Profile of Janet M. Thornton

Profile of Janet M. Thornton lthough many scientific disci- Thornton particularly enjoyed the plines have experienced vast computing aspects of her dinucleotide growth over the past three de- project and wrote several software pro- cades, few may have come as grams to visualize conformations and Afar as bioinformatics. When Janet calculate free energies (3). ‘‘But regret- Thornton, a structural and computa- tably I never used them again after I tional biologist, first began analyzing left,’’ she says, ‘‘and neither did anyone protein structures in 1973, the structures else.’’ Still, her computing skills came in for only a handful of proteins had been handy when she began looking for post- solved, and the genome for even the graduate work in 1973. ‘‘I wanted to smallest virus was unknown. Today, the deal with real, hard experimental data,’’ number of solved protein structures has she says, ‘‘but no jobs were advertised grown to over 30,000, and complete se- for people like me.’’ Thornton eventu- quences for dozens of organisms have ally landed a position as both a research been decoded. ‘‘We went from having fellow and systems administrator in virtually nothing to having almost the David Phillips’s crystallography labora- whole biological spectrum of protein tory at Oxford University (Oxford). types,’’ says Thornton. One of the founding leaders of struc- Director of the European Bioinfor- tural biology, Phillips was a generous and supportive advisor to Thornton. Her matics Institute (EBI) in Cambridge, Janet M. Thornton England, Thornton has led the charge move to his group proved to be a re- throughout the bioinformatics boom, freshing return to a familiar world. ‘‘I especially as it relates to protein struc- scriptive science and not an understand- found my graduate work difficult at ture. In addition to her position at EBI, ing science,’’ she explains. ‘‘I think I was times,’’ says Thornton. ‘‘Mill Hill was she is also coordinator of the BioSapiens drawn to physics because it was all heavy on cellular biology, and coming in project, which aims to address the cur- about how you could describe things and as a physicist, I didn’t know any of the rent fragmentation of European bioin- make equations to understand why language,’’ she says. ‘‘And when I got to formatics by creating a virtual research things worked the way they did.’’ Oxford, it was wonderful because every- institute. A wish to avoid comparison and com- body was molecular again.’’ Thornton’s main research goal has petition with her older sister Margaret Physics vs. Proteins, Order vs. Chaos been to tie together the relationships may have helped as well. ‘‘She was al- between protein sequence and structure ways a bit cleverer than me,’’ Thornton At Oxford, Thornton began working in and, more recently, between structure jokes. So, after her sister went on to the then-emerging field of bioinformat- and function. ‘‘We’re now at the stage pursue a classics degree, Thornton de- ics, so nascent that it had yet to be of trying to understand how protein cided the best way to avoid further sib- named. ‘‘I started out trying to under- function evolves, either in different or- ling rivalry would be to get a degree in stand how the protein sequence deter- ganisms or cell types, to ultimately cre- a field as distant from classics as possi- mines the three-dimensional structure,’’ ate life,’’ she says. Along the way, ble, and, for her, physics fit the bill. she says. ‘‘My goal was to see if one Thornton has helped design myriad Thornton enrolled at the University really could predict a structure based computer programs and databases to of Nottingham (Nottingham, England) on the sequence.’’ The process was com- analyze protein sequence and structure in 1967, but even as she was completing plicated by a lack of structural data to data. In her Inaugural Article in this her degree in physics, she knew she use as a resource. ‘‘When I began, I issue of PNAS (1), she presents a com- wanted to apply her knowledge outside think that only about 10 protein struc- puter application that can predict func- of pure physics. ‘‘I wasn’t interested in tures were available in the data bank.’’ tional similarities among proteins in a machines, I was more interested in the Further complicating matters for some- given family by comparing key func- natural world,’’ she says. ‘‘So when the one accustomed to the ordered world of tional residues. option came to work at the National physics were the chaotic tendencies that Thornton has received numerous Institute for Medical Research (NIMR) proteins sometimes exhibited. Thornton awards and honors, including being at Mill Hill, that gave me a chance to noticed this messy behavior when she be- named as a Commander of the British merge my physics background into a gan studying the sequences of numerous Empire, Fellow of the Royal Society, and more biological research career.’’ proteins and comparing proteins from Honorary Professor at Cambridge Univer- At NIMR, Thornton studied the con- different families. ‘‘In physics, you have a sity (Cambridge, England). In 2003, she formations of dinucleotides by using set of laws, and nature obeys those laws,’’ was elected to the National Academy of spectroscopic and computational meth- she says, but ‘‘simple rules describing Sciences as a Foreign Associate. ods (2). ‘‘I approached my project from [proteins] are elusive because of their a physics end, exploring various combi- complexity and are therefore often best Sibling Rivalry nations to try and find the lowest-energy captured as propensities rather than Thornton first developed a curiosity conformations,’’ she says. ‘‘I wasn’t wor- rules.’’ about nature and the world around her rying too much about what dinucleotides Thornton began making sense out of early on in life. Growing up, she en- did functionally. I was much more fo- the chaos by focusing on the smaller joyed taking nature walks along the cused on shape and structure.’’ While English coast and became interested in working on her Ph.D. project, Thornton This is a Proﬁle of a recently elected member of the National fields such as geology and astronomy. ‘‘I also pursued a Master’s degree in bio- Academy of Sciences to accompany the member’s Inaugural really enjoyed biology as well, but at physics at King’s College in London, to Article on page 12299. that stage biology was more of a de- help direct her research toward biology. © 2005 by The National Academy of Sciences of the USA 12296–12298 ͉ PNAS ͉ August 30, 2005 ͉ vol. 102 ͉ no. 35 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0505819102 Downloaded by guest on September 24, 2021 PROFILE units of protein structure, the motifs. Thornton and her group devised a in terms of simple deposition, reliable She characterized how specific motifs clever method, termed ‘‘protein thread- curation and annotation, and easy access. within a structure related to sequence. ing,’’ to predict a protein’s tertiary ‘‘EBI combines the handling of these ‘gold Along with colleague Mike Sternberg, structure by using these protein folds nuggets’ of data with a thriving commu- she published several articles examining (8). The technique involved threading a nity of young bioinformatics research how certain features of amino acids, protein sequence onto the frameworks groups, who seek to unravel the mysteries especially chirality, could affect protein of known protein folds and finding the the data hold,’’ she says. ‘‘Combining conformations (4–6). One study de- most energetically favorable conforma- knowledge derived from many different scribed the direction of the connecting tion. In 1997, after years of work, types of biological data will be the key to turns in a ␤–␣–␤ motif. Thornton found Thornton also designed a new classifica- unraveling the molecular basis of life.’’ that these motifs almost always took tion system for proteins based on struc- As Thornton explains, ‘‘For me, it’s right-handed turns (5). With a chuckle, ture instead of sequence, called CATH been a journey of being a physicist to she notes ‘‘that finding was really nice, (Class, Architecture, Topology, Homolo- being a biologist.’’ Over the past several because that rule is actually obeyed gous Superfamily) (9). years, she has shifted her research to about 95% of the time.’’ As techniques improved, researchers continue this trip into the life sciences. In 1979, Thornton left Phillips’ group also found that the structures for many ‘‘The function is the critical thing about and moved on to Birkbeck College proteins in the database contained in- proteins,’’ she says. ‘‘What they do and (London) as an advanced fellow in the consistencies or local errors. Because how they do it. I’ve started looking at laboratory of Tom Blundell, a well Thornton relied heavily on these older known and respected structural biolo- structures, she decided that an improved gist. She continued studying sequence– method to validate structural data was “For me, it’s been structure relationships and examined the needed. In 1993, she and colleagues, molecular interactions that stabilize ter- including Roman Laskowski, designed a a journey of being tiary protein structure, such as salt computer program, PROCHECK, that ex- bridges and disulfide bonds. Thornton amines the stereochemistry of a pro- a physicist to being stayed on at Birkbeck for over 11 years, tein’s structure and compares its quality first as a fellow and then as a lecturer. with structures of similar resolution a biologist.” She primarily worked part-time so she (10). PROCHECK has since become one could spend time at home with her fam- of Thornton’s most notable applications and has been cited nearly 5,000 times in ily, balancing the chaos of proteins with how the structure affects the function, the literature.

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