Profile of Alec J. Jeffreys

Profile of Alec J. Jeffreys s one of the great contributors to modern genetics, Sir Alec Jeffreys was born with curiosity in his genes as the son and Agrandson of prolific inventors. Jeffreys displayed an insatiable quest for knowl- edge, and his father fostered his son’s budding scientific interests with gifts of a microscope and chemistry set, the latter of which produced one of Jeffreys’ most memorable scientific ventures. ‘‘Those were back in the happy days of chemistry,’’ Jeffreys points out, ‘‘where you could go down to your local pharmacist and get virtually everything you wanted.’’ The end result of that chemistry experiment was the detonation of his aunt’s apple tree and a set of scars that Jeffreys still bears today. ‘‘You learn science very fast that way,’’ he says, ‘‘but it was quite fun.’’ Jeffreys’ scientific curiosity only in- creased after the apple tree incident, and years later it would lead to one of the Alec J. Jeffreys most widely used applications in genetics: DNA fingerprinting. Among other uses, the DNA fingerprinting technique has freys go there, so Jeffreys entered the turn led to another groundbreaking find- helped solve numerous criminal investi- university in 1968. He was at first intent ing about the composition of eukaryotic gations, settle countless paternity dis- on pursuing a degree in biochemistry DNA: introns (3). ‘‘I was 27 at the time, putes, and spark a resurgence of interest but soon decided to alter his course. so still a real rookie, with the ability to in the forensic sciences. That achieve- ‘‘This was no criticism of the way it was detect single-copy DNA by Southern blot ment alone is worthy of merit, contrib- taught,’’ he says of biochemistry at Ox- hybridization and a nice paper on introns uting to Jeffreys’ receiving three high ford, ‘‘but rather a reflection of the fac- under my belt, which is, yeah, not a bad distinctions in 2005: the Albert Lasker ulty’s research, which leaned heavily to start,’’ he says. Clinical Research Award, induction into physical biochemistry.’’ Jeffreys had be- the National Inventors Hall of Fame, come more interested in genetics and DNA’s First Fingerprint and election to the National Academy molecular evolution, so after he received After these heady research achievements, of Sciences as a Foreign Associate. his B.A. in biochemistry in 1972, he Jeffreys was faced with the question of Aside from the invention of DNA fin- remained at Oxford to complete his ‘‘What next?’’ In 1977, he returned to gerprinting, Jeffreys has made many other D. Phil. in genetics in 1975. England to accept a Lecturer position pioneering contributions to the field of Jeffreys then received an European in the Department of Genetics at the human genetics. These accomplishments Molecular Biology Organization (EMBO) University of Leicester (Leicester, include the discovery of eukaryotic in- research fellowship to work with Piet United Kingdom), where he remains trons, further understanding of the evolu- Borst at the University of Amsterdam in today as a professor, but scientifically tion of gene families, and insight into the The Netherlands. His project was in- the decision of what to do next was secrets of genetic recombination. Some of tended to study yeast transfer RNA genes, problematic. The logical course seemed these secrets are documented in Jeffreys’ but then he met up with another re- to be to study introns, but Jeffreys ex- Inaugural Article in this issue of PNAS searcher, Richard Flavell. Says Jeffreys, pected that a lot of major laboratories (1), which looks at the mechanisms of ‘‘[Flavell] said, ‘We’ve got this crazy would move into this field. ‘‘And it was ectopic recombination, in which locally project attempting to isolate and purify obvious to me that, being essentially by similar DNA sequences are exchanged. mammalian genes, specifically the rabbit myself—I had just a part-time technician This recombination process can generate ␤ -globin gene. Would you be interested?’ working for me—with no funding, and variation in gene copy number and lead to I mean, at the time, nobody had ever de- really having to start from scratch, that inherited pathological disorders. tected or cloned or analyzed a single-copy to carry on with the intron work would mammalian gene. So I said, ‘Yeah, bet not be competitive,’’ he says. Instead, Oxford to Introns your bottom dollar, I’m in.’’’ Jeffreys sought to combine his recently Born in 1950 in Oxford, England, Jef- Jeffreys and Flavell hoped to biochemi- acquired molecular biology experience freys grew up in the shadow of the Uni- cally purify a vast amount of rabbit DNA with his interests in human genetics. versity of Oxford, but he did not have via mRNA hybridization enrichment, but ‘‘The first question we asked was, ‘If any connections to the storied institu- their plan ultimately did not work. In the you can see DNA restriction fragments, tion. ‘‘We were very much on the other process, however, Jeffreys, with the aid of side of the tracks,’’ he says of his family. the then-new technology of Southern blot- Thus, Jeffreys never gave much thought ting analysis, developed a way to probe This is a Profile of a recently elected member of the National to attending Oxford University, but his and detect the globin gene. The probes Academy of Sciences to accompany the member’s Inaugural high school headmaster, an Oxford led to the creation of the first physical Article on page 8921. alumnus, seemed determined that Jef- map of a mammalian gene (2), which in © 2006 by The National Academy of Sciences of the USA 8918–8920 ͉ PNAS ͉ June 13, 2006 ͉ vol. 103 ͉ no. 24 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0603953103 Downloaded by guest on September 26, 2021 PROFILE can you see variation between people in identification. My life completely changed DNA fingerprinting. This was science, those fragments?’’’ says Jeffreys, who ulti- at that point,’’ he says. helping this poor family who got them- mately was able to, in the form of the selves in a bureaucratic tangle,’’ says Jef- second-ever description of restriction frag- The Boy from Ghana freys. He dreads to think of what would ment length polymorphisms (RFLPs) (4). After the discovery of the first DNA fin- have happened had he found the opposite ‘‘We were beaten to the post by Y. W. gerprint, Jeffreys rushed out of the x-ray result, but as it was, this heartwarming Kan, bless him, he well deserved it,’’ says developing room and proclaimed to his story made national headlines and helped Jeffreys. Although RFLPs would help ad- group, ‘‘I think we’re onto something re- open the floodgates for DNA fingerprint- vance several areas of genetics research, ally exciting here.’’ Within a half-hour, he ing technology. Jeffreys was a bit frustrated with them. and his laboratory had written down a ‘‘They were hard work to detect at the slew of potential applications, including Forensic Crimefighting time, and they weren’t very genetically forensics, paternity or twin testing, and In 1986, as Jeffreys and his small labora- informative. We felt that there must exist conservation biology. ‘‘We were then tory handled all the DNA test requests for bits of DNA that are far more variable faced with two challenges, really. The first issues regarding immigration, paternity, than standard RFLPs,’’ he says. was to improve the technology from that and the like, Jeffreys faced challenges for Three years and an assortment of un- blurry mess to something that would actu- making DNA fingerprinting appropriate successful approaches later, Jeffreys found ally be reliable enough for real casework. for use in forensics. Together with Peter a clue in a completely different project The second was whether anybody would Gill at the United Kingdom’s Home Of- looking at the organization and evolution pay a blind bit of notice,’’ he says. A few fice Forensic Science Service, he quickly of globin genes, particularly the often- months of tinkering solved the first chal- established that DNA could survive in overlooked myoglobin. The trail began lenge to Jeffreys’ satisfaction, and an op- forensic samples, clearing one potential with a lump of seal meat donated by the portunity to meet the second arrived soon hurdle. Another obstacle was that DNA British Antarctic Survey (Cambridge, after. fingerprint blots were fairly complex and United Kingdom). ‘‘Seals express myo- needed to be simplified. The solution for globin at very high levels in their muscle,’’ this problem came from Jeffreys’ work in explains Jeffreys, ‘‘and that made the mes- The first DNA cloning individual minisatellites from senger RNA, and hence the gene, much the fingerprints (10). ‘‘Once you get the easier to isolate.’’ Successful isolation of fingerprint was ‘‘a cloned minisatellite, you can make the the seal myoglobin gene paved the way thing locus-specific,’’ he explains. These cloned probes could detect highly variable for the isolation of the human myoglobin horrible, smudgy, alleles of different lengths and produce gene, and within that gene Jeffreys found easy-to-read two-band patterns, one for a short stretch of DNA with tandem blurry mess.’’ each copy of the allele. By sampling multi- repeats: a minisatellite (5, 6). ple loci on each sample, a ‘‘DNA profile’’ ‘‘At first, it was a little bit of ‘so what?’’’ could be built. recalls Jeffreys of the finding. ‘‘This wasn’t In April 1985, Jeffreys received a letter In 1986, Jeffreys was contacted by local even variable.’’ But a few examples of from Sheona York, a London lawyer. police regarding a murder case where two York had read about DNA fingerprinting variable minisatellites had emerged in re- schoolgirls had been raped and murdered in the newspaper and wondered whether cent literature, and they seemed to share 3 years apart in an apparent copycat kill- this technique could help sort out a tricky some sequence similarity.

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