Articles

From Metabolic Pathways Charts to Animaps in 50 Years

Received for publication, March 28, 2005

Donald Nicholson‡

From the School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom

My first move toward a conscious interest in metabolismtook place in the unlikely setting of a tiny cinema in amountain village above Huddersfield where in 1940 I hadgone to see a film that I thought was The Magic Flute butthat turned out to be The Magic Bullet. It was an “inform-ative and inspiring story” of Paul Ehrlich and his search inthe early 1900s for the elusive chemical, the magic bullet,that would show a “selective toxicity” between differentorganisms such as a bacterium and its host, a conceptbased on the well known ability of dyes and stains toselectively dye or stain different fibers or tissues. Theclimax of the film was his discovery of salvarsan, theorganic arsenical compound that because of its success inthe treatment of syphilis was the forerunner of chemother-apy. Some 30 years later, around 1930, another Germanscientist, Gerhard Domagk, working in the IG Farbenindus-trie, discovered an azo dye, Prontosil, that had a differentantibacterial activity that was later shown to be dependentnot on the azo group but on one of the products of itsreduction, sulfanilamide. For virtually the first time in his-tory, streptococcal and other bacterial infections could betreated by chemicals, chemotherapy. At this time, I was atHuddersfield Technical College just starting post-graduateresearch in Color Chemistry and getting very familiar withazo compounds. I was being sponsored by the BritishDyestuffs Corporation, which was the British equivalent ofthe IG Farbenindustrie.

The autumn of 1940 was a desperate time in Britishhistory, and I was sent as an industrial chemist to BootsPure Drug Company in Nottingham where to my completesurprise and delight I was given the job of developing thelarge scale manufacture of sulfanilamide, and then sulfa-pyridine (the famous M&B 693) and sulfathiazole and otherdrugs. A few years later, a huge incubator was built tohouse thousands of Roux bottles to grow a fungus calledpenicillium and produce (very inefficiently) a desperatelyneeded “antibiotic” called penicillin. The ability to treatbacterial infections by synthetic chemicals was now en-hanced by drugs of biological origin. The age of “chemo-therapy” had really arrived, and in a strange way we feltprivileged to be involved.

After the war, ICI wanted to encourage the integration ofresearch between industry and the universities by spon-

soring a number of research fellowships, one of which wasin chemotherapy at the Department of Bacteriology atLeeds University Medical School. I was reasonably wellqualified in chemistry but was completely ignorant of ther-apy, but I applied and was successful. This was my firstexperience of university life and particularly a medicalschool with its hitherto unknown world of 24-hour urines,blood samples, tuberculous sputum, diphtheria swabs,and the ubiquitous Gram stain. My professor, McLeod,was very encouraging and set me to work on two “chem-ical” problems: the nature of diphtheria toxins and thegrowth requirements of the tubercle bacillus. This struckme as a highly appropriate introduction to a new sciencebecause in early childhood I had had both diphtheria andtuberculosis, Now, for the first time in my life, at the age of30 I had started to learn about the chemistry of livingorganisms (biochemistry) and now, nearly 60 years later, Iam still learning.

1946 saw the rebuilding of the universities after thetraumas of the war. At Leeds, Biochemistry became anautonomous department, no longer an offshoot of Physi-ology, and in Bacteriology, teaching was restructured. Iwas thrown in at the deep end when a shortage of staffrequired me to give a lecture to the medical students onmalaria. That was an ordeal that made me realize (andwarned me) that it was possible to give a lecture on asubject you knew almost nothing about provided no ques-tions were asked. Those were days when a good memorywas sometimes equated with a good brain, and quality ofteaching was rarely assessed. I began to think a lot aboutthis, so that when we had to redesign our own courses anew and inelegant word had entered my vocabulary andhas remained there ever since, “meaningfulness.” 1946was a wonderful time to start teaching bacterial metabo-lism. Lederberg and Tatum had just described the sexualtransmission of genetic material in bacteria, and their in-terrupted-mating experiments made a huge contribution toan understanding of DNA and gene mapping and was agift to a teacher. The first metabolic pathway, glycolysis,had been completed only a few years earlier and hadstimulated an explosion of research into other pathways.

A decade later, a great complexity of pathways hadbeen elucidated, and it became clear that although stu-dents had learnt a lot about these individual pathways andhad often memorized hundreds of names and formulaeand equations and enzymes, it was only if they were puttogether that they would make biochemical sense. To

‡ To whom correspondence should be addressed: Schoolof Biochemistry and Microbiology, University of Leeds, LeedsLS2 9JT, UK. E-mail: d.nicholson@leeds.ac.uk.

© 2005 by The International Union of Biochemistry and Molecular Biology BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATIONPrinted in U.S.A. Vol. 33, No. 3, pp. 156–158, 2005

This paper is available on line at http://www.bambed.org156

become meaningful, biochemistry needed an integratedmap or chart that would show metabolic interrelationshipsin a way that no textbook did or perhaps could. Jigsawpuzzles always came with a picture on the box that greatlysimplified the integration of the pieces. Could the same bedone for metabolic pathways? The objective would be tocomplement textbooks by providing an overall picture thatwould encourage an understanding and appreciation ofthe significance and elegance of interrelated metabolicpathways.

The original map in 1965 was hand drawn with UNOstencils on tracing paper and was “blueprinted” in theuniversity architect’s department in rather limited quanti-ties. It was immediately popular with students, and evenmore encouraging, with colleagues in the BiochemistryDepartment who knew far more biochemistry than I did.During the next few years, three further, updated, copieswere made, but a serious problem persisted. To differen-tiate different aspects of metabolism such as carbohy-drates, amino acids, and lipids, color was needed, and thiswould require a real printer and a proper publisher. I ap-proached the leading publishers and biochemicals manu-facturers but met with unanimous rejections until I had anencouraging response from a small biochemicals firm,Koch-Light Laboratories. The Metabolic Pathways Chart(Fig. 1) was born, and this was the start of a long andfruitful relationship that lasted 28 years and produced 18editions and some 800,000 copies The 1960s and 70swere times in which productive research into metabolicpathways was so intensive that an annual edition becameeducationally and commercially desirable, but for me itbecame a sort of annual pregnancy. The gestation periodwas always about 9 months, labor was intense and pro-longed, and the safe delivery of a hopefully beautiful baby

had often to be induced to coincide with the annual FASEBmeeting in America.

The Bacteriology Department in those days was part ofthe medical school, and I got to know some of the medicalstudents well. Bacteriology was an acceptable part of theircurriculum because it was “relevant” (it was clearly relatedto disease), whereas biochemistry was often considered tobe “irrelevant.” The Metabolic Pathways Chart did notalways help and could itself become the potential cause ofa disease that I called the “O-Hell Syndrome,” a phobiainduced by the unfounded but not irrational fear that itmight have to be memorized. What then was its use to abusy medical student? Metabolic pathways were driven bymore or less specific enzymes that in turn were determinedby our genetic makeup. If a gene was defective, it wouldresult in a defective enzyme that could lead to a build up ofits substrate, usually in the blood or urine. Metabolic Path-ways could illustrate this by pinpointing defective enzymesand linking them to known metabolic deficiency diseases.The Inborn Errors of Metabolism maps were thus createdto encourage medical students to realize that an under-standing of biochemistry (and genetics) could be an im-portant asset in their understanding of clinical medicine.

In these earliest years, I had inestimable encouragementfrom different sources. Foremost was a colleague in theBiochemistry Department, Stan Dagley (Dag) with whom in1970 I wrote what proved to be a very popular book, AnIntroduction to Metabolic Pathways. Most of this collabo-ration took place when he was professor at the Universityof Minnesota where he won local and national awards notonly for research but also for teaching. His weekly trans-atlantic letters taught me a lot about the meaning andpresentation of biochemistry and were often enlivened byspicy biochemical gossip. His premature death was agreat loss. The professors at both Cambridge and Oxfordwere hugely encouraging. Rudolph Peters at Cambridgeused one of the earliest maps in a prestigious lecture andin a book. Hans Krebs at Oxford had a long lasting influ-ence. I well remember going to hear him give a lecture onmetabolic interrelationships soon after the map was firstpublished, and his first slide was my map, which was thebasis of his lecture. He used to write regularly to acknowl-edge new editions, and at the FEBS meeting in Prague in1968 he asked me if I would edit the biochemistry sectionof the prestigious Geigy Scientific Tables for which he hadhitherto been responsible. Such confidence from such asource did wonders for my morale.

Since 1990, the maps have been published by Sigmaand were initially encouraged by its founder and thenpresident, Tom Cori, a biochemist of unique biochemicalpedigree. Both his parents were Nobel Laureates, andsome of their work stands at the very center of my mapsand of biochemistry itself. The approach by Sigma to thepublication was a revelation, and when about 10 years ago“digitization” was suggested, I tried to look intelligent, butwas in fact ignorant of the word. I soon found out what itreally meant; after 20 editions, never again would I have tostick thousands of bits of paper on one big piece of card-board because it was all “on the computer,” and futurechanges would be relatively simple. I had always tried tomake Metabolic Pathways attractive because they had

FIG. 1. The author and the Metabolic Pathways Chart.

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become a feature on the walls of thousands of laborato-ries, but it took the wizards of Sigma’s Graphics Depart-ment to create pictures that were not only attractive anduseful, but also, I believe, works of art.

About 10 years ago I began to take the future of themaps seriously. I had lived with them for 40 years, andnobody else would be likely to take them so seriously. ButI knew that many people valued them and it might be a pityto let them die. I therefore, with some trepidation, ap-proached the IUBMB, offering them the copyrights, whichto my reassurance and pleasure was accepted with en-thusiasm. But a new and totally unexpected era was aboutto dawn. Sigma had taught me the potentialities of digiti-zation so to celebrate my 80th birthday I bought a com-puter and (honestly!) for the first time touched a keyboard.I wanted to design “minimaps” that would take individualpathways and enlarge them to include additional factorsthat could not be shown on the big maps such as com-partmentation, co-factors, and regulation. They would re-ally be the modernization of the small maps that were thebasis of An Introduction to Metabolic Pathways writtenwith Stan Dagley 20 years earlier. They were immediatelyadopted by the IUBMB and named IUBMB-NicholsonMinimaps. Thirty-five have so far been created and can beseen on www.iubmb.org. Most are basic pathways visual-ized within the cellular environment so as to illustrate theimportance of organelles in making metabolism possible.In the minimaps, the enzymes involved in the various re-actions are identified as in the large maps by their ECnumbers, but this is enhanced by the ability to click on anynumber and be directed to information on the enzyme,which is in turn linked to other data bases. The minimapsare available in three formats: GIF for screen viewing, SVGfor enlarging without loss of resolution, and PDF, which isbest for printing.

In all the years, my greatest frustration has been thetwo-dimensional, static nature of the maps. Biochemistryis BIO-chemistry and should be animated, and the adventof PowerPoint a few years ago made this possible. I foundI could make reactants flow into the inside of (two-dimen-sional) enzymes and align with their “active sites,” mainlystructural amino acids, before reacting. I called them “ani-maps.” This was a real advance because it could illustratethe basic importance of enzyme-substrate relationships,but had severe limitations; it could not show the intramo-lecular movements of bonds and electrons, which are thebasis of biochemical reactions. PowerPoint cannot “swivel,”which is what the traditional curly arrows of static two-

dimensional texts are designed to illustrate, but more re-cent programs have a much greater versatility. Flash hasworked wonders and makes possible a visual illustration ofbond movements. The first animap to be completed inFlash was ATP synthase, which was designed to illustratehow retrolocating protons drive the molecular motor thatsynthesizes ATP. It is an immensely complicated and un-likely structure, the details of which are still the subject ofmuch research. The structure and mechanism have inev-itably been simplified and are presented as an “interpre-tation.” But it is hoped that, viewed as an animation, it maystimulate an appreciation that although of very differentarchitecture, in elegance and in beauty and in biochemicalsignificance is akin to DNA. The present objective in Flashanimation is to create a synchronized picture of the basicpathways that start with glycolysis and end with ATP-driven endergonic reactions via the TCA cycle, the elec-tron-driven proton translocation in the mitochondrial mem-brane, and the formation and utilization of ATP.

What of the future? As a near-nonagenarian, that willclearly depend on others, but the way ahead has greatpotential. All the copyrights belong to the IUBMB, theNomenclature Committee has an overall guiding influence,and the financial future is ensured for years ahead by therecent agreement between IUBMB and Sigma-Aldrich.Above all, my good friend and Leeds colleague, Ed Wood,has already been actively involved in the dissemination ofthe maps. As a leading protagonist of biochemical educa-tion and as editor of BAMBED for much of its lifetime, thereis no one in whom I would have greater confidence for thefuture. The designing of minimaps and animaps can be ahugely satisfying and creative educational activity. It en-courages a wide understanding of metabolism, its regula-tion, and the significance of compartmentation of mem-branes and organelles and organs. In recent years, postershave become an increasingly important and attractivemeans of disseminating biochemical research, particularlyby younger scientists, and prizes are often used as anincentive to quality of design and presentation. In the fieldof education, this same approach could well have thesame stimulating results. Biochemistry can still be a boringrequirement for some courses, and new means of makingit attractive are constantly needed. The work that is heredescribed can all be seen on www.iubmb.org and hasbeen driven over the last 50 years by one very clear aspi-ration to: MAKE METABOLISM MEANINGFUL, WONDER-FUL, AND FUN.

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