Metabolism is good foryou: sixty years ofnurtureDonald Nicholson, Leeds University

The invitation from PeterHowdle to write an article forThe Clinical Teacher intrigued

me. What could a 90-year-old lifescientist, ‘retired’ for more thanquarter of a century and not evena medic, have to contribute to ajournal of this character? Clearly,just the story of a teacher in aschool of medicine who had apassion for half a century to makethe often unpopular subject ofclinical science meaningful,‘wonder-full’ and fun.

I first arrived at the Bacterio-logy Department of the medicalschool at Leeds around 60 yearsago. Prior to this, during the war,I had been a chemist with a bigpharmaceutical firm responsiblefor the large-scale manufacture of

the very first antibacterial drugs –sulphonamides. I had been in atthe very start of a new era inmedicine – the age of chemo-therapy – and had come to Leedsas an ICI Research Fellow inChemotherapy. I had a fairunderstanding of chemistry – butnone at all of therapy. The Pro-fessor set me to work on two‘chemical’ problems – the growthrequirements of the tuberclebacillus, which grew very slowly,and the nature of diphtheria tox-ins. Such a task appealed to mebecause in early childhood I hadhad both TB and diphtheria – notunusual in those days.

My Fellowship required me todo a little teaching, and I wasthrown in at the deep end. A few

weeks after I arrived, theProfessor asked me to give alecture to the medical studentson malaria – a subject aboutwhich I knew virtually nothing.The philosophy of those days wasthat if you had a degree youcould teach. So I taught. Thesewere times when a good memorywas often equated with a goodbrain, and quality of teachingwas rarely assessed. This lecturewas an ordeal that made merealise (and warned me) that itwas possible to give a talk on asubject about which you knewlittle – provided no questionswere asked. I began to thinkabout this a lot, so that yearslater, when I had become auniversity lecturer, a new andinelegant word had become

The philosophywas that if youhad a degreeyou could teach

Focus onLeeds

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entrenched in my vocabulary,and has remained there eversince – meaningfulness.

Apart from research, I had tolearn, very rapidly, two entirelynew sciences – bacteriology andbiochemistry. But what a time tolearn! In retrospect, the late1940s and the 1950s must havebeen uniquely fascinating times inwhich to be learning about andteaching bacterial metabolism.Bacteria were the major source ofmuch of our enlightenment aboutthe basic facts of life. Their hugenumbers and rapid generationtimes made them ideal organismsfor revealing the chemical natureof metabolism, of genetics and ofDNA – whose structure was ulti-mately elucidated by Crick andWatson in 1953.

METABOLIC PATHWAYSCHARTS

At the same time as theseinvestigations on the genetics ofbacteria were evolving, anexplosion was taking place in ourunderstanding of the chemicalnature of living organisms – ofmetabolism. The first metabolicpathway, glycolysis, had beencompleted around 1940, and thishad stimulated research intoother pathways to such an extentthat, by the mid-1950s, dozenshad been described. This createda growing problem for a teacherof bacterial metabolism. Studentswould memorise lots of pathways,structures and enzymes, butcould not put them together tomake it all meaningful. Somepathways were clearly related toeach other, but for an organismto live it was necessary for themall to be integrated into a livingconcerto. The situation was akinto an unmade jigsaw puzzle,which would only become fullymeaningful when all the pieceshad been put together – a pro-cess greatly simplified if thepuzzle is accompanied by a pic-ture of how it will look whencompleted.

My challenge as a teacher wasto design an integrated picture ofmetabolic pathways that wouldcomplement textbooks by provi-ding an overall picture of meta-bolism. The aim was to stimulateexploration, and encourage anunderstanding and appreciationof the significance and eleganceof interrelated pathways. My firstMetabolic Pathways Chart wascreated around fifty years ago andsince then over a million copiesand 22 editions have been pro-duced. These charts have beenincorporated in over a dozenbooks, including some of the mostprestigious biochemistry text-books (see Figure 1).

INBORN ERRORS OFMETABOLISM

The Bacteriology Department waspart of the medical school and Igot to know some of the medicalstudents well. Many of them feltthat, while bacteriology wasclearly an acceptable part of theircurriculum, biochemistry was not.

My Metabolic Pathways Chart didnot help, and might in fact inducea transient ‘disease’ that I calledthe ‘O-hell syndrome’ – anxietycaused by the unfounded but notirrational fear that it might haveto be memorised. In fact, it wasnever really designed for medicsbut, being in a medical school, Ikept wondering whether it couldbe revised so as to becomeacceptable (or even an inspira-tion) to choosy, often over-worked, medical students.Genetics seemed to be the answer.If a gene is defective it may resultin a defective enzyme in a part ofa metabolic pathway, and thiscould result in the concentrationof its substrate – usually in theblood or urine. More than a hun-dred such potentially defectiveenzymes existed on my MetabolicPathways Chart and could belinked with the known diseasesfor which they were responsible.An ‘Inborn Errors of Metabolism’map (see Figure 2) was thereforecreated to encourage medicalstudents to realise that an

Figure 1. � International Union of Biochemistry and Molecular Biology (reproduced with permission).

The situationwas akin to anunmade jigsaw

puzzle

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understanding of biochemistryand genetics could be an import-ant asset in their understandingof clinical medicine.

MINIMAPS

About the same time, togetherwith a good friend and colleague,Stan Dagley, I wrote what was tobecome a standard referencebook: An Introduction to MetabolicPathways. This took individual

pathways and enlarged them toinclude details of enzymes, lots ofreferences and a bit about regu-lation (because relatively littlewas known about it at that time).

Some 25 years later I wassearching for ways of updatingthese small maps using moderntechnology, so on my 80th birth-day, I bought my first computer,and minimaps were born. Eachminimap is a colour picture of a

separate pathway and includesco-factors, regulation, compart-mentation and other features toillustrate their significance withinthe cell. Thirty-five minimaps arenow freely available on the inter-net on www.iubmb-nicholson.Some are specifically medicallyorientated, such as ‘Folic Acid andEarly Chemotherapy’, or ‘Prosta-glandins’, but all are, as far aspossible, designed to relate to‘real life’ metabolism. An example

Figure 2. � International Union of Biochemistry and Molecular Biology (reproduced with permission).

The aim was tostimulateexploration

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of this is the minimap entitled‘Products of Isoprene Metabolism’(see Figure 3), which illustratesthe exciting variety of productsthat derive from isoprene. Theseinclude natural rubber, plant,insect and animal hormones, andthe side chains of many vitaminsand of chlorophyll. They providethe colour, smell and flavour ofmany plants such as carrots, lem-ons and roses. They include someof the vital reactions that convert

light into vision, and, in adifferent pathway, the steroids,including oestrogens and testost-erones, with all their implica-tions. Many of the sensual andsexual pleasures of life can thusbe seen to derive from the same,simple, 5-carbon compound,isoprene.

While preparing this minimapI became the victim of a hazard ofmy age – an enlarged prostate.

This was treated with Finasteride,which inhibited the enzyme thatreduces testosterone to its activedihydro- compound, and thusinitiated the shrinkage of theoffending gland. This was really‘real-life metabolism’, so I inclu-ded it in the minimap!

ANIMAPS

The response to the minimaps hasbeen hugely satisfying, but a

Figure 3. � International Union of Biochemistry and Molecular Biology (reproduced with permission).

On my 80thbirthday, I

bought my firstcomputer

146 � Blackwell Publishing Ltd 2006. THE CLINICAL TEACHER 2006; 3: 143–147

basic drawback remained unre-solved. They were just static por-trayals of what are really dynamicprocesses. Biochemistry is a livingsubject – bio-chemistry, and tomake it meaningful, metabolismhad to be animated, so minimapsbecame animaps.

The first animap I made, someyears ago, was created in Power-point. It started with the ‘bio-chemistry’ to be found on the sidepanel of a packet of All-Bran,which I linked to 13 features inthe glycolysis and citric acid cyclepathways. This was very basicenergy biochemistry, but import-ant educationally. Coming fromthe side of a cereal packet made itboth relevant and fun.

Powerpoint had significantlimitations for animations, butFlash has proved to be a much

more versatile medium and hasenabled the animation of some ofthe basic pathways in metabo-lism. These can now show the flowof reactants into the inside of thecell and the detailed reactionsthat result. The most exciting ofthe Flash animations so far is thatof ATP synthase (see Figure 4),which illustrates how protonsdrive the molecular motor thatsynthesises ATP. This motorstands at the very heart of meta-bolism – between breakdownproducts and their re-creation:between catabolism and anabol-ism. It is the major source ofenergy for all life, with hugeclinical implications.

This does not perhaps make anobvious appeal to a medical stu-dent until we realise that we allsynthesise and degrade our body’sweight of ATP every day. At a

recent meeting of clinical bio-chemists in Paris I heard of thisanimation being used creativelyat the very beginning of a newcourse in medical biochemistry –to stimulate curiosity, excitementand questioning.

I am now 90 and can only lookback in amazement at the mag-nitude and range of our under-standing of biochemistry andmolecular life sciences – andwonder what is the contributionof the teacher. It is not merely toassimilate and interpret the workof others but, at a more basiclevel, at the very beginning, toencourage and inspire a desire fora fuller understanding – forenlightenment. And what can bemore exciting than the science oflife?

Over the years, I have receivedthousands of (mostly) enthusias-tic messages of appreciation,especially from students. One ofthe most gratifying was to receivea book written by a former stu-dent who has had a very success-ful career in the media. It wasinscribed simply: ‘To a teacherthat made the difference’. All thework described here has beenaimed at ‘making the difference’,and the most satisfying achieve-ment of that aspiration is thateverything I have described,including animations, is nowfreely available to all, throughoutthe world, however impoverished,on www.iubmb.org. All my work isnow the copyright property of theInternational Union of Biochem-istry and Molecular Biology(IUBMB), and Sigma-Aldrich playsa vital role in its presentation.

An affinity for biochemistrycan be an important asset tomedical students whatever theirfuture area of specialisation, andfor 60 years, my aim, and morerecently my aphorism, has been‘To make metabolism meaningful,wonder-full – and fun’.

Figure 4. � International Union of Biochemistry and Molecular Biology (reproduced with permission).

What can bemore excitingthan the scienceof life?

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