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Schrödinger and Delbrück: their status in biology
232
TIBS 1 3 - June 1988
Reflections on biochemistry II
SchrSdinger and Delbriick: their status in b|ology Neville Symonds For quite different reasons the names of Schr6dinger and Delbriick have taken on an almost mythical status in biology. Their careers (for short biographies see Refs 1 and 2) did however have certain features in common. Both were quantum physicists from central Europe, Schr6dinger from Austria where he was born in 1887, and Delbriick (who was 20 years younger) from Germany. For a brief spell in 1932-1933 each was in Berlin, Schr6dinger as a professor and Delbriick as assistant to Lise Meitner, although there are no reports that they then knew each other. Both left central Europe in the late 1930s, Schr6dinger spending the years 1939 to 1957 in Dublin, while Delbriick lived alraost continuously in the USA from 1937, for the most part at the California Institute of Technology (Caltech) where from 1946 he was a professor, and at Cold Spring Harbor where he loved to spend his summers, They both lived to be close to 75, and each received a Nobel Prize. The main link between the two proposed is that a inmolecu1935 Delbriick lar model of the gene which was virtually ignored at the time but received a great deal of publicity almost a decade later when it was discussed at length in Schr6dinger's book. Another link, inconsequential except with regard to this article, is that I was a very junior colleague of both of them, from 19481950 in Dublin working on unified field theories, and from 1951-1953 at Caltech being initiated into phage genetics. N. Symonds is at the School of Biological Sciences, The University of Sussex, Falraer, Brighton BN19QG, UK. ~) 1988, ElsevierPublications Cambridge 0376-5067188/$02.00
Schr&linger
Schr6dinger's interaction with biology is entirely due to the little book What is Life? 3 (abbreviated to WIL). Two factors led to the writing of this book. The first was the challenge presented to Schr6dinger, as a physicist, of explaining life in physical terms. The second the necessity to give a series of
f
Si/
impact ofscience, the bookrather as a tract popular than ina consequence of any specific pro~ ~,¢ posals or insights it contained. ~ ~ Schr6dinger's masterly ability to popular lectures. When the Dublin talk about genes and development in Institute for Advanced Studies was terms of molecules, quantum theory, set-up around Schr6dinger in 1941 by thermo-dynamics and the code, led to the Irish Prime Minister Eamon De biology being viewed in a different perValera (himself no mean mathemati- spective by many non-biologists, and by cian), one of the requirements was that quite a lot of biologists as weli. Between each year the Institute should provide a 1944 and 1953 this altered perspective series of public lectures to the people of didn't have much effect in introducing Dublin. This is where WIL was first fresh ideas or faces into biology as it was a aired, in 1943, to a crowded audience of period during which the foundations of over 400. The lectures were published biochemical genetics were being estabas a book in 1944, and immediately lished by relatively simple biological aroused tremendous interest. Un- and biophysical techniques. Few sciendoubtedly part of the impact of the tists moved into the field at that time, elbruckandSchrod
tI ~ I,
book derived from the fact that SchrOdinger was already famous as one of the founders of wave mechanics. But the clear statements it made concerning the molecular and thermodynamic implications that inevitably followed from considering living systems in physical terms struck a common chord among many biologists, physicists and chemists. Views concerning the scientific importance of the ideas discussed in WIL vary widely. At one extreme are the opinions that the book introduced into biology the notions of the genetic code and of the aperiodic structure of the genetic material 4's'6, that it gave an impetus to important research on the thermodynamics of open systems7, and that it addressed a basic problem in developmental genetics, namely the explanation of how the genetic information in a single cell is able to control the myriads of reactions that lead to the formation of a mature organism (Schr6dinger hoped that the solution to this 'order from order' problem would necessitate the introduction of new physical lawsS'9). At the other extreme is the view that all the original ideas expressed in WlLare wrong lo. My own opinion IL~2 is that WlL did play an important role in shaping the course taken by research in molecular biology, but its influence wasn't appreciable until almost ten years after publication, and was due to the
TIBS 13 -June 1988 and those who did were mainly motivated by personal contacts. However, the situation changed suddenly in 1953 with the formulation of the structure of DNA, and it was in the following years that I believe WIL exerted its influence. An increasing number of scientists then began to enter biology as it became apparent that biological questions could be posed in molecular terms. By then, largely due to Schr6dinger's book, a mood had been created in which (probably for the first time) molecular biology vied with mathematics and physics as a challenge for the brighter research workers. It was this influx of new blood which led to many of the new initiatives that enabled molecular biology to blossom in the succeeding years. Apart from WIL, Schr6dinger made no other contribution to biology. The book was written 'as a hobby' to use his own words m~,and he never returned to the problems it raised. Schrrdinger had extremely wide interests and although he had an abiding involvement with relativity and quantum theory he also made brief intellectual sorties into numerous other areas. During his Dublin days biology was one such outlet, another was pre-Socratic philosophy about which he wrote another little book based on a further set of public lectures 13. Schr6dinger worked almost entirely alone. He never became the centre of a 'School' and didn't have any desire to be the focus for that kind of group activity. He worked mostly at home during the period I was in Dublin, sitting at a large kitchen table from which a couple of inches had been removed from the two front legs to give a slight raking surface. He would arrive by moped each day at the Institute in time for morning tea, usually armed with some new enthusiasm. One that remains a vivid memory is a particularly subtle proof he had unearthed that all triangles were isosceles. De|briiek Delbriick's legendary position in biology is more difficult to explain than Schr6dinger's. His interest in biology was first aroused while he was in Berlin by the experiments of TimofeeffRessovsky on Drosophila, which were the first to show that mutations could be induced by irradiation. It was the attempt to explain this finding that led Delbriick to propose the molecular model of the gene 14, which was later resurrected by SchrOdinger in WIL. In
233 1937 Delbriick went to Caitech ,'n order to pursue his studies in the Drosophila laboratory which was flourishing there at the time. The relationship between Delbriick and the 'drosopholists' did not prosper, but in the basement of the biology school Delbriick found Emory Ellis, who was experimenting with coilphage. Delbriick quickly realized this was an ideal biological system in which to perform quantitative studies. There were simple assays for the host bacteria and the phage, experiments could be done in a day, the techniques were easy to learn, and as a bonus for physicists both the phage and bacteria were harmless. Between 1937 and 1953 Delbriick actively pursued, supported, and promoted phage research. After that time, and until his death in 1981, he shiRed his own research activity to the study of phototropism in the fungus Phycomyces. However, he retained his enthusiasm for phage and it is with his contributions to molecular genetics and relationship with the so-called 'phage school' that his name is usually assodated. It is possible to distinguish four strands which determined DelbRick's influence on molecular biology. In order to appreciate the first it is necessary to realize that up to 1953 biological research was still largely a qualitative subject, and there was a great deal of resistance to quantitative experiments in microbiology. Delbriick, along with Hershey, Luria, and the small number of other phage workers, found little support during that period from the scientific establishment. It was Delbrfick's conviction that what they were doing was so worthwhile, and his del:ermination to ensure that the research continued which held the group together. Hershey once told me there were a number of occasions when he would have packed in phage research if it hadn't been for Delbriick's encouragement. Secondly, in the summer of 1945, Delbrfick initiated the phage courses at Cold Spring Harbor, which have run with variations ever since. These introduced scores of scientists to the new techniques and ideas of phage genetics. It was mainly the group composed of the early participants in these courses, together with visitors who worked in his laboratory at Caltech, who became known as the phage school and whose achievements were catalogued in the festschrift volume dedicated to Delbriick on his 60th birthday is.
Thirdly, although Delbriick was not an outstandingly original scientist, he had one of the best analytical minds I ever came across, and brought a clarity into biological thinking which was rarely evident before. His insistence on clear experimental results and rational explanations influenced enumerable research projects. Both in conversation and at lectures Delbriick was an acute critic. There are many stories of his intervention in and after seminars. One often recounted is of Delbriick taking the speaker aside after a talk and telling them that that was the worst seminar he'd ever heard- and then following up with some words of advice and encouragement. In my case the crunch came in a seminar I gave concerning some experiments which showed streptomycin could inhibit the growth of phages in streptomycin-resistant bacteria by binding to the phage DNA and preventing injection. The sensitivity of the effect varied from phage to phage, and was dependent on salt concentration. After half an hour, when I was describing how the sensitivity went up and down as salt concentration went down and up, Delbriick interrupted loudly 'Let me know when you get out of the kitchen sink', and proceeded to read a newspaper. Afterwards he said he'd heard worse seminars, but few more boring. As a cesult my lecture technique improved considerably, but perhaps unfortunately in retrospect we never published the streptomycin findings, which constitute one of the few cases where the mode of action of an antiviral agent has been clearly demonstrated. The last strand regarding Delbrikk's influence is the hardest to g~asp, but probably the most important. This relates to the strength of his personality. Just as there was a minority who was unimpressed by WIL, there was also a minority who found Delbriick arrogant and something of an intellectual bully.To the majority however he was a man with a wonderfully c|ear mind, who had great integrity, a delightfulsense of fun, and a facilityfor friendship. He loved to be surrounded by colleagues, particularly younger ones, and the phage group was basically a collection of biologists joined loosely together by respect and friendship for Delbdick, not primarily a group of phage workers.
Conclusion Delbriick had considerable influence on the development of molecular 0io-
TIBS 13 -June 1988
234 2 Hayes, W. (1982) Biogr. Mem. Fellows R. Soc. 28, 59-90 3 Schr6dinger, E. (1944) What is Life? Cambridge University Press 4 0 l b y , R. C. (1971)J. Hist. Biol. 4,11.o--148 5 0 l b y , R. C. (1974) The Path to the Double Helix Macmillan 6 Witkowski, J. (1986) Trends Biochem. Sci. 11,266-268 7 Schneider, F. (1987) Nature 328, 300 8 Yoxen, E.J. (1979)Hist. Sci. 17,17-52 9 Jacob, F. (1974) The Logic of Living Systems: A History of Heredity Allen Lane
10 Perutz, M. (1987) Nature 326,555--55a 11 Symonds, N. (1986) Q. Rev. BioL 61,221-226 12 Symonds, N. (1987) Nature327, 663--664 13 Schr6dinger, E. (1954) Nature and the Greeks Cambridge University Press 14 Timofeeff-Ressovsky, N. W., Zimmer, K. G. and Delbriick, M. (1935) Nachr. Ges. Wiss. Gottingen, Math-Phys. Kl., Fachgruppe 6 1, 18,0--245 15 Cairns, J., Stent, G. S. and Watson, J. D., eds (1966) Phage and the Origins of Molecular Biology, Cold Spring Harbor
'Rows' between reservoirs which act to accumulate or provide material. Thus, if one wished to simulate transformaAcademic S T E L L A TM tions occurring within the cell, then the 'flow' control could be provided by Apple Mac systems modelling and enzymes and reservoirs would contain simulation program by High Perform- either products or substrates. Of ance Systems, 13 Dartmouth College course, any dynamic transformation Highway, Lyme, NH 03768, USA. UK (such as changes in biomass, cell numdistributors are Logotron Ltd., Dales ber, active/inactive transitions and Brewery, Gwydir Street, Cambridge gene expression) can be modelled. The CB1 2L J, UK. £199.00 (for those in way in which any particular simulation education) or £249.00 (for others) (plus is achieved first utilises a 'diagram' VAT in UK) $250.00 (for those in window (see Fig. 1) where you assemble your model by 'plumbing' together education) or$350.00. 'reservoir' icons, which represent Consumable budget run out? Centri- stocks of material, using 'valve' icons, fuge broken down? Spectropho- which contro! the flow into and out of tometer developed a mind of it's own? the reservoirs. You then simply point Grant alpha rated but, sorry no and select each icon in turn in order to money? Yes, these and other problems introduce either the 'priming' values of make it just another day in the life of a materials into the reservoirs or the scientist. However, now there is a pal- equations and conditions that control liative for these distressing conditions: the 'valves'. The numerical constants STELLA TM. The initial hurdle is to that may be required for the 'valves' to scrape enough money together to buy operate, such as Km and Vm~,values for an Apple Macintosh and then buy the enzymes, are supplied in 'information High Performance Systems STELLA spheres' which you 'wire up' to the software package. For STELLA allows relevant valve by pointing with the you to simulate all those preconceived mouse in the 'diagram' window. Such ideas that you had about your experimental system but were always afraid product1 product2 to put to the test. STELLA is a stunning package which allows you to simulate dynamic processes rapidly and interactively. It achieves, on your desktop, in minutes, simulations which fifteen years ago took days to assemble and test. Now the Apple Macintosh computing system goes a long way to achieving a simple interface between user and computer: no more grappling with Vmax2 Km2 handbooks to remember control codes or to do simple things like 'trash' and Fig. 1. The 'diagram' window. Space limitations allow only for a very simple scheme to be shown. copy files or format discs. Before you This simulates the activity of two enzymes where begin to apply STELLA you are asked enzyme 2 is undergoing product inhibition (by to think of your model in terms of product2).
'wires' can also be used to provide information to the appropriate valves of changes in substrate or product concentrations which occur in the '~eservoirs' as the simulation proceeds. The soRware makes it very easy to supply the information which is needed to control valves. Selection of a valve immediately displays a visual key pad which prompts you to supply the relationships between the variables and constants that are needed for the valve to function e.g. Michaelis equation for an enzyme which obeys such kinetics. Once you have supplied a relationship, which encompasses all of the inputs needed to control the valves (the software prompts you if you have not), then STELLA obligingly generates all the equations that are necessary to link each of the individual portions of your model together. These equations can be viewed in a separate window and printed out together with all the values of constants and all the priming values that you have given to each of the reservoirs. At this point you are ready to begin your simulation and so can proceed to summon up the graph window (see Fig. 2). This window allows you to follow changes in up to four items of your model at one time. After a simple selection, there is no subsequent trauma in setting the limits of the axes for the graphs; you simply select 'autoscale' and the software runs through a rapid trial simulation which yields optimized value ranges for the axes of each variable to be plotted as a graph. (A simple manual override permits you to select a particular scale if desired.) After this, the simulation can be run using one of a number of mathematical methods (Euler, Runge-Kutta 2•4), which can be selected either for precision or for speed. The graph pad has a number of pages, so that you can preserve a siren-
iogy. However it is with him as a person rather than as a scientist that the Delbriick legend is associated. Schr6dinger had only a brief flirtation with biology. His legendary status rests on a small book which has stimulated countless readers and probably helped initiate several seminal lines of research. References 1 Heitler, W. (1961) Biogr. Mem. Fellows R. Soc. 7,221-228
Microfile Into STELLAR Space
© 1988.ElsevierPublicationsCambridge 0376-5067188/$02.00
TIBS 1 3 - June 1988
Reflections on biochemistry II
SchrSdinger and Delbriick: their status in b|ology Neville Symonds For quite different reasons the names of Schr6dinger and Delbriick have taken on an almost mythical status in biology. Their careers (for short biographies see Refs 1 and 2) did however have certain features in common. Both were quantum physicists from central Europe, Schr6dinger from Austria where he was born in 1887, and Delbriick (who was 20 years younger) from Germany. For a brief spell in 1932-1933 each was in Berlin, Schr6dinger as a professor and Delbriick as assistant to Lise Meitner, although there are no reports that they then knew each other. Both left central Europe in the late 1930s, Schr6dinger spending the years 1939 to 1957 in Dublin, while Delbriick lived alraost continuously in the USA from 1937, for the most part at the California Institute of Technology (Caltech) where from 1946 he was a professor, and at Cold Spring Harbor where he loved to spend his summers, They both lived to be close to 75, and each received a Nobel Prize. The main link between the two proposed is that a inmolecu1935 Delbriick lar model of the gene which was virtually ignored at the time but received a great deal of publicity almost a decade later when it was discussed at length in Schr6dinger's book. Another link, inconsequential except with regard to this article, is that I was a very junior colleague of both of them, from 19481950 in Dublin working on unified field theories, and from 1951-1953 at Caltech being initiated into phage genetics. N. Symonds is at the School of Biological Sciences, The University of Sussex, Falraer, Brighton BN19QG, UK. ~) 1988, ElsevierPublications Cambridge 0376-5067188/$02.00
Schr&linger
Schr6dinger's interaction with biology is entirely due to the little book What is Life? 3 (abbreviated to WIL). Two factors led to the writing of this book. The first was the challenge presented to Schr6dinger, as a physicist, of explaining life in physical terms. The second the necessity to give a series of
f
Si/
impact ofscience, the bookrather as a tract popular than ina consequence of any specific pro~ ~,¢ posals or insights it contained. ~ ~ Schr6dinger's masterly ability to popular lectures. When the Dublin talk about genes and development in Institute for Advanced Studies was terms of molecules, quantum theory, set-up around Schr6dinger in 1941 by thermo-dynamics and the code, led to the Irish Prime Minister Eamon De biology being viewed in a different perValera (himself no mean mathemati- spective by many non-biologists, and by cian), one of the requirements was that quite a lot of biologists as weli. Between each year the Institute should provide a 1944 and 1953 this altered perspective series of public lectures to the people of didn't have much effect in introducing Dublin. This is where WIL was first fresh ideas or faces into biology as it was a aired, in 1943, to a crowded audience of period during which the foundations of over 400. The lectures were published biochemical genetics were being estabas a book in 1944, and immediately lished by relatively simple biological aroused tremendous interest. Un- and biophysical techniques. Few sciendoubtedly part of the impact of the tists moved into the field at that time, elbruckandSchrod
tI ~ I,
book derived from the fact that SchrOdinger was already famous as one of the founders of wave mechanics. But the clear statements it made concerning the molecular and thermodynamic implications that inevitably followed from considering living systems in physical terms struck a common chord among many biologists, physicists and chemists. Views concerning the scientific importance of the ideas discussed in WIL vary widely. At one extreme are the opinions that the book introduced into biology the notions of the genetic code and of the aperiodic structure of the genetic material 4's'6, that it gave an impetus to important research on the thermodynamics of open systems7, and that it addressed a basic problem in developmental genetics, namely the explanation of how the genetic information in a single cell is able to control the myriads of reactions that lead to the formation of a mature organism (Schr6dinger hoped that the solution to this 'order from order' problem would necessitate the introduction of new physical lawsS'9). At the other extreme is the view that all the original ideas expressed in WlLare wrong lo. My own opinion IL~2 is that WlL did play an important role in shaping the course taken by research in molecular biology, but its influence wasn't appreciable until almost ten years after publication, and was due to the
TIBS 13 -June 1988 and those who did were mainly motivated by personal contacts. However, the situation changed suddenly in 1953 with the formulation of the structure of DNA, and it was in the following years that I believe WIL exerted its influence. An increasing number of scientists then began to enter biology as it became apparent that biological questions could be posed in molecular terms. By then, largely due to Schr6dinger's book, a mood had been created in which (probably for the first time) molecular biology vied with mathematics and physics as a challenge for the brighter research workers. It was this influx of new blood which led to many of the new initiatives that enabled molecular biology to blossom in the succeeding years. Apart from WIL, Schr6dinger made no other contribution to biology. The book was written 'as a hobby' to use his own words m~,and he never returned to the problems it raised. Schrrdinger had extremely wide interests and although he had an abiding involvement with relativity and quantum theory he also made brief intellectual sorties into numerous other areas. During his Dublin days biology was one such outlet, another was pre-Socratic philosophy about which he wrote another little book based on a further set of public lectures 13. Schr6dinger worked almost entirely alone. He never became the centre of a 'School' and didn't have any desire to be the focus for that kind of group activity. He worked mostly at home during the period I was in Dublin, sitting at a large kitchen table from which a couple of inches had been removed from the two front legs to give a slight raking surface. He would arrive by moped each day at the Institute in time for morning tea, usually armed with some new enthusiasm. One that remains a vivid memory is a particularly subtle proof he had unearthed that all triangles were isosceles. De|briiek Delbriick's legendary position in biology is more difficult to explain than Schr6dinger's. His interest in biology was first aroused while he was in Berlin by the experiments of TimofeeffRessovsky on Drosophila, which were the first to show that mutations could be induced by irradiation. It was the attempt to explain this finding that led Delbriick to propose the molecular model of the gene 14, which was later resurrected by SchrOdinger in WIL. In
233 1937 Delbriick went to Caitech ,'n order to pursue his studies in the Drosophila laboratory which was flourishing there at the time. The relationship between Delbriick and the 'drosopholists' did not prosper, but in the basement of the biology school Delbriick found Emory Ellis, who was experimenting with coilphage. Delbriick quickly realized this was an ideal biological system in which to perform quantitative studies. There were simple assays for the host bacteria and the phage, experiments could be done in a day, the techniques were easy to learn, and as a bonus for physicists both the phage and bacteria were harmless. Between 1937 and 1953 Delbriick actively pursued, supported, and promoted phage research. After that time, and until his death in 1981, he shiRed his own research activity to the study of phototropism in the fungus Phycomyces. However, he retained his enthusiasm for phage and it is with his contributions to molecular genetics and relationship with the so-called 'phage school' that his name is usually assodated. It is possible to distinguish four strands which determined DelbRick's influence on molecular biology. In order to appreciate the first it is necessary to realize that up to 1953 biological research was still largely a qualitative subject, and there was a great deal of resistance to quantitative experiments in microbiology. Delbriick, along with Hershey, Luria, and the small number of other phage workers, found little support during that period from the scientific establishment. It was Delbrfick's conviction that what they were doing was so worthwhile, and his del:ermination to ensure that the research continued which held the group together. Hershey once told me there were a number of occasions when he would have packed in phage research if it hadn't been for Delbriick's encouragement. Secondly, in the summer of 1945, Delbrfick initiated the phage courses at Cold Spring Harbor, which have run with variations ever since. These introduced scores of scientists to the new techniques and ideas of phage genetics. It was mainly the group composed of the early participants in these courses, together with visitors who worked in his laboratory at Caltech, who became known as the phage school and whose achievements were catalogued in the festschrift volume dedicated to Delbriick on his 60th birthday is.
Thirdly, although Delbriick was not an outstandingly original scientist, he had one of the best analytical minds I ever came across, and brought a clarity into biological thinking which was rarely evident before. His insistence on clear experimental results and rational explanations influenced enumerable research projects. Both in conversation and at lectures Delbriick was an acute critic. There are many stories of his intervention in and after seminars. One often recounted is of Delbriick taking the speaker aside after a talk and telling them that that was the worst seminar he'd ever heard- and then following up with some words of advice and encouragement. In my case the crunch came in a seminar I gave concerning some experiments which showed streptomycin could inhibit the growth of phages in streptomycin-resistant bacteria by binding to the phage DNA and preventing injection. The sensitivity of the effect varied from phage to phage, and was dependent on salt concentration. After half an hour, when I was describing how the sensitivity went up and down as salt concentration went down and up, Delbriick interrupted loudly 'Let me know when you get out of the kitchen sink', and proceeded to read a newspaper. Afterwards he said he'd heard worse seminars, but few more boring. As a cesult my lecture technique improved considerably, but perhaps unfortunately in retrospect we never published the streptomycin findings, which constitute one of the few cases where the mode of action of an antiviral agent has been clearly demonstrated. The last strand regarding Delbrikk's influence is the hardest to g~asp, but probably the most important. This relates to the strength of his personality. Just as there was a minority who was unimpressed by WIL, there was also a minority who found Delbriick arrogant and something of an intellectual bully.To the majority however he was a man with a wonderfully c|ear mind, who had great integrity, a delightfulsense of fun, and a facilityfor friendship. He loved to be surrounded by colleagues, particularly younger ones, and the phage group was basically a collection of biologists joined loosely together by respect and friendship for Delbdick, not primarily a group of phage workers.
Conclusion Delbriick had considerable influence on the development of molecular 0io-
TIBS 13 -June 1988
234 2 Hayes, W. (1982) Biogr. Mem. Fellows R. Soc. 28, 59-90 3 Schr6dinger, E. (1944) What is Life? Cambridge University Press 4 0 l b y , R. C. (1971)J. Hist. Biol. 4,11.o--148 5 0 l b y , R. C. (1974) The Path to the Double Helix Macmillan 6 Witkowski, J. (1986) Trends Biochem. Sci. 11,266-268 7 Schneider, F. (1987) Nature 328, 300 8 Yoxen, E.J. (1979)Hist. Sci. 17,17-52 9 Jacob, F. (1974) The Logic of Living Systems: A History of Heredity Allen Lane
10 Perutz, M. (1987) Nature 326,555--55a 11 Symonds, N. (1986) Q. Rev. BioL 61,221-226 12 Symonds, N. (1987) Nature327, 663--664 13 Schr6dinger, E. (1954) Nature and the Greeks Cambridge University Press 14 Timofeeff-Ressovsky, N. W., Zimmer, K. G. and Delbriick, M. (1935) Nachr. Ges. Wiss. Gottingen, Math-Phys. Kl., Fachgruppe 6 1, 18,0--245 15 Cairns, J., Stent, G. S. and Watson, J. D., eds (1966) Phage and the Origins of Molecular Biology, Cold Spring Harbor
'Rows' between reservoirs which act to accumulate or provide material. Thus, if one wished to simulate transformaAcademic S T E L L A TM tions occurring within the cell, then the 'flow' control could be provided by Apple Mac systems modelling and enzymes and reservoirs would contain simulation program by High Perform- either products or substrates. Of ance Systems, 13 Dartmouth College course, any dynamic transformation Highway, Lyme, NH 03768, USA. UK (such as changes in biomass, cell numdistributors are Logotron Ltd., Dales ber, active/inactive transitions and Brewery, Gwydir Street, Cambridge gene expression) can be modelled. The CB1 2L J, UK. £199.00 (for those in way in which any particular simulation education) or £249.00 (for others) (plus is achieved first utilises a 'diagram' VAT in UK) $250.00 (for those in window (see Fig. 1) where you assemble your model by 'plumbing' together education) or$350.00. 'reservoir' icons, which represent Consumable budget run out? Centri- stocks of material, using 'valve' icons, fuge broken down? Spectropho- which contro! the flow into and out of tometer developed a mind of it's own? the reservoirs. You then simply point Grant alpha rated but, sorry no and select each icon in turn in order to money? Yes, these and other problems introduce either the 'priming' values of make it just another day in the life of a materials into the reservoirs or the scientist. However, now there is a pal- equations and conditions that control liative for these distressing conditions: the 'valves'. The numerical constants STELLA TM. The initial hurdle is to that may be required for the 'valves' to scrape enough money together to buy operate, such as Km and Vm~,values for an Apple Macintosh and then buy the enzymes, are supplied in 'information High Performance Systems STELLA spheres' which you 'wire up' to the software package. For STELLA allows relevant valve by pointing with the you to simulate all those preconceived mouse in the 'diagram' window. Such ideas that you had about your experimental system but were always afraid product1 product2 to put to the test. STELLA is a stunning package which allows you to simulate dynamic processes rapidly and interactively. It achieves, on your desktop, in minutes, simulations which fifteen years ago took days to assemble and test. Now the Apple Macintosh computing system goes a long way to achieving a simple interface between user and computer: no more grappling with Vmax2 Km2 handbooks to remember control codes or to do simple things like 'trash' and Fig. 1. The 'diagram' window. Space limitations allow only for a very simple scheme to be shown. copy files or format discs. Before you This simulates the activity of two enzymes where begin to apply STELLA you are asked enzyme 2 is undergoing product inhibition (by to think of your model in terms of product2).
'wires' can also be used to provide information to the appropriate valves of changes in substrate or product concentrations which occur in the '~eservoirs' as the simulation proceeds. The soRware makes it very easy to supply the information which is needed to control valves. Selection of a valve immediately displays a visual key pad which prompts you to supply the relationships between the variables and constants that are needed for the valve to function e.g. Michaelis equation for an enzyme which obeys such kinetics. Once you have supplied a relationship, which encompasses all of the inputs needed to control the valves (the software prompts you if you have not), then STELLA obligingly generates all the equations that are necessary to link each of the individual portions of your model together. These equations can be viewed in a separate window and printed out together with all the values of constants and all the priming values that you have given to each of the reservoirs. At this point you are ready to begin your simulation and so can proceed to summon up the graph window (see Fig. 2). This window allows you to follow changes in up to four items of your model at one time. After a simple selection, there is no subsequent trauma in setting the limits of the axes for the graphs; you simply select 'autoscale' and the software runs through a rapid trial simulation which yields optimized value ranges for the axes of each variable to be plotted as a graph. (A simple manual override permits you to select a particular scale if desired.) After this, the simulation can be run using one of a number of mathematical methods (Euler, Runge-Kutta 2•4), which can be selected either for precision or for speed. The graph pad has a number of pages, so that you can preserve a siren-
iogy. However it is with him as a person rather than as a scientist that the Delbriick legend is associated. Schr6dinger had only a brief flirtation with biology. His legendary status rests on a small book which has stimulated countless readers and probably helped initiate several seminal lines of research. References 1 Heitler, W. (1961) Biogr. Mem. Fellows R. Soc. 7,221-228
Microfile Into STELLAR Space
© 1988.ElsevierPublicationsCambridge 0376-5067188/$02.00