FEATURE AN INTERVIEW WITH... AN INTERVIEW WITH... PHIL LOWRY INTERVIEW BY MILES LEVY I have been collecting a list of names suggested by colleagues as good people to read about in this series of interviews. Phil Lowry is a name that crops up all the time. Recognised as one of most influential basic scientists in our specialty, Lowry is the one who hypothesised that hormones such as adrenocorticotrophin (ACTH) are produced as precursors – a concept that was entirely new at the time. I am looking forward to finding out more about how this man from working class Birkenhead ended up playing a key role in modern endocrinology... When I initially asked him to take part, Phil was refreshingly modest and +H GHVFULEHV KLV ÀUVW GD\ DUULYLQJ DW XQLYHUVLW\ GLJV EHLQJ JUHHWHG E\ SOHDVHGWREHWKHÀUVWQRQFOLQLFLDQLQYROYHG²¶,WKRXJKWLWZDVDZLQGXS his landlady standing at the door ‘with a fag in her mouth’ and being DWÀUVW,PXVWDGPLWLWZRXOGEHDQKRQRXUSDUWLFXODUO\DV,DPIURPWKH introduced to his 80-year-old fellow lodger. Despite this inauspicious fundamental spectrum of the Society and it may be encouraging for the start, the curriculum was perfect – it covered the three forms of pure troops.’ chemistry (physical, inorganic and organic, he reminds me). Inspired by early lectures in physiology at the medical school, where basic science was I am greeted by a smiling Phil Lowry as I pull up in the driveway of his applied to humans, he was a natural in the lab. ‘We were allowed to do KRXVH+HLVZHDULQJEHLJHVODFNVLVWDOODQGORRNVÀWIRUKLV\HDUV+H UHDOH[SHULPHQWVZLWKDQLPDOV,ORYHGVROYLQJGLIÀFXOWSUREOHPVUHODWLQJ speaks with a subtle ‘Scouse’ accent, probably watered down from years to human physiology.’ of living in the south, and has a very down to earth manner. I have already been invited to stay for dinner, ‘We have a pheasant in the freezer which JIMMIE DODD, -MSH AND GRIMSBY DOCKS should stretch to three servings – you would have a much easier journey $NH\ÀJXUHLQ/RZU\·VOLIHZDVKLV3URIHVVRURI=RRORJ\DQGPHQWRUWKH back [if you leave later].’ His wife Sue has even made up a bed in case I am late James Munro Dodd FRS (‘Jimmie Dodd’), a pioneer of comparative too tired to drive back. HQGRFULQRORJ\ )RU KLV 3K' SURMHFW 'RGG ZDQWHG /RZU\ WR ÀQG RXW ZKHWKHU WKH KRUPRQH WKDW FDXVHG GRJÀVK WR FKDQJH WR D EODFN FRORXU 2QHRIWKHÀUVWWKLQJVZHGRLVJRLQWRKLVJDUGHQZKHUHKHVKRZVPH on a dark background was similar to that found in mammals, including a slate sundial with an engraved message on the plinth. This is a gift humans, who did not. Unwittingly, Lowry had just irreversibly embarked from past and present members of his research group, presented as his on a life’s work on endocrine peptides. ‘festschrift’, and he seems visibly moved when he reads the affectionate message aloud. We go into his lounge where Sue brings us tea and we 3KLOVSHQWPXFKWLPHZLWKWKHÀVKHUPHQRI*ULPVE\)LVK'RFNVFROOHFWLQJ make a start. WKHSLWXLWDU\JODQGVRIFRXQWOHVVGRJÀVK+HUHFDOOV¶7KH\FXWRIIWKHKHDG RIWKHÀVKDQG,ZRXOGKRRNRXWWKHQHXURLQWHUPHGLDWHOREHZKLFKZDV How did he discover he was good at laboratory science? ‘I just had a feel the size of a matchstick head. I must have hooked out literally thousands of for things – I take a DIY approach to experiments; I am good at thinking on GRJÀVKSLWXLWDULHV%\WKHZD\WKH\GRWKHEHVWÀVKDQGFKLSVLQ*ULPVE\· my feet and making it up as I go along,’ he says as we embark on his story. IN THE BEGINNING ‘The high quality of Lowry’s GH preparation was %URXJKWXSLQ%LUNHQKHDG0HUVH\VLGH3KLO/RZU\ZDVGHÀQLWHO\QRWERUQ with a silver spoon in his mouth. His father left school at 14 and eventually singled out for praise by Mr Justice Morland in joined the police force. Phil’s mother had high hopes that her son might become a supervisor in the local soap factory and wear a white coat, a sure his report on the case that found the Government sign of respectability. culpable for children who contracted CJD from Phil went to the local grammar school, doing well at science. ‘I was the only one who passed A-level biology – even though my school reports elsewhere’ commented on a lack of concentration after I discovered the fairer sex.’ +HKDGDÁDLUIRUFKHPLVWU\DQGJRWFKDWWLQJDERXWFDUHHUVWRDORFDOODG in a youth club, who happened to be a medical student. ‘Why not do biochemistry?’ he suggested. This was enough for Phil to apply for a BSc Lowry mastered column chromatography, a method for purifying chemical in Biochemistry at Leeds. compounds according to molecular weight and ionic charge, which was VLPLODU WR WKH PHWKRGV XVHG E\ KLV VFLHQWLÀF KHUR )UHGHULFN 6DQJHU ¶, ZRXOG PDVK XS WKH GRJÀVK SLWXLWDULHV DQG OHW WKH H[WUDFW WULFNOH GRZQ HDFKUHVLQXVLQJDIURJVNLQELRDVVD\WRPRQLWRUWKHSXULÀFDWLRQZKLFK ZRXOGHYHQWXDOO\UHVXOWLQDSXULÀHGZKLWHSRZGHU,ZRXOGK\GURO\VHD 26 | THE ENDOCRINOLOGIST | SPRING 2014 AN INTERVIEW WITH... FEATURE sample to release its amino acids and analyse them to get the composition. A VERY PURE GROWTH HORMONE I would then digest another sample into bits and analyse the amino acids Human GH (hGH) was becoming an important new treatment for from either end so I could piece it all together.’ FKLOGUHQZLWK*+GHÀFLHQF\²¶%RYLQH*+ZDVQRJRRG·7KH05&QHHGHG a scientist to purify hGH. ‘A minimum of 200 or 300 human pituitary In a series of classical experiments, Lowry showed that the amino glands were needed to extract a decent quantity of the hormone.’ Lowry acid sequences of Į-melanocyte-stimulating hormone ( Į-MSH) in rose to the challenge, recalling, ‘Me being me, I read all about it and really PDPPDOVDQGGRJÀVKZHUHLGHQWLFDODSDUWIURPDVLQJOHPHWKLRQLQH FOHDQHGXSWKHPHWKRG·+HKHOSHGWRSURGXFHWKHUDSHXWLFSXULÀHGK*+ valine substitution. The larger ACTH molecule had exactly the on a large scale, and was determined that it would not be contaminated. same substitution. This was too much of a coincidence, and Lowry hypothesised that a precursor molecule was broken down into smaller Alan Dickinson at the MRC Neuropathogenesis Unit in Edinburgh, an components including ACTH and Į-MSH. H[SHUW RQ ¶VORZ YLUXVHV· KDG DOHUWHG +HDG 2IÀFH WR WKH SRVVLELOLW\ RI contamination of hGH extracted from cadaver pituitary glands, so Lowry Not only had Lowry answered Jimmie Dodd’s research question, he had ÁHZWR(GLQEXUJKWRSODQDVWXG\WKHUHWRLQIHFWDKXPDQSLWXLWDU\H[WUDFW also proposed a fundamental hypothesis regarding post-translational with 10 8 units of scrapie virus, to show his method could purify material PRGLÀFDWLRQRIKRUPRQHV+LVÀUVWSDSHULQZDV3KLO·VÀUVWDXWKRU to be free even of that. A neuro-degenerative disease, scrapie is now 1DWXUH paper 1 and he became Dodd’s ‘blue-eyed boy’. known to be closely related to bovine spongiform encephalopathy (BSE) and Creutzfeld-Jakob disease (CJD), all caused by a common infectious His career as a research scientist took off and he was snapped up prion protein. E\WKH6ZLVVVFLHQWLÀFDUPRI1RYDUWLV&,%$ &KHPLFDO ,QGXVWULHV Basel). The UK base was in Horsham, Sussex, where he moved with $IWHU SXULÀFDWLRQ QR VFUDSLH RU S\URJHQV ZHUH SUHVHQW DQG LW ZDV Sue, whom he had met at university whilst she was a fellow zoology concluded that his GH was safe. ‘Talk about Dickinson’s crystal ball!’ PhD student. The Swiss had a good tradition of synthetic peptide H[FODLPV/RZU\+HH[SODLQVZLWKMXVWLÀDEOHSULGHKRZKLV*+KDVOHG chemistry: ‘They were very encouraging and I got on well.’ As well to not a single case of CJD. 3,4 The high quality of Lowry’s GH preparation as developing ACTH analogues, CIBA also synthesised salmon was singled out for praise by Mr Justice Morland in his written report calcitonin for use in Paget’s disease, so Lowry was able to persuade on the case that eventually found the Government culpable for children WKHPWRDOORZKLPWRJHWKROGRIPRUHGRJÀVKSLWXLWDULHVWRFRQWLQXH who contracted CJD from elsewhere. his passion for all matters ACTH-related. ADRENAL HYPERPLASIA, VASOPRESSIN AND CRF COLLABORATION WITH CLINICAL MEDICINE Lowry remained fascinated by adrenal endocrinology. He published At this time, John Landon, pioneer of antibody use in clinical work on pro-enkephalin, a natural opiate precursor expressed in brain, endocrinology, had started measuring ACTH by radioimmunoassay adrenal medulla and adrenal medullary tumours. He became interested and needed a talented basic scientist. Sandy Scott, a PhD student, was in the observation that, following unilateral adrenalectomy, ‘the other ‘getting funny results using ACTH anti-sera in detecting peptides in one grew by at least 50% due to increased cell number [hyperplasia] in pars intermedia and couldn’t work out what was going on’. Scott visited the cortex.’ Jimmie Dodd for advice, who didn’t know the answer but suggested he should ‘go and see Phil’ for help. Mirroring similar studies on pro-insulin, Lowry showed that pro- DŽ-MSH was activated into a mitogen by cleavage near its N-terminal Lowry solved Scott’s ACTH problem and was now on Landon’s radar. via a neurally mediated mechanism after removal of one adrenal. This It was not long before he became Principal Biochemist and Honorary led to 2 more of his 15 1DWXUH papers. 5,6 He showed that pro- DŽ-MSH was Lecturer in Chemical Pathology at Barts. Lowry developed a sensitive not only important in adrenal cell hypertrophy, but also increased the analyser for amino acids that required only small amounts of material effect of ACTH on the adrenal cortex by increasing the amount of mRNA DQGFRQWLQXHGZRUNRQ$&7+,QZLWK6DQG\6FRWWKHLGHQWLÀHGD involved. new corticotrophin-like intermediate peptide, otherwise known as CLIP. 2 Lowry did seminal work on the interaction between corticotrophin- He concluded that ACTH was produced from a precursor (later known releasing factor (CRF) and vasopressin. With PhD student Glenda Gillies as pro-opiomelanocortin, POMC), and that ACTH, which comprises 39 (now Professor of Neuroendocrinology at Imperial College London), he amino acids, is processed to form Į-MSH (ACTH 1–13) and CLIP (ACTH developed a column of stable live pituitary cells for in vitro studies. Their 18–39). The incontrovertible evidence that pituitary hormones were experiments demonstrated that vasopressin and CRF act synergistically broken down into biologically active compounds changed the world of to release ACTH from the pituitary.