on the novelty of multiple enzymes was at first rejected by the Journal of Molecular Biology with a curt note saying that “since bacteria have a single RNA polymerase there is no reason to accept that animal cells should have more”! (The paper was published in another journal.) Later, the groups of Bob Roeder (University of Washington, Seattle) and Pierre Chambon (Institut de Chimie Biologique, Faculté de Médecine, Strasbourg) resolved three polymerases synthesizing different classes of RNA by exploiting the enzymes’ differential inhibition by the fungal toxin
-amanitin. But one should not be too greedy for luck, as Widnell and I soon showed that T3 did stimulate RNA polymerase II and mRNA synthesis, preceding that of protein synthesis. The kinetics of stimulation of nuclear RNA polymerase II could be superimposed on the accumulation of T3 by nuclei — undoubtedly reflecting the binding of the hormone to nuclear T3 receptor. The intimate association between the steroid/retinoid/T3 receptor superfamily and regulation of transcription is now part of the established dogma of ‘receptorology’. Clearly, the risky move, followed by generous help and inspiration from some leaders in my field, made this my turning point. Within a period of three years, the dominoes had fallen down correctly and in rapid succession. Had I been obliged to apply for separate grants at each point, or taken the sure and safe route, this would not have been possible. I was truly a most lucky postdoc! ■ Jamshed Tata is at the National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. 513

©2004 Nature Publishing Group