PROFILE Profile of Steve Kay linking mustard plants and glow- Rockefeller University (New York) lab of ing fruit flies are just a few of the Nam-Hai Chua, who is a leader in the clever tricks that Steve Kay de- study of light-dependent gene expression vised to explore the molecular in plants. B ‘‘We were collaborating closely with genetic basis of circadian clocks in plants, flies, and mammals. Monsanto on constructing some of the Kay, who was elected into the National first vectors for making transgenic plants, Academy of Science in 2008, has spent mostly tobacco and petunias,’’ he said. ‘‘It two decades identifying the photorecep- was very, very exciting.’’ tors, genes, and complex networks that Kay and another postdoc named Ferenc make these internal clocks tick. Nagy began studying the light-activated Kay’s work has revealed applications chlorophyll a/b binding (CAB) gene. They from agriculture to disease. For exam- were trying to discover how plants convey ple, by tweaking one of the clock genes, light signals to the nucleus where they researchers can engineer crops to alter rapidly alter CAB expression level. their growth patterns, ultimately increas- While recording CAB mRNA levels, ing yields and possibly expanding the the two noticed that their results con- geographical range where the plants can flicted. To resolve the discrepancy, they thrive. Circadian clocks are also impor- began conducting around-the-clock experi- tant for how plants deal with stresses ments for several days. such as drought and salinity. ‘‘We discovered that our results were Kay’s work linking the clock to human different because I was doing my experi- health suggests that chemicals targeting Steve Kay ments in the morning, because I’m an the body’s timing system may lead to new early bird, and Ferenc was a night owl and doing his experiments in the treatments for bipolar disorder, diabetes, evening,’’ said Kay. and cardiovascular disease. Although his parents had not pursued college, they were phenomenally support- The finding implied that a circadian Although Kay, dean of biological sci- ive of his interest in science. clock regulated the CAB gene; some ences at the University of California, San ‘‘When you come from generations of mechanism switched it on in the morning Diego, is best known for his work on cir- fishermen,” Kay said, “they realize that and off in the late afternoon. cadian rhythms, his inaugural article (1) is there are better things to do than being ‘‘That [3] was my first clear glimpse of a divergence from his mainstream work frozen in the middle of the ocean. The something called a circadian rhythm,’’ said on circadian networks. North Sea is not the most inviting place Kay. It was 1985 and no one had de- The article is a tribute to his mother, Ͼ in the world, however thrilling!’’ scribed circadian rhythms acting at the who died 2 years ago of a progressive molecular level in any organism. Re- neurodegenerative disease. The article Planted in the Beginning searchers had only recently cloned the identifies a novel E3 ubiquitin ligase as Kay began his studies at the University of period (PER) gene in flies, which con- the culprit behind some types of motor Bristol in the United Kingdom, where he trolled the insects’ 24-h body clock, and and sensory neuron degeneration in a mu- earned a bachelor’s degree in biochemis- researchers had not yet identified such a tant mouse model. try. There he met a Welshman named gene in plants. Seduced by Nature’s Rhythms Trevor Griffiths who would become his Ph.D. supervisor and introduce him to the Blinking Mustard Plants Another of nature’s rhythms inspired world of plants. To examine the idea of a circadian clock Steve Kay’s interest in biology: the ex- Griffiths had observed that plants grow in plants, Kay developed transgenic plants traordinary tides that sculpted his birth- differently in the dark than they do in in which he fused a light-dependent pro- place and childhood home on Jersey, the light. Previous studies had found that moter to the reporter gene LAC Z. This southernmost of the Channel Islands lo- plants stop producing chlorophyll, the key meant that the LAC Z gene was turned cated between England and France. to transforming light into energy, when off and on in a circadian manner. Ͼ On those shores, the sea receded 3 grown in darkness. Kay’s doctoral project When Kay presented his work at the miles at some low tides, he recalled, leav- was to identify and characterize the en- annual meeting of the Society for Re- ing beaches pockmarked with rock pools zyme that catalyzes the light-dependent search on Biological Rhythms in 1988 ‘‘ev- of the English Channel. In this environ- step of chlorophyll synthesis. erybody went absolutely nuts,’’ he said. ment, he discovered ‘‘amazing creatures’’ Kay noticed that the concentration of ‘‘We showed we had a promoter element and other oddities of marine life, and his the enzyme seemed to rise and fall regulated by the clock.’’ interest in science was born. throughout a day–night cycle. Kay’s results were among the first ob- When he was Ϸ9 years old, his life Using molecular biology techniques that servations to suggest that clocks were not changed when a teacher from mainland were just being developed in England and just clusters of neurons in the brain that England brought a microscope to his the United States, he discovered, to his synchronized each other and regulated small elementary school. surprise, that light regulated the expres- sleep/wake cycles. Instead, his findings ‘‘That absolutely blew me away,’’ he sion of the gene that produced the en- showed that an individual cell could dis- recalled. ‘‘I’d never known what was in zyme for chlorophyll synthesis (2). pond water or what the edges of a torn To further pursue this research, Grif- piece of paper looked like.’’ By his early fiths advised Kay to study in the United This is a Biography of a recently elected member of the National Academy of Sciences to accompany the member’s teens he knew he wanted to study for a States. After completing his thesis, Kay Inaugural Article on pages 2097–2103 in issue 7 of volume Ph.D. secured a postdoctoral fellowship at The 106. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0910583106 PNAS ͉ October 27, 2009 ͉ vol. 106 ͉ no. 43 ͉ 18051–18053 Downloaded by guest on October 1, 2021 play circadian rhythms and that clocks ing used by the whole circadian field,’’ photoreceptor while screening their mu- could regulate intracellular processes such said Kay. tant flies (7), a discovery Science hailed as as gene expression. one of the top 10 breakthroughs of 1997. The circadian field reacted to Kay’s Flashing Flies Also in 1997, Joe Takahashi, then at work with enthusiasm and excitement. At In 1996, Kay moved to the Center for Bi- Northwestern University (Evanston, IL) the time, he understood the importance of ological Timing at the University of Vir- found the mouse circadian clock gene and his findings and decided to shift his focus ginia (Charlottesville, VA). Along with wanted to find its counterpart in the fly. to plant circadian rhythms. trying to identify all parts of the plant He and Kay teamed up. Later, while still at Rockefeller, Kay clock, he wanted to find more fruit fly Kay and Takahashi’s teams worked to- collaborated with geneticist Mike Young clock genes. To this end, he engineered gether and identified not only the fly to use fly clock genes to search for homo- flies with the luciferase gene. When he CLOCK gene, but the fly partner of logues in plants. When that approach fed these transgenic flies luciferin they CLOCK, a gene called BMAL1. failed, he realized that they had to de- started glowing. ‘‘It is a complete reversal of what nor- velop a method to ‘‘visualize the circadian ‘‘And so we had these Drosophila run- mally happens in biology,’’ said Kay, rhythms in plants’’ and developed trans- ning around that were ‘fire-fruit’ flies,’’ he meaning that in this case a mouse forward genic Arabidopsis plants. said. genetics screen led to the identification of Kay and graduate student Andrew Mil- In collaboration with Jeff Hall at new genes in flies. lar took photos of the Arabidopsis plants Brandeis University (Waltham, MA), Kay continued to tease apart to ulti- every few hours with a sensitive camera. Kay used these flashing flies to search mately define a molecular feedback loop. ‘‘We were just shocked and elated to dis- for clock genes. Kay and Hall discov- The two then demonstrated that CLOCK cover we could see the plants glowing on ered fly mutants that could not be en- and BMAL1 acted to turn on the PER and off in a circadian fashion. That was trained by light; these flies were glowing gene and a gene called TIM. They later definitely a ‘eureka!’ moment,’’ said Kay. all over. This finding led the pair and showed that PER and TIM proteins re- Because the CAB promoter is light- their collaborators to discover a fly ver- pressed their own expression by antago- dependent, the plants glowed early in the sion of a gene called cryptochrome that nizing CLOCK and BMAL1. This was the morning. But when he mutated these Kay’s lab had been working on in plants. first demonstration of a molecular feed- glowing plants, he identified individuals Kay recalled being perplexed by the back loop defining the core mechanism of that glowed out of sync, for example, once glowing flies.