RETROSPECTROSCOPE

The Mathematization of Biology and Medicine

Who, When, How?
By Max E. Valentinuzzi and Alberto J. Kohen
Nessuna umana investigazione si puo dimandare vera scienza sessa non passa per le matematiche dimostrazione. Leonardo da Vinci (14521519)

ne objective of bioengineering is the quantification of the biological and medical sciences, with the goal of improving their exactness and preciseness, always in an attempt to remove as many indeterminations and uncertainties as possible, especially when seeking predictions. The extract at the beginning of the column, which is attributed to Leonardo da Vinci, seems to reflect a very early Renaissance concept in such a direction; this concept is indeed more general because it encompasses all the sciences [1]. The famous Vitruvian Man, so many times reproduced on book covers and posters, appears perhaps as an anticipatory geometrical epitome of that modern recent aim (Figure 1). However, 200 years before da Vinci was Ramon Llull (ca. 12321315), a Majorcan philosopher, member of the Third Order of Saint Francis, and author of important works of Catalan literature. Lull is considered by some to be a pioneer of computation theory because of his contributions to logics. Should he also be considered a very early predecessor of biomathematics? We leave this question dangling for the historian and/or the philosopher of history. In Spain, there is a journal carrying his name, Llull (see [12]). The objective herein is to review and collect the most important efforts made
Digital Object Identifier 10.1109/MPUL.2012.2228591 Date of publication: 13 February 2013

medical alchemists who called their practice iatrochemistry, meaning the chemistry of healing (should we consider it an ancestor of biochemistry?) and is the source of the modern word ped-iatrics. Thus, iatromechanics would be the predecessor of our current biomechanics. Somehow, Borelli followed the mechanistic philosophy inaugurated to mathematize biology by Ren Descartes (1596 and medicine from da 1650), that is, believing The objective herein is Vincis time to the presthat living things behave to review and collect ent, where mathematical like machines or artifacts. the most important biology (often including Philosophers of science efforts made to biophysics by sheer need) call such a view a reducmathematize biology has become an estabtionist approach, that and medicine from lished discipline with is, attempting to reduce departments, congresses, complex biological sysda Vincis time to and journals devoted to tems to simpler ones (such the present. its further development. as mechanical, hydraulic, No doubt, it supplies an or electrical systems). essential background to bioengineering. Perhaps other examples could be It must be mentioned that the initial found, like the simple numerical thinking chronology and a few concepts were of William Harvey, who on the basis of anitaken from the introduction of Mximo mal experimentation, asserted that blood Valentinuzzis doctoral dissertation (Max moves in a closed circuit, accepting this fact E. Valentinuzzis father [2]). A short hisas a biomathematical achievement. Luigi torical summary can also be found in [3]. Galvani (17371798), an experimental biophysicist and the discoverer of animal electricity, might be included as a foreEarly Attempts father of biomathematics, for many were Giovanni Alfonso Borelli (16081679) the mathematical trials and developments was an Italian physicist and mathematithat much later explored electrophysiolcian who made significant contributions ogy. We must philosophically mention to medicine [4]. In the city of Pisa, Italy, the contributions made by Carl Ludwigs he met Marcello Malpighi (16281694), a school during the 19th century as well as physician who encouraged him to get into that of several of his followers and discimedical subjects (by the way, Malpighi is ples [5]. They certainly gave a significant well known for the discovery and descripimpulse to the quantification of physiology tion of the pulmonary capillaries, thus and medicine; however, the true completing what William Harvey (1578 mathematical model of a biological system 1657) had anticipated regarding the blood had to await more maturation. pathway as a closed circuit). As a result, and after studies and experimentation, Borelli came up with an opera magna, The 20th Century De Motu Animalium (On Animal Movement), which was published two years after his Alfred James Lotka, Vito Volterra, death. The book deals with mechanics Pierre Francois Verhulst, and and mathematics as applied to medicine. Vladimir Alexandrovitch Kostitzin He used the term iatromechanics (iatros is Perhaps the first significant contribution, the ancient Greek word for physician). systematically starting the mathematizaThis root was later used by the medieval tion of biology, belongs to Alfred James

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Lotka (18801949), who was born in Lviv (which was at that time situated in Austria and is now located in Ukraine) and died in the United States, where he moved in 1902. He is the author of a number of theoretical articles on chemical oscillations during the early decades of the 20th century and of the first book on theoretical biology, which appeared in 1925 [6], [7]. That book, full of deep philosophicalepistemological citations and digressions and not an easy read, indeed, goes into difficult areas such as consciousness and the concept of life itself. Lotka is best known for the predatorprey model, now called the Lotka-Volterra model, which he developed independently from Vito Volterra (18601940). This model is still the basis of many others, as, for example, in such odd fields (at least for us bioengineers) as the relatively recent re-engineering of corporations [8]. Vito Volterra, 20 years older than Lotka, was an Italian mathematician and physicist. After World War I, he turned his attention to the application of mathematics from biology, principally reiterating and developing the previous work of Pierre Francois Verhulst [9]. The Lotka Volterra equations, or predatorprey equations [10], are a pair of first-order, nonlinear differential equations describing the dynamics of certain biological systems. Two species interact: one is a predator and the other is its prey; they can refer to bacteria, insects, or any other kind of animal that responds to such competitive interaction. Something of the type would also be the acetylcholineacetylcholinesterase kinetics at the myoneural junctions. They evolve in time according to the hypothesis that states that the rate of growth of the prey is proportional to the number of prey units minus a nonlinear term that includes the number of prey units and the number of predator pieces; besides, the rate of growth of predators is accepted as being negatively proportional to the number of predator units plus a nonlinear term including both prey and predator units, that is, dx = x (a - by) (1) dt dy =-y (c - dx), (2) dt

FIGURE 1 Leonardo da Vincis Vitruvian Man is based on the specifications given by Vitruvius in De Architectura (first century BC). da Vinci tried to find the perfectly proportioned body. It was created circa 1487, with pen and ink on paper, depicting a male figure in two superimposed positions with his arms and legs apart and simultaneously inscribed in a circle and square. Stored in the Gallerie dellAccademia, Venice, Italy.

where x is the number of prey (say, mosquitoes in a swamp) y is the number of predators (for example, frogs in the same swamp) dy/dt and dx/dt represent the growth of the two populations against time t stands for time a, b, c, and d are parameters taking into account the interaction of the two species. And who was Pierre Franois Verhulst? Born in Belgium in 1804, he died young in 1849. An accomplished mathematician,

Verhulst in 1838 came up with the following equation: dN = rN 1 - N , (3) ` dt Kj

where N(t) represents the number of individuals at time t, r is the intrinsic growth rate, and K is the carrying capacity or the maximum number of individuals an environment can support. He called its solution the logistic function, the name that is still kept, that is, N (t) = K , (4) 1 + CKe -rt

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FIGURE 2 The front page of Kostitzins book Biologie Mathmatique. This image was taken from a copy belonging to the authors personal library, bought by the authors father, Mximo Valentinuzzi, who was an active biomathematician and biophysicist who spent several years with Nicolas Rashevsky in Chicago in the late 1950s and early 1960s. (Image courtesy of Max E. Valentinuzzi.)

training, he produced a book on mathwhere C = 1/N ^0 h - 1/K is determined ematical biology, originally written in by the initial condition N(0). More inforFrench, with a preface by Vito Volterra mation about the latter equation can [11]. In the preface, Volterra says that, be found either on the Internet or in after a number of papers on this subject up appropriate textbooks. to its publication in 1937, Vladimir Alexandrothere was no other such vitch Kostitzin must be didactic and complete mentioned as a prominent Lotka is best known piece collecting essential scientist, though perhaps for the predatorprey knowledge where general not well recognized. He model, now called the mathematical notions, was born in 1883 in RusLotka-Volterra model, frequency curves, corre sia, although his death which he developed lations, differential equadoes not seem to have tions, and many basic been registered (perhaps independently from biological phenomena it occurred in Paris in Vito Volterra. such as circulation of 1963). A mathematician by
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organic compounds, carbon, oxygen, and nitrogen were considered. One chapter is devoted to the logistic equation, which had already been introduced by Verhulst long before (see above), with other chapters dealing with growth at large, populations, milieu (environment, culture broth), relationships between species, symbiosis and parasitism, embrionary growth, the shape of living organisms, and evolution, that is, all very fundamental and purely biological subjects (Figures 2 and 3). But there is much more to be said about Volterra and Kostitzin. Giorgio Israel and Ana Lilln Gasca, in a comprehensive and superb paper done at the Universit di RomaLa Sapienza, Italy [12], explain well the relationship between Volterra and Kostitzin in an overview of the biomathematical concepts of the 1930s, which was in many respects a worldly dramatic decade, along with the intervention of other distinguished scientists of those days. From the somewhat translated, paraphrased, and much summarized information in the report by Israel and Gasca, let us proceed by saying that Volterra offered during the winter of 19281929 a course on biomathematics at the Institut Henri Poincar, Paris. Those lessons were published in 1931 under the French title Leons sur la Thorie Mathmatique de la Lutte pour la Vie (in English, Lessons on the Mathematical Theory of the Struggle for Life). There are international bookstores, which can be found on the Internet, that offer copies of either the original publication or a more recent reprinted issue. Volterra studied the evolution of populations of different species that share a medium and a biological association, such as competition for food or a prey predator or parasitehost relationship. The reductionist approach triggered much discussion and objection. The long correspondence between Volterra and Kostitzin contains moving testimony. They met when, for unknown reasons (perhaps political), Kostitzin and his wife, Julie (a parasitologist who got a professorship at La Sorbonne), moved to France. Kostitzin considered Volterra to be his teacher, and together they initiated a rebirth of Darwinism, clashing against many opposing positions. Helped by Volterra,

Kostitzin was appointed Charg de Rchrches at the Conseil National des Rchrches Scientifiques (founded in 1939). During the Second World War (19391945), Kostitzin was taken by the Germans to a concentration camp, where he remained from 22 June 1941 until 3 March 1943. Recall that France was occupied by the Nazi Regime. Things improved a little after his liberation, but the situation was still difficult. After the war was over, he almost fully abandoned biomathematics. His wifes demise in 1950 also left a deep mark. Kostitzins last letter was to Virginia Almagi, Volterras widow, in December 1962. The Kostitzin Volterra correspondence is kept in the Accademia dei Lincei (Rome). The letters are written in French, and biomathematics is the central subject, although they also touch on other general questions of the times. All in all, they reflect the tremendous scientific and human personalities of both. For example, one of the letters states Mathematics have got into the natural sciences via statistics, but this phase must yield to the analytic phase, as it happened in the rational disciplines. Thus, the statistical method clears the field, it establishes some empirical laws and so it makes easier the entrance of the analytical variables. In Kostitzins case, there was a coexistence of the mathematician and the naturalist, always searching for experimental validation. Often, he and Volterra showed understanding of the rejection faced by some biologists. Kostitzin kept his optimism in spite of the difficulties, as he pointed out, in a time when the world changes but does not improve [13]. Kostitzin, unfortunately, never received full recognition of his outstanding and remarkable contributions to mathematical biology [13]. These authors of [13] bluntly recall the historiographic tradition re garding evolutionary synthesis, which emphasized the names of Ronald A. Fisher, John S. Burdon Haldane, and Sewall Wright as the theoreticians who laid the quantitative foundations of the mechanisms of change in gene and genotypic frequencies in

FIGURE 3 The third page of Kostitzins book. Mximo Valentinuzzis signature is shown indicating the date on which it was obtained: 13 June 1940. It clearly depicts the beginning of the preface written by Vito Volterra. Volterras and Kostitzins texts were the first devoted to mathematical biology. (Image courtesy of Max E. Valentinuzzi.)

phenotypes in his models to arrive populations, particularly those of at similar conclusions to the Fisher natural selection, mutation, genetic HaldaneWright position. drift, and gene flow. From these as well as other contributions, there is a widespread misconBalthasar van der Pol ception that evolution Balthasar van der Pol is a change in gene (18891959) deserves In Kostitzins case, frequencies. Within a special section, as he, there was a coexistence this context, articles with his collaborator van of the mathematician postulating changes der Mark, specifically and the naturalist, in the frequencies of dealt with the heart as the always searching phenotypes (not genes) objective of a model based were not well received. on oscillations by relaxfor experimental Kostitzins standing ation [14], [15]. He studvalidation. favored essentially the ied in England under two
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grand physicists, John Ambrose Fleming (18491945), remembered for the diode, and Joseph John Thomson (18561940), remembered for the electron, and spent all his productive years with Philips Laboratories until his retirement. Van der Pol clearly stood out among the biologists of his time. Van der Pols relaxation paper referred to in the above paragraph starts by refreshing the usual sinusoidal oscillations stemmed at a linear second-order differential equation (well known to any electrical or mechanical engineering student), wherein the squared damping factor a must be much smaller than the squared natural frequency, ~, or

Nicholas Rashevsky was the man who systematized modern mathematical research Trelax = ~ 2 /a. in the biological and medical sciences. (7) Born in Chernikov, Russia, Rashevsky studied physics in Kiev, Ukraine, where he Hence, the time period, which is obtained his degree in 1919. After teachdetermined by the discharge of a capaciing in Kiev, Istanbul, Turkey, and Prague, tor, is called the relaxation time. It was Czechoslovakia, he moved to the United pointed out that these types of oscillaStates in 1924, where he spent a period tions are found in nature. Van der Pol in the Research Labs of Westinghouse, actually constructed a four-element in Pittsburgh, Pennsylvania. Somesimple electrical circuit (capacitor, neon how, his interests shifted tube, battery, and resistor) toward biology. He got and demonstrated several Nicholas Rashevsky his fundamental training features related to cardiac was the man who under Davenport Hooker activity. Students were (18871965), an anatogiven a laboratory exersystematized modern 2 2 mist, and Charles Claude cise which required them a 11 ~ . (5) mathematical Guthrie (18801963), a to check how the differresearch in the physiologist and vascular ent elements influenced The relaxation idea is based on reversbiological and medical surgeon, both active at the output signal. All this, ing the above-mentioned inequality, sciences. the medical school at the no doubt, represented one that is, University of Pittsburgh of the first fully bioengi2 2 [16]. In 1934, Rashevsky got a position neering accomplishments, as it gathered a 22 ~ . (6) at the University of Chicago, where he a rather solid theoretical background later created the outstanding and faralong with a hard model aimed at a speIn the latter condition, the system reaching Committee on Mathematical cific physiological system. Thus, it went tends initially to jump off from zero to a Biology. There are innumerable contribeyond biomathematics. positive value, decreasing gradually, and butions from renowned authors serving as members of the Committee. Several students obtained their doctorate degrees from the university, which disseminated the discipline on national and international levels. His culture was ample and deep, projected to music, literature, and philosophy. He spoke several languages fluently. Emily, his wife, also a mathematician, was his companion throughout his life. Rashevskytall, bearded, and patriarchalalways showed a strong and contagious dynamism, displaying good humor, lively comments, and unrelenting serious criticism. Often, he dearly and protectively referred to his mathematical biology family. He was the founder of the Bulletin of Mathematical Biology, which is still an active and prestigious publication [17], [18]. The 1961 Cullowhee Conference in North Carolina had two contributions outlining the historical development of mathematical biology since its inception: one was by Rashevsky [19] and FIGURE 4 From left: Nicolas Rashevsky, his wife Emily, and Mximo Valentinuzzi, Sr., another by Max Valentinuzzi, Sr. [20] taken during the Conference on Biomathematics in Cullowhee, North Carolina, on (Figure 4). Rashevskys contribution 1418 August 1961. The photo was taken by Max E. Valentinuzzi, who also participated deals with general and specific subjects, in that conference.

then suddenly jumping to a negative level. This cycle is continued indefinitely. The relaxation period is given by

Nicolas Rashevsky (18991972) and his Chicago School

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highlighting the concept that theoretical biology should be the counterpart of theoretical physics. Valentinuzzis contribution presents a definition of mathematical biology as a branch of natural philosophy that embeds biological thought into mathematical scheme. It contains a review similar to that by Rashevsky in some aspects, but which includes other less-known researchers such as two Argentinian scientists, Florentino Ameghino (18541911) and ngel Gallardo (18671934), and the Italian physicist Luigi Fantappi (19011956) [21]. In 1942, Fantappi presented to the Accademia dItalia a theory attempting to unify the physical and the biological world. In 1938, Rashevsky produced the first edition of a significant book on mathematical biology, which comprehensively collected well-thought knowledge and set the framework of the emerging discipline (Figure 5) [22]. One of the many subjects found there refers to excitable tissues, using the so-called two-factor theory, also called the activationinhibition theory. It is based on two differential equations, or df = KI - k (f - f ) (8) 0 dt dk = MI - m (k - k ), (9) 0 dt
FIGURE 5 The front page of the third edition of Rashevskys book, which was published by Dover in 1960.

where K , M, k, and m are constants. In other words, whenever a current flows through an excitable tissue (nerve or muscle), ions are transported, say of the activating type f and of the inhibiting kind k. It is assumed that the rate of change of the activating or excitatory type and also of the inhibiting kind is proportional to the current flow I. Besides, any excess of f or k over the threshold values f 0 or k 0, respectively, or any deficiency below those levels tends to decrease at a rate proportional to the excess or deficiency. Relationships with other similar theories are well covered in addition to a good number of predictions and explanations. Another excellent book, Some Medical Aspects of Mathematical Biology, must be mentioned. It is a simpler but very didactic book published in 1964, divided into six parts: retention of particulate material in respiratory passages, the cardiovascular

them or even to offer an exhaustive list. The disThe currently available cipline stands well on its computational power own feet, offering a solid is a tool to solve and ever-increasing founany mathematical dation to bioengineerproblem, irrespective ing, biology at large, and of the complexity, medicine. The currently available computational thus, slowly and power is a tool to solve steadily improving the any mathematical probpredictive capabilities. lem, irrespective of the complexity, thus, slowly and steadily improving the predictive capabilities. However, Discussion and Conclusions these solutions are still quite distant from Many books have been published on the extraordinary situations encountered mathematical biology since the 1960s. in the physical sciences. The scientist It is not the intention here to review
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system, pharmacological problems, the endocrine system, the central nervous system, and some abstract speculations and their potential value, as well as a final appendix offering mathematical derivations. It can still be used as an orientation text for an introductory course in mathematical biology [23].

behaves as some kind [3] M. E. Valentinuzzi, of conqueror, endlessly Objetivos de la bioingeniThe scientist behaves searching for newer and era, (in Spanish), in Introas some kind of better roads to get to the duccin a la Bioingeniera, conqueror, endlessly objective. As I. Newton Series Mundo Electrnico. Barsearching for newer Kugelman [24], foreword celona, Spain: Boixareu Ediand better roads to author of Rashevskys tores, 1988, ch. 1, pp. 311. get to the objective. book mentioned in [23], [4] [Online]. Available: stated in 1964, Mathehttp://es.wikipedia.org/wiki/ matics is gradually becomGiovanni_Alfonso_Borelli ing the language of medicine. Good [5] M. E. Valentinuzzi, K. Beneke, and G. E. prediction, indeed, because a model as Gonzlez, Ludwig: The bioengineer, old as Kotitzins is today being used with IEEE Pulse, vol. 3, no. 4, pp. 6878, 2012. success, and we find reports stating [25] [6] A. J. Lotka. (1925). Elements of Physical BiolKostitzins demogenetic model ogy. Baltimore: Williams & Wilkins. [Ondescribes local interactions between line]. Available: http://ia600307.us.archive. three competing pest genotypes org/35/items/elementsofphysic017171mbp/ with alleles conferring resistance or elementsofphysic017171mbp.pdf susceptibility to transgenic plants, [7] [Online]. Available: http://users.telenet. the spatial spread of insects being be/ronald.rousseau/html/lotka.html modeled by diffusion. This new [8] T. Modis, Genetic re-engineering of corapproach makes it possible to comporations, Technol. Forecast. Soc. Change, bine a spatial demographic model vol. 56, pp. 107118, 1997. of population dynamics with clas[9] V. Volterra, Leons sur la thorie mathsical genetic theory. matique de la lutte pour la vie (in French). The latter paper calls for a slight Paris: Gauthier-Villars, 1931 (Reissued in change in Kugelmans statement by add1990 by J. Gabay, Ed.). ing the language of medicine and [10] [Online]. Available: http://en.wikipedia. biology. Unfortunately, Kostitzins work org/wiki/Lotka%E2%80%93Volterra_ is poorly known today, as the authors of equation. [25] have complained. [11] V. A. Kostitzin, Biologie Mathmatique Max E. Valentinuzzi (maxvalentinuzzi@ ieee.org) and Alberto J. Kohen (ajkohen@ yahoo.com) are with the Instituto de Ingeniera Biomdica (IIBM), Universidad de Buenos Aires (UBA).
(preface by V. Volterra). Paris: Libraire Armand Colin, 1937. [12] G. Israel and A. Milln Gasca, La correspondencia entre Vladimir A. Kostitzin y Vito Volterra (19331962) y los inicios de la biomatemtica, (in Spanish), Llull, vol. 16, pp. 159224, 1993. [13] A . Mellender de Arajo, Vladimir A. Kostitzin, terico, ignorado pelos arquitetos da sntese evolutiva, (in Portuguese), Filosofia e Histria da Biologia (Brazil), vol. 2, pp. 522, 2007. [14] B. van der Pol, On relaxation oscillations, Jahrbuch der drahtlosen Telegraphie, vol. 28, p. 178, 1926.

[15] B. van der Pol and J. van der Mark, The heartbeat considered as a relaxation oscillation, and an electrical model of the heart, Archives des Nederdlands de Physiologie de lHomme et des Animaux, vol. 14, pp. 418443, 1929. [16] A . Carrell and C. C. Guthrie, The transplantation of veins and organs, Amer. Med., vol. 10, pp. 11011102, 1905. [17] Bull. Math. Biol., vol. 27, no. suppl. 1, pp 34, 1965; doi: 10.1007/BF02477255. [18] M. Valentinuzzi Sr. and M. E. Valentinuzzi, Nicols Rashevsky, La Semana Mdica, vol. 140, no. 25, pp. 737738, 1972. [19] N. Rashevsky, A birds eye view of the development of mathematical biology, in Proc. Cullowhee Conf. Training in Biomathematics, Cullowhee, NC, 1962, pp. 819. [20] M. Valentinuzzi Sr., Notes on the history of biomathematics, in Proc. Cullowhee Conf. Training in Biomathematics, Cullowhee, NC, 1962, pp. 2038. [21] [Online]. Available: http://www-history. mcs.st-and.ac.uk/Biographies/Fantappie. html [22] N. Rashevsky, Mathematical Biophysics: Physico-Mathematical Foundations of Biology, 3rd ed., vols. 12. New York: Dover, 1960. [23] N. Rashevsky, Some Medical Aspects of Mathematical Biology. Springfield, IL: Charles C. Thomas, 1964. [24] J. I. Wasserman. (2012). From Shtetl to Park Avenue: Isaac Newton Kugelmass, M.D. (18961979). [Online]. Available: ht t p://w w w.ja net wa sser m a n .com / from-shtetl-to-park-avenue-i-newtonkugelmass-md-18961979.html [25] Y. Tyutyunov, E. Zhadanovskaya, D. Bourguet and R. Arditi, Landscape refuges delay resistance of the European corn borer to Bt-maize: A demogenetic dynamic model, Theoretical Population Biology (Elsevier), vol. 74, no. 1, pp. 138146, 2008. 

References
[1] L. Carlo Pedretti. (1999). Le Macchine. Firenze, Italy: Giunti Gruppo Editoriale [Online]. Available: http://books.google.com. [2] M. Valentinuzzi Sr., Contribucin al estudio fsico de la contraccin uterina, (in Spanish), Ph.D. dissertation, Medical School, Univ. Buenos Aires, 1950.

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