Liesbeth De Mol

Maarten Bullynck

William Aspray

Martin Campbell-Kelly

Edgar Daylight

Thomas Haigh

David Nofre

Mark Priestley

MAKING THE HISTORY OF COMPUTING. THE HISTORY OF COMPUTING IN THE HISTORY OF TECHNOLOGY AND THE HISTORY OF MATHEMATICS

Keywords: Historiography of computing, History of mathematics, History of technology, History of disciplines

A history of writing the history of computing is presented in its relationship to the history of mathematics. As with many historiographies, the initial history of computing was very much an internalistic history. In the late 1970s, the field became more serious and started looking at the histories of mathematics and technology for (methodological) inspiration. Whereas the history of mathematics was initially quite influential, it is the history of technology (in its U.S. form) that has become the dominant framework for doing history of computing since the 1990s.

The history of computing is a relatively young discipline, that formed slowly since the 1970s at a time when the discipline of computing itself was hardly established yet. It need not surprise that in its beginnings, the history of computing looked towards other historiographies for inspiration, for formats and methods for conserving and writing their histories. In the early days, it was influenced most by the history of technology and the history of mathematics.

While the history of computing is still closely allied with U.S. history of technology today (see section 4), its relationship with the history of mathematics or history of science in general has evolved over time and become distant, not directly contributing to its disciplinarisation. Instead sociology, business history, gender studies and other disciplines have been integrated into the philosophy and methodology of computing historiography following methodological developments of the Society for the History of Technology (SHOT for short). 1 The aim of this paper is to offer a historical analysis of the history of the history of computing from the perspective of its relation with the history of mathematics,. We explain the distancing between the history of mathematics and computing by sketching their complex and at times strained relationship. 2 1. HISTORY OF COMPUTING GETS ON ITS FEET It is a typical phenomenon, in the process of a discipline becoming established, that its actors start to reflect on the past and take the initiative to write their own history. This is also true of the history of computing. Indeed, with the computer coming of age and in particular with the establishment of computer science and/or computer engineering departements in the United States. and the industrialized world during the 1970s, one sees also the first initiatives towards documenting, preserving and writing a history of computing. 3 Part of this was supported by organisations and institutions such as the Smithsonian that started an oral history project on computing in the late 1960s 4 , or the professional association AFIPS (American Federation for Information Processing Societies) that encouraged historical reflection including so-called Pioneer Days in their bi-yearly conferences. 5 Computer companies also played an important part in financing some of the events. Another part was done by actors who started writing up their stories or even tried their hand at a more general, larger history.

An important event, especially for the larger public, was the big IBM exhibition A Computer Perspective, curated by the Eames's. It ran from 1971 to 1975 and attracted hundreds of thousands of visitors. It was documented by a lusciously illustrated catalogue offering a tour of the computer's history and prehistory. 6 Together with two other, contemporary works, the Eames's catalogue provided the first book-length introduction to computing history. The other books were, first, H. H. Goldstine's personal account of the history of the computer, The Computer from Pascal to von Neumann (1972), featuring John von Neumann as a central figure, and second, Brian Randell's collection of primary sources, The Origin of Digital Computers (1973). 7 Both books went through subsequent editions and became classic references to the field. 8 1 It should be remarked that this evolution does not hold true for the history of computing outside the U.S., e.g. in many European countries the history of computing is written by historians of science or of mathematics. In much the same way, the separate ways of history of science and of technology described infra is a U.S. phenomenon that is not replicated in other countries, though its impact may be felt.

It should be pointed out that especially Goldstine's book is today considered to be a source that needs to be treated with great care, given the personal involvement of Goldstine with the history he is describing.

In the second half of the 1970s, possibly profiting from a wave of public interest in computing, as witnessed by the many popular publications on the microcomputer (now: personal computer), a consolidation and institutionalisation started. Firms and institutions started to back more enduring forms of doing history. A landmark event was the International Research Conference on the History of Computing at Los Alamos (June 10-15, 1976) which resulted in the most important early edited volume on the history of computing.9 Amongst papers by various pioneers describing the machines and projects of the 1940s and 1950s, the book also included Donald Knuth and L.T. Pardo's long paper on the "Early Development of Programming Languages". 10 This was one of the first more scholarly papers on the history of programming, together with Martin Campbell-Kelly's work on programming the early British computers (1979-1980). 11 By the end of the 1970s, the Association for Computing Machinery (ACM) occasionnally began to organise focused sessions on the history of computing such as on the history of programming languages (1977) 12 or on the history of workstations (1986). Also, the American Federation for Information Processing Societies (AFIPS) continued its involvement. In 1979 it became a sponsor of the International Charles Babbage Society, founded 1978 by Erwin Tomash and associates. It was renamed the Charles Babbage Institute (CBI). The institute started an important oral history project, interviewing many historical actors, and built a big collection of books and documents. It remains an important center of documentation and scholarship in the history of computing until today. AFIPS also shouldered the creation of the specialized journal, IEEE Annals of the History of Computing, under the editorship of Bernie Galler, a computer pioneer who had done, amongst others, major work in timesharing. At first, the Annals published mostly actors' papers and recollections, but as history of computing become more professional, it has evolved into a journal that mainly publishes scholarly work. Today, Annals still are the main venue to publish in the history of computing.

Finally, Ken Olson and Gordon and Gwenn Bell, of the computer company Digital Equipment Company (DEC), founded the Digital Computer Museum in 1980 and started publishing some works on computer history through their Digital Press. 13 The main driving forces of these initial years were institutions, organisations, companies and some prominent personalities from the field itself. They helped to create the first big collections, archives and publications for the history of computing. But it also implied that most of this early work was a rather internalistic, if not often whiggish, kind of history. They mostly focussed on the machines, or on important projects and persons, but generally did not go beyond the immediate historical context. Discussion of the broader sociohistorical background or the longer technological and scientific evolution was mostly absent.

THE HISTORY OF COMPUTING WITHIN THE HISTORY OF MATHEMATICS

As is clear from the previous section, the history of computing was first of all an initiative from within the computing field itself. Few professionally trained historians were involved. This initiative from several computing pioneers and institutions should certainly be seen against the background of the field's struggle for disciplinary independence. Indeed, it is only in 1962 that the first study program in "computer science" was launched at Purdue University. By the 1970s the discipline had become more established with a large number of established journals and conferences, graduate programs and PhDs in computer science but it was still struggling. Amongst others, in funding agencies, computing was still frequently grouped with mathematics . 14 It is against this background that one can detect a number of particular viewpoints, agendas and philosophies on what the discipline actually is (about). One dominant viewpoint in the 1960s and 1970s was the idea that computing is in fact mathematics. 15 It is no surprise that this viewpoint also colours some of the most prominent historical works from the 1970s, trying to embed the history of computing into the history of mathematics.

H. H. Goldstine was trained as a mathematician before he became an officier in the U. S. military and got involved with one of the first computers, ENIAC. In his book on the history of the computer, he emphasized the mathematical pedigree of the computer, and highlighted his colleague John von Neumann's rôle in the creation of the modern digital computer. In a completely different way, the Stanford computer scientist Donald E. Knuth's early writings on computing history also focused on the mathematical aspect of computing, but this time to advance his agenda of founding "computer science" as the science of algorithms. Both authors tried their hands at the historiography of computing using an older and respected tradition in the history of mathematics, viz. the history of mathematics as practised in Göttingen just before the 2 nd World War. This vision on the history of mathematics was voiced most influentially by Otto Neugebauer, specialist of Babylonian mathematics. He stood for an internalist, mathematical history of ideas embedded in an acribic, even philological model of editing and commenting (ancient) mathematical sources . 16 When Neugebauer, as many other German mathematicians, emigrated in the 1930s to the United States, he continued to teach his historiographic vision there too.

In his book on the computer (and later in his History of numerical analysis (1977)) Goldstine placed the history of the computer in the lineage of the history of mathematics. In both books, he explicitly thanked Otto Neugebauer for his advice. In the part on computing before World War II, it is mostly mathematicians (Pascal, Boole, etc.) and mathematical problems (Fourier analysis, ballistics etc.) that make up the story, and with the focus on John von Neumann this co-evolution of mathematics and the computer reaches its apogee.

Donald. E Knuth's paper "Ancient Babylonian algorithms" , written for the 1972 anniversary issue of the Communications of the ACM, used Babylonian mathematics to construct an intellectual prehistory for programmers.17 To do this, he relied on Neugebauer's edition and interpretation of Babylonian mathematical texts. Tying together a long-term history of doing mathematics from the Babylonians to the digital computer, insisting on how difficult it is to properly formalize a computation, served Knuth's goal to legitimize his science of algorithms. Knuth also included copious historical notes and references in his 3volume The Art of Computer Programming (1968, 1969, and 1973) and has published a number of historical articles on programming concepts (compilers, programming langages etc.) that remain standard references for people in computer science.

The emulation of a technically oriented, internalistic approach to history as practiced in the Göttingen environment, is by no means a coincidence. Because of the prestige Göttingen carried for the U.S.'s intellectual elite, its invocation by a young historiography of computing helped to legitimize itself, though by then, the history of mathematics was already on a new path, away from an internalistic and purely technical historiography (see Sec. 3).

This respectful reverence to a technically oriented, internalistic approach to history that meticulously edits and comments its sources, as practiced in the Göttingen environment, is by no means a coincidence, but rather served as a prestiguous example for the young historiography of computing.

The historical foundation of the field of computing into the history of mathematics is pursued by the chairs of the important International Research Conference on the History of Computing at Los Alamos (June 10-15, 1976). In the foreword to the proceedings of that conference, the so-called "computer revolution" is historically rooted into early 20 th century developments in mathematical logic, with reference to Turing, Church, Peano and Russel and Whitehead, and it is claimed that:

"The improbable symbolism of Peano, Russel, and Whitehead, the analysis of proofs by flowcharts spearheaded by Gentzen, the definition of computability by Church and Turing, all inventions motivated by the purest of mathematics, mark the beginning of the computer revolution. Once more, we find a confirmation of the sentence Leonardo jotted despondently on one of those rambling sheets where he confided his innermost thoughts : « Theory is the captain, and application the soldier." 18 At that same conference, two researchers were asked to give a more reflective talk on the historiography of computing. The first was by Hamming, a mathematician turned computing pioneer who received the Turing award in 1968, with a talk titled "We would know what they thought when they did it". 19 In the talk he developed the idea that the history of computing should not be a mere recollection of "firsts, names, places, dates, numbers, speeds, etc." but rather study the "creation, development and spread of ideas" and argued for the significance of a history which is not just written by (and for) historians who do not know much of computer science nor by computer scientists who do not know much of historical methods. Moreover, he invited historians to go beyond the documents to "informed speculation" about what the computer pioneers thought and did.

The second talk was by Kenneth O. May, a renowned historian of mathematics, founding chair of the International Commission for the History of Mathematics 20 and cofounder of the journal Historia Mathematica. May belonged to a new generation of historians of science who was "squared of Sarton" . 21 Sarton was the founder of the well-known Isis journal for the history of science and promoted a view on the history of science that fitted his so-called New Humanism and which required that historical work should be done collaboratively by historians and scientists. 22 The objective then is to unveil the hidden history of science which is, ultimately, rooted in mathematics which thus becomes a "secret within a secret". 23 May derived exactly this philosophy from Sarton in his plea for heterogeneity in the history of mathematics and the need for generalists "who can be mathematicians, historians of science and historians at the same time". 24 In his talk at the Los Alamos conference titled "Historiography : A perspective for computer scientists", May insisted on integrating the computer in the history of mathematics, even introducing a "new" tradition in mathematics. Next to "mathematical science", May has also "mathematical technology" which includes numeration, calculating devices (on the hardware side) and algorithmic traditions (on the software side) :

"If we look at the history of mathematics this way, it seems to me that one of the effects of the coming of the electronic computer is that for the first time mathematical technology has become a consciously recognized discipline […] instead of just being for practitioners who didn't seem to be in the mainstream, computing now becomes the Queen of Technology." 25 May's remarks go into two directions, attracting the history of computer science in the realm of the history of mathematics (which did not work out), but also enlarging the focus of historians of mathematics to mathematical technology and computing (which did happen). Indeed, the advent of the digital computer had an impact on the historiography of mathematics where a number of researchers began to actively study computing and algorithms in their own right. 26

CRISIS IN THE HISTORY OF MATHEMATICS AND ITS IMPLICATIONS FOR THE HISTORY OF COMPUTING: HOW M.S. MAHONEY TURNED TO THE HISTORY OF COMPUTING

The mid 1970s was an important transition period for the historiography of mathematics. History of mathematics had slowly emancipated itself from being a marginal occupation of mathematicians to become an academic discipline for itself. It is also from that context of a more professional history of mathematics that May makes his plea for a heterogenuous history of mathematics. It is the growth in number and quality of historians of science which is :

"creating an employment crisis in a context of shrinking budgets, in spite of the continuing relative strength of the discipline. Many young scholars are getting along with makeshift arrangements, and some may leave the field […] If we recognize the need for heterogeneity in training and approach […] and if we agressively take advantage of employment opportunities in all areas […] the present employment crisis could be 22 See for instance SARTON, 1924. 23 Here is the full citation : "If the history of science is a secret history, then the history of mathematics is doubly secret, a secret within a secret, for the growth of mathematics is unknown not only to the general public, but even to scientific workers." (SARTON, 1936, p. 4) 24 MAY, 1974, p. 128. transformed into an opportunity for healthy development of a fourth and successive generations." 27 The new generation of historians turned their attention to the more practical and mundane aspects of mathematics as well as on reading ancient mathematical cultures not with the lenses of modern mathematics but as a discourse in its own right. The raised selfawareness of the discipline, however, also led to some fierce debates between historians and mathematicians. It basically came down to the question of whether the history of mathematics should be done by historians and/or by mathematicians.

This crisis in the historiography of mathematics was fought most virulently over the interpretation of Babylonian and Greek mathematics, notably in the so-called Unguru debate. 28 In 1975 Sabbetai Unguru published a paper in the Archive for the history of exact sciences where he argued that Greek (or Babylonian) mathematics is not algebra, and should thus not be put in modern mathematical terms, but has to be considered as a discourse in its own. In the process, Unguru referred to a 1971-paper by Princeton-based Michael S. Mahoney that suggested that you can only speak about algebra from the 17 th century onwards. 29 Unguru's paper resulted into a controversy during which a number of famous mathematicians would send angry letters to the editors of the Archive. These mathematicians included the Bourbaki mathematician André Weil30 and B.L. van der Waerden, both of which wrote some important work on the history of mathematics. This discussion, symptomatic of the growing divide between mathematicians and historians vis à vis history of mathematics, eventually led to a greater intellectual independence of the historians from mathematicians and to the slow recognition of the history of mathematics as a specialisation in its own right, though part of the tensions between mathematicians and historians would remain unresolved until today.

One of the historians of mathematics that became tied up into these disputes eventually became the inhouse historian for the first generation of (mostly U. S .) historians of computing. Michael S. Mahoney had published a book on the career of Pierre de Fermat in 1973 probably as part of getting tenure as a professor at Princeton. The book was met with one of the most scathing reviews ever written. The review's author was Weil who was also at Princeton around the time. Weil found Mahoney's book lacking in knowledge of mathematics, of French, of Latin but also in history and context, and detailed over 12 pages many misinterpretations and errors he found in the book. Weil wrote that "a student of 17 th century mathematics will find little in that volume that could be helpful to him, and much that can only confuse and mislead him."31 Though Weil's criticisms were, in part, correct 32 , their general tenet has to be seen in the light of the contemporary debates between historians and mathematicians.

According to William Aspray, Weil's review had a lasting impact on Mahoney's research direction and output and eventually helped him to get involved with the history of computing "Between the mathematics that makes the device theoretically possible and the electronics that makes it practically feasible lies the programming that makes it intellectually, economically, and socially useful. Unlike the extremes, the middle remains a craft, technical rather than technological, mathematical only in appearance. It poses the question of the relation of science and technology in a very special form." 39 To Mahoney, to get away from a machine and person centered history written by those who lived it, a turn towards the history of software and of computing systems would connect directly to many of the then current issues in the history of technology, such as the interaction between industry, business, society and technology. According to Mahoney, the computer has a tripartite nature : computer science, electrical engineering, and programming/software engineering. While the first two aspects might fall under the more classical histories of science and technology respectively, the proper home of the history of computing as a new field would be within the larger history of technology as it was developing in the U.S. in the 1980s:

"What is truly revolutionary about the computer will become clear only when computing acquires a proper history. [...] Pursued within the larger enterprise of the history of technology, the history of computing will acquire the context of place and time that gives history meaning." 40 Through his involvement in the ACM, in the Annals and his scholarly articles Mahoney helped shape the field and set an agenda for the younger generation of researchers, focusing more on the social aspects of computing, taking on software and moving to business history. He was also important in keeping contact with leading computer scientists and getting them to write historical contributions. He was an important motor in this change of research direction, away from the history of science (and of mathematics in particular), towards more sociological, institutional and economical histories of computing. Paradoxically though, he devoted most of his output in the history of computing to one of the most mathematical aspects of computing, viz. the development of theoretical computer science and the research into mathematical theories and structures of computation.41

HISTORY OF COMPUTING IN THE HISTORY OF TECHNOLOGY

Ironically then, it was thus a historian of mathematics who, together with many others, led the way to the steady dissociation of the history of computing from the history of mathematics and science proper and helped paved the way to its integration into the U. S. history of technology. While Mahoney himself certainly remained engaged as much with the history of science as with the history of technology, the effect of inscribing the history of computing into the history of technology, has affected the field fundamentally.Also Martin Campbell-Kelly, another pioneer historian of computing, advocated such a turn away from history of science: "In fact, I would argue […] that the history of computing is a special case, and not really like the history of mathematics or physics at all. Computing is the dominant technology of the second half of the twentieth century, which pervades all aspects of economic life. In this, it is more akin to business history." (Campbell-Kelly in ROSIN, 1993, p. 804) 42 This turn away from the history of science reflects, with a delay, the evolution of the field itself. While scientific computing was a very important catalysator in the early history of computing (the 1940s and 1950s), other forms of computing became increasingly important later. From the 1950s onwards business computing and data processing became more and more important. Later still, (tele)communications, realtime systems and networking also became important areas for computing. As a consequence, the field itself had to diversify its methodologies and, in the meantime, try to keep up with the new demands from the application-side. Whereas, to this day, several computer scientists remain convinced of the need for a mathematical foundation of the computing field, including the engineering of software, it is clear that the reality requires a more diversified approach which does not reduce to one or the other field. This broadening and deepening of the field of computing slowly had an impact on the history of computing. Its original contact with history of science and of mathematics watered down, while its ties to history of technology, history of information processing and business history43 strengthened. In recent years especially, it has been suggested to inscribe the history of computing in a much broader history of information,44 which is perhaps again a reflection of the field's own self-perception as being the science of information processing. 45 The trend away from the history of science towards the history of technology was reinforced by the constitution in 1987 of the Special Interest Group Computers, Information, Society, SIGCIS for short, that has currently evolved into the main community for historians of computing. 46 SIGCIS was founded during the annual Society for the History of Technology (SHOT) convention, and remains, until today, embedded in that society with, amongst others, the annual SIGCIS workshop held during the annual SHOT conference.

SHOT was founded in the United States in 1958. The the main motivation for the creation of SHOT was the impression that historians of science did not take history of technology seriously enough, an impression that was strengthened by the refusal of the reputed Isis, journal of the History of Science Society to devote more space to papers on the history of techology. SHOT consequently started its own journal Technology and Culture. This tension, if not divide, between the history of science and the history of technology remains very much alive. SHOT still suffers from a "self-perception of marginality", and is "a tightly knit organization, and, among its members, the distinction between outsiders and insiders remains highly salient". 47 One of the most debated issues, it need not wonder, was and is the difficult, strained relationship between science and technology. The quite recent debate around a paper by Paul Forman (2007), who argued that the traditional, modernist primacy of science over technology has been reversed since the (postmodern) 1980s, 42 As many others around that time, Campbell-Kelly singles out James Beniger's book Control Revolution (1986) as showing "the vast canvas on which the history of computing will ultimately be painted".

illustrates amply how central and how controversial the issue remains. 48 Embedding the history of computing in the history of technology thus also means that the SIGCIS community inherits from SHOT's history and many a historian of computing will go look for methods and viewpoints in the community of historians of technology. This has led U.S. historians of computing to adopt SHOT's emphasis on "storytelling" 49 sometimes to the detriment and ignorance of technical details, and to follow current opening of SHOT to narratives of class, race and gender. It has equally and often led to ignoring the history of science, especially when technical. 50 Of course, the history of computing has not remained confined to SHOT and it has learnt much from other histories such as business history or communications history. From the 1990s onwards, history of computing has become less a predominantly anglosaxon field, to become a more diverse and international discipline, as witnessed by the publications in the Annals and by a steady volume of book publications on a variety of topics. A first generation that had a some training in history of computing proper started to publish and the discipline has become increasingly self aware within and outside of SHOT. 51 Important landmarks were the first historian's textbooks on the computer's history: Martin Campbell-Kelly and William Aspray's Computer: A history of the information machine (1996), and Paul Ceruzzi's A history of modern computing (1998). 52 Both books went through updated editions later on and still are standard reference works often used for teaching a class on the history of the computer. More recently, one sees that more attention has been going to the application side of computing. 53 It is within that development that one can notice an increased interest for the use of computing technology and its effects on science. 54 A number of national and international committees and musea were founded outside of the United States which also contributed to this process of internationalisation and diversification. 55 This process of both methodological diversification 48 FORMAN, 2007. 49 For instance, on the website of SHOT in the section of "Doing history of Technology" one finds a quote from Usselman, a well-known historian of technology, saying that : "Historians of technology […] are storytellers. More than any other practitioners among the humanities and social sciences, historians practice the art of narrative, and in doing so we face many of the same challenges as the fiction writer" (see : https://www.historyoftechnology.org/doing-history-oftechnology/, accessed May 22, 2018). 50 So, for instance, in his opinion piece "The tears of Donald Knuth" (HAIGH, 2015), Thomas Haigh sketches a development of the history of computing which should be non-technical (because written by and for historians). He concludes that a history of computing which engages more with the science of computing and which is written by professional historians also with an eye on a computer science public is "almost impossible to accomplish" (with the exception of Martin Campbell-Kelly). See Sec. 5 for more details. 51 Indeed, it is no accident that the SIGCIS workshop has evolved from a rather small event within SHOT to one of the events with the highest number of contributions. This growing self-awareness is witnessed by the fact that in 2016 SIGCIS held its first meeting which was not co-located with SHOT. In 2007 Martin Campbell-Kelly published an analysis of the evolution in the historiography of computing, "The history of the history of software". 57 Central to the paper is a table in which he lists publications on the history of software starting in 1967 and ending in 2004. Each publication is assigned one of four classification types: T(echnology), S(upplyside industry), I(institutional,social, political) and A(pplications) and it is observed that whereas initially all papers are assigned the label T, later on there are no more T publications to be found. This development is applauded by Campbell-Kelly, identifying the more technical publications as being of the "low-hanging fruit variety 58 " and concludes that: "[T]he subject matter has broadened. In the 1960s and 1970s, people wrote about technology --code and software engineering practices. Starting in the 1980s, people began to write about software as an economic activity. [...] In the 1990s, especially, we began to see books that set software in a much broader institutional, social, or political setting. [...] It is only in the past 10 years that scholars also began to look at applications. [...] Thus, over time, software history has evolved from narow technical studies, through supply-side and economic studies, to broad studies of applications." 59 Initially the paper did not result in much debate. It was only when Donald Knuth, famous computer scientist and strong advocate of the history of computing, publicly expressed his feelings about the paper on several occasions, that the community of historians of computing started a serious discussion. During his Kailath lecture at Stanford University titled "Let's not dumb down the history of computing" (2014), Knuth explained that: "when I was reading [the] Haigh argued that there are currently two « disciplinary base camps » from which writing the history of computer science might be undertaken: computer science itself and history. Both approaches could be complementary, but to Haigh, combining both is « almost impossible to accomplish .» computer science itself and the history of computing. To Haigh, Knuth cannot expect historians of computing to write more technical histories of computer science since their social and academic context is one that does not appreciate this kind of writing. As a consequence, the job opportunities for the more technically oriented historian are quasi nihil and it is up to the computer science departments themselves to make possible the kind of history that Knuth wants. Thus, Haigh concludes : "Work in the history of computing has been seen by most in the humanities as dull and provincial, excessively technical and devoid of big historical ideas [...] I share Knuth's regret that the technical history of computer science is greatly understudied. The main cause is that computer scientists have lost interest in preserving the intellectual heritage of their own discipline [...] More work by professionally trained historians on social, institutional, and cultural aspects of computing does not have to mean less work by computer scientists themselves. They cannot count on history departments to do this for them, and I hope Knuth's lament motivates a few to follow his lead in this area." 62 computing, and that historiography has set its thematic and methodological preferences accordingly.

DISCUSSION : A CHALLENGE FOR « THE » HISTORY OF COMPUTING

It is perhaps no accident that Knuth quoted exactly the history of mathematics as a counter example to the evolution in history of computing he deplored. Indeed, the discussions of the 1970s (see section 3) have also estranged a part of the mathematical community from history of mathematics, but both the fact that a technical knowledge is needed to write the history of mathematics and that an important number of mathematical institutes have supported historians to be part of their institutes have prevented that a communication gap would have established between groups. It is, however, an enduring struggle and effort to keep this line of communication open, and to be both tolerant and exacting enough to keep it going.

The history of computing today seems to be in a situation not completely unlike the one mathematics historiography was in the 1970s and 1980s. Some of the Practitioners of the field have become estranged from the history now being written, and the historians have adopted new methodologies, bringing in institutional, economic and social motives, that have put the technical details of the machinery (both hard-and software) and the scientific underpinnings and usages in the background. The computer then often appears as a blackbox that, supposedly, need not be understood to tell the story. 63 On top of that, In the meantime, computing has pervaded much if not all technologies and communications of today and also has started to affect scientific practice. Also here, it mostly functions as a black box which, so we are told by the businesses selling us the technology, need not be understood or reflected upon in order to be used. It has become part of everyday experience though its actual contribution almost always remains hidden and notunderstood. The computer as an actual, specific machine interacting with both machines and human beings, or the computing practice as a usage have become eroded in meaning and in historical situatedness. Moreover, the diversification of the field has resulted not just in a broad range of highly-specialized methods and approaches, but also in a fragmentation of communities who are no longer able or willing to talk to each other. This lack of communications across the field is intensified by commercial and political interests which are, today, more impacting than the scientific on the development of the field. By consequence, we are in a situation whereby a (critical) reflection on the whole field is either considered impossible or, worse even, discouraged. What is required then is not a modernist framework whereby the diversity of approaches is replaced by one ultimate approach64 nor a postmodern one where the diversity per se is being celebrated, but an approach which opens up the communication lines and allows to reconnect rather than to unify or reduce.

It is perhaps here that lies a challenge for historians of computing who profess their work not just for the sake of their fellow historians. Indeed, if the history of computing develops towards an all-encompassing but fragmented field which hides from itself in its specializations and applications, then the real challenge for the historians might be to try and take distance from current developments. Instead, retracing histories, making them visible and transparent, is the kind of answer history of computing can contribute to debates today, not just to render understandable the current situation, but also to change it by making it

  52 CAMPBELL-KELLY & ASPRAY, 1996; CERUZZI, 1998. 53 CAMPBELL-KELLY, 2007. 54 See for instance the work by Paul N. Edwards on climate science (EDWARDS, 2010) or the work by Joseph November on the computerization of biomedical research (NOVEMBER, 2012). 55 Well-known examples are the Heinz Nixdorf museum in Paderborn or the Computer Conservation Society in the UK. In Switserland the Association Histoire et Informatique was founded in 1989. It focuses mostly but not exclusively on the use of the computer in historical research. In France there was a series of conferences on the history of computer science from the late 1980s until the early 2000s in which the French historian Pierre Mounier-Kuhn played a signficant rôle. In the (following SHOT in part) and internationalisation can also be observed when going through the list of recent winners of the Computer Museum Prize or the Mahoney Prize that honour important work in the history of computing. 56 5. DONALD KNUTH'S TEARS -A CRISIS IN THE HISTORY OF COMPUTING?

  page [explaining the table] I broke down and started to cry and I finished reading it only with great difficulty because tears had made my glasses wet". Addressing Campbell-Kelly in his talk Knuth said: 60 "Do you not see any blind spots in your outlook when your table 1 shows 68 % class T articles in the first 20 years and 0 % class T in the last 5 years? And then you say the table Netherlands Gerard Alberts brought together an important number of historians (European and non-European) for a research project on ALGOL (cfr « Software in Europe »). More recently still, the International Commission for the History of Science and Technology (ICHST) and the Commission for Logic, Methodology and Philosophy of Science (CLMPS), both falling under ICSU (International Council for Science), approved the proposal to create an interdivision Commission for the History and Philosophy of Computing (www.hapoc.org). 56 See https://www.sigcis.org/chmprize for the Computer History Museum Prize (since 2009) and https://www.sigcis.org/mahoneyprize for the Mahoney Prize (since 2015). Also the recent literature overview in HAIGH, 2011a surveys the diversity of the field. 57 CAMPBELL-KELLY, 2007. 58 Ibid., p. 44. 59 Ibid., p. 43. 60 The video of the talk is available here : http://kailathlecture.stanford.edu/2014KailathLecture.html Last accessed May 22, 2018. shows how the subject matter has broadened. It has not broadened it has totally shifted. All we get nowadays is dumbed down [...] Thank Goodness historians of mathematics have not [....] entirely abandonened writing articles that contain formulas or explain scientific ideas rather than just sticking to things like the strategies a mathematician has used to get into academy or something.[...] I'm sure that business histories are as difficult to write as technical histories and they are no doubt also as valuable to business man as technical histories are valuable to technicians. But you seem to be celebrating the fact that nobody writes technical CS history at all anymore. When you speak of obvious holes you are thinking of obvious holes in business history and you mention the video game industry for example [...] The lack of anything even close to describing these techniques [invented in the video game industry] and how they were discovered and under what constraints they were discovered seems to be a much more obvious hole but you show no indication even to admit its existence." 61 Knuth's talk was picked up by Thomas Haigh who initiated a vivid internal discussion on the SIGCIS mailing list. Haigh eventually published his take on the discussion in a Viewpoint written for the reputed computer science journal Communications of the ACM . Knuth's talk was picked up by the SIGCIS mailing list and resulted in a vivid internal discussion. Thomas Haigh eventually summarized and analyzed the discussion in a Viewpoint written for the reputed computer science journal Communications of the ACM.

[START_REF] Metropolis (nicholas | Preface" in A History of Computing in the Twentieth Century, Metropolis[END_REF]

KNUTH & PARDO, 1976.

[START_REF] Martin | Programming the EDSAC: Early Programming Activity at the University of Cambridg[END_REF]

WEXELBLATT, 1981.

The influence of DEC on the history of computing, not only material but also conceptual, would be an interesting story in itself, but falls outside the bounds of this article.

[START_REF] Tedre (matti | The Science of Computing: Shaping a Discipline[END_REF]

Matti Tedre gives an in-depth analysis of the disciplinary formation of computing and concludes that even today there is no consensus about the field's identity. Based on Tedre's work, one can identify four main positions, viz. computing as engineering, computing as mathematics, computing as a science and computing as an entirely new kind of interdisciplinary discipline.

[START_REF] Rowe (david | Otto Neugebauer's vision for rewriting the history of ancient mathematics[END_REF]

KNUTH, 1972.

METROPOLIS, HOWLETT & ROTA,

1980 , p. xvi. 19 HAMMING, 1980, quotes from p.9 and 6.20 Initially the commission was a subcommittee of the DHS (which later became DHST -Division for the History of Science and Technology). In 1985 it became an inter-unary commission of the ICSU unions International Mathematical Union and the International Union of the History and Philosophy of Science.

MAY, 1980, p. 17.

KNUTH, 1972 was quite influential here ; a seminal article was CHEMLA, 1987. See BULLYNCK, 2016 for a more complete overview and assessment.

MAY, 1974, p. 128.

For more on the context of the debate around Unguru, see SCHNEIDER, 2016.

[START_REF] Mahoney (michael | Die Anfänge der algebraischen Denkweise im 17. Jahrhundert[END_REF]

Weil,would publish an important book on number theory using history, Number theory: An approach through history from Hammurapi to Legendre, doing the exact opposite, reading and interpreting history with the newest developments in mathematics at the horizon.

[START_REF] Weil (andré | Review: M. S. Mahoney, The mathematical career of Pierre de Fermat[END_REF]WEIL, , p. 1149. .

Compare with Itard's review[START_REF] Itard (jean | A propos d'un livre sur Pierre Fermat[END_REF], who is equally critical of the book, but less polemical in his remarks.

MAHONEY, 1988, p.117.

MAHONEY, 1988, p.123.

SeeMAHONEY, 2011, part 3.

For business history, especially the influence of Alfred D. Chandler Jr. was important.

[START_REF] William | The History of Computing Within the History of Information Processing[END_REF] was one of the first to point out it might be useful to treat the history of computing, communications and broadcasting in the same framework. See HAIGH, 2011a and ASPRAY, 2015 for more recent viewpoints on this issue.

See e.g. DENNING 2009.

An overview of its history may be found at https://www.sigcis.org/about_history. Remark that SIGCIS has both a Mahoney fund and a Mahoney prize, which is indicative of Mahoney's standing within that community.

Of course, there are some exceptions. See for instance PRIESTLEY, 2011, DAYLIGHT, 2014 ; DE MOL, CARLÉ AND BULLYNCK, 2015.

See e.g. BOURBAKI ,1950 for a classic case of modernist mathematics. historically responsible.

to 2008 he was a fellow of the Alexander-von-Humboldt-Stiftung with a project on J. H.

some ten years later. 33 After Weil's rip-up of his book, Mahoney shied away from writing on the history of mathematics proper, and concentrated mainly on his teaching. Through his teaching at Princeton, and its vicinity to some of the important sites of computing such as Bell Labs, Mahoney got gradually more involved in the history of computing. This involvement spread to his research in the late 1980s. In 1987, Mahoney was asked to become editor of the ACM History Series and in 1988 he published the article "The History of Computing in the History of Technology", which became one of the most quoted papers ever to appear in the IEEE Annals for the History of Computing. 34 His work in the history of computing ranges from developments in theoretical computer science to social aspects of developments in software engineering but he his mostly known in the community for his more methodological viewpoints on how the history of computing should be conducted and what its topics should be. Although Mahoney started to publish about computing after a first generation of professional historians had already started their work in the early 1980s, [START_REF] Such | 36 A more measured assessment of Mahoneys work can be found in Martin Campbelly-Kelly's review (CAMPBELL-KELLY, 2013) who points out that Mahoney's prestige as a Princeton professor played[END_REF] the impact of his work on the community of historians of computing should not be underestimated. Even today, he is still regarded by many as the most important and influential historian of computing. 36 Thomas Haigh, who is one of the most active and appreciated historians of computing of today, describes the impact of his methodological work as follows: "Mahoney's most influential contribution to the development of the history of computing as a thriving and somewhat respectable field of scholarly labor came from his series of historiographic papers published from 1988 to 2008. […] These papers constitute the most sustained and self-conscious examination so far attempted of the fundamental question hanging over our growing body of work: what is the history of computing a history of?" 37 His methodological work was considered so important that one of Mahoney's short methodological papers titled "What makes history?" was "used as a primary reference for prospective authors to the Annals for several years". 38 That same paper was also added as an Appendix to the proceedings of the second conference on the History of Programming Languages which was basically modeled after the Los Alamos conference from 1976 and for which Mahoney was the so-called "conference historian". That paper goes back to Hamming's paper, discussed in Section.2, and offers some "advices" to the computer scientist who wants to write and reflect on his/her own history. Amongst others he warned exactly against what was considered to be the main issue within the previously mentioned Unguru debate and what is known as whiggism: to reread history through our contemporary perspective.

But it is worthwhile to go back to Mahoney's first written contribution to the field. Its basic methodological viewpoint is summarized in the paper's title "The history of computing in the history of technology". He situates computing at the nexus of science and technology, taking up contemporary discussions on the history of science and technology in the United


Jean-Patrick Francoia

Laurent Vial

Everything you always wanted to know about poly-L-lysine dendrigrafts (but were afraid to ask)

Keywords: Dendritic polymers, Poly-L-lysines, Non-viral vectors, Antibacterial agents, Material and Tissue engineering, Biosensing

Less than a decade ago, dendrigrafts of poly-L-lysine (DGLs) joined the family of polycationic dendritic macromolecules. Resulting from the iterative polycondensation of a N-carboxyanhydride in water, four generations of the dendrigraft can be obtained on a multi-gram scale and without chromatographic purification. DGLs share features with both dendrimers and hyperbranched polymers, but turned out to have unique biophysical and bioactive properties. The macromolecules -in their native form or functionalized -have been extensively characterized by various analytical and computational methods, and already found numerous applications in the biomedical field such as drug and gene delivery, biomaterials, tissue engineering, bioimaging, and biosensing. Despite a growing interest for DGLs, there is still plenty of room for further exciting developments that could result from a better exposure of these macromolecules, which is the ambition of this short review.

Introduction

Dendritic polymers are the fourth major class of synthetic polymer architectures (after linear, crosslinked and branched polymers). Among them, dendrimers are macromolecular objects obtained after a generational synthesis (Figure 1). [1] This route engages successive cycles of protection/deprotection or activation steps on monomeric building blocks, resulting into the formation of theoretically monodisperse structures. At the opposite of dendrimers, hyperbranched polymers are polydisperse. They are obtained by the self-condensation of unprotected building blocks, in a so-called one-pot synthesis. Starting from a building block with three branching points, one can theoretically obtain 2 n-1 (excluding any operation of symmetry) structures for a polymer made of n monomers. Finally, dendrigrafts -the youngest member of the family of dendritic polymers -lies in between the above two. [2] The synthetic route to dendrigrafts is generational, but usually involves cycles of polymerization initiated from functional sites located on a core polymer. As a result, dendrigrafts share features with both dendrimers (i.e. generation-based growth and narrow molecular weight distribution), and hyperbranched polymers (i.e. broad number of regioisomers and rapid increase in molecular weight per generation).

Figure 1: Each dot represents a monomeric building block, and each generation is highlighted with a distinct color.

Among the impressive number of dendritic polymers reported in the literature so far, the poly(amine)based ones, which are represented by the prominent poly(amidoamine) (PAMAM) and poly(L-Lysine) (DPL) dendrimers, the hyperbranched poly(ethylenimine) polymers (PEI) and poly(LLysine) (HPL) polymers, and the linear poly(L-Lysine) polymers (LPL), certainly attracted the most attention from the community of researchers working in the field of chemical biology. Historically, poly-L-lysine dendrons were reported for the first time in a patent by Denkewalter et al. before the advent of PAMAMs, [3,4] and were rapidly exploited during the 1980s for the creation of synthetic vaccines. [START_REF] Tam | Proc. Natl. Acad. Sci[END_REF] The polycationic nature of these poly(amine)-based polymers at physiological pH is appropriate to cellular adhesion, endocytosis, and intracellular trafficking for therapeutic delivery, genetic material transfection, or imaging in cellulo. [START_REF] Samal | [END_REF] However, these abiotic macromolecules exhibit some unwanted features considering their cytotoxicity and non-degradability (PAMAM and PEI), low synthetic availability (PAMAM and DPL), non-sustainable synthesis (PAMAM, DPL and PEI), high dispersities (PEI, HPL and LPL), and batch-to-batch variation (PEI and HPL), [7,8,9,10] highlighting therefore the need of a new generation of dendritic polymers that overcome those major drawbacks for real-world bio-applications. [11] This review aims at concisely presenting the innovative works reported to date in the literature on a very recent class of polycationic dendritic polymers, the poly-L-lysine dendrigrafts (DGLs), regarding their chemical and biological features.

Chemistry

Synthesis

Through investigations on the possible role of the N-carboxyanhydride (NCA) motif in the chemistry of the prebiotic world, Commeyras et al. discovered that its aminolysis occurs one hundred times faster than its hydrolysis in weakly acidic aqueous solutions, paving the way of a new synthetic route toward dendritic polypeptides. [12] In water at pH 6.5, the slow hydrolysis of the side chain-protected building block Lys(Tfa)-NCA (Figure 2) unlocks its α-amine function that quickly react with a non-hydrolysed Lys(Tfa)-NCA molecule to form an amide bond for, after multiple similar condensation reactions, leading to the spontaneous precipitation in the reaction medium of a side chain-protected linear poly-L-lysine. A key factor in the success of this synthetic route is certainly the decrease in solubility of the macromolecules as their molecular weight increases, which is due to the hydrophobicity of Nprotected side chains. Subsequent isolation by centrifugation and aqueous alkaline deprotection afford poly-L-lysine G1. By applying the previous sequence in the presence of G1 as a macro-initiator, the second-generation dendrigraft G2 is obtained. It was essential to limit the Lys(Tfa)-NCA/macroinitiator ratio during this step, so that linear oligomers do not grow in the reaction medium. From this generational approach four generations of DGLs G1-G4 can be synthesised with typical yields of 50-60% on a multi-gram scale, thanks to a simple, sustainable, and scalable procedure with no batch-tobatch variability (up to the seventh-generation dendrigraft can actually be obtained using this protocol, but all the reported applications in this review only involve the first-to fourth-generation DGLs).

Figure 2: Synthetic route toward first-to fourth-generation DGLs G1-G4, and their respective schematic representation (each dot represents a L-lysine residue, pending free amino groups are not represented). The synthesis of each generation involves the following sequence: polycondensation in water, centrifugation for collecting the precipitate, alkaline deprotection of the side chains, and concentration in vacuo.

Characterization

Various analytical techniques were used to extensively characterize the poly-L-lysine dendrigrafts, including NMR spectrometry, [12] dynamic light scattering, Taylor dispersion analysis, size exclusion chromatography, [13] refractometry, [14] capillary isotachophoresis, [15] potentiometry, [16] colorimetry, [17] cyclic voltametry, [18] and Raman spectroscopy. [19] Table 1 gathers few selected physicochemical properties for DGLs G1-G4. It should be highlighted that such a simple synthetic procedure exerts an unexpected control on the molecular weight and diversity of the resulting dendrigrafts. Indeed, polydispersity indexes measured for DGLs (1.20-1.46) are below those of both LPLs and HPLs (1.3-2.6 and 1.8-2.6, respectively), and are comparable to those of genuine DPLs (1.1-1.5) that are only accessible via a laborious multistep process. [9] One may assume that it results from a kinetic control linked to steric hindrance between the growing chains, as well as a thermodynamic control linked to the precipitation of the protected polymers in water. Since DGLs are made of L-lysine residues, they could initially be assimilated to proteins. However, some of the residues are linked to each other through isopeptidic bonds (i.e. amide linkages that involve the nitrogen atom of the lateral chain of the amino acids), resulting in the simultaneous presence of free -and α-amino groups in the biopolymers. Potentiometric titrations suggested that only the -amines were protonated at physiological pH. [16] In addition, microsecond molecular dynamics simulations on DGLs G1-G4 revealed that the dendrigrafts Net charge at physiological pH -+41 +92 +280 [16] adopt intermediate morphologies between DPLs and LPLs, which may remind those of unfolded and intrinsically disordered proteins respectively. The simulations also highlighted their unique conformational plasticity (Figure 3), which may explain why DGLs are such efficient binders for anionic biomolecules, even in the most competitive media (vide infra). Adapted with permission from ref. [16], copyright: 2017 American Chemical Society.

Functionalization and immobilization

The presence of multiple amino groups on the arms, but also a free carboxylic acid function at the core of the native biomacromolecules, opens the door to various modifications toward the implementation of tailored features such as targeting, immobilization, fluorescence, or pharmacokinetic effects (Figure 4). The desired feature can be introduced either: i) directly (e.g. via a reductive amination for addressing DGLs with sugar moieties), if the chosen motif is adapted to coupling reactions that involve an amino group, or ii) through an intermediate linker (e.g. via a Michael addition for addressing DGLs with thiol-containing peptidic residues) if the chosen motif is unreactive in -or not compatible with -coupling reactions that involve an amino group. The linker may also carry non-innocent properties. For instance, a polyethylene glycol (PEG)-based linker may be of interest in order to extend the residence time in blood, reduce non-specific cellular uptake, or further lower the cytotoxicity of the nanoparticles. On the other hand, the core functionalization of DGLs involved the use of a prefunctionalized lysine building block that is introduced during the preparation of the first-generation dendrigraft. Contrary to the functionalization on their arms that leads to the simultaneous introduction of multiple motifs, the latter approach allows the introduction of a single motif on DGLs' skeleton.

Figure 4: All reactions for arm and core modifications of the native DGLs reported in the literature so far. A unique example of introduced motif per type of reaction is showed here (with the corresponding references [20,21,22,23,24,25]).

The chemical modification of few terminal amine groups through the succinic anhydride motif led to efficient grafting of the third-generation DGL G3 onto plasma activated surfaces (i.e. PPE, polyimide, polystyrene, PTFE). [26] It turned out that the interactions of anionic ATP molecules on the surfaces were identical to that of the free DGL in solution in term of stoichiometry, showing that the immobilization procedure does not alter the binding properties of the dendritic polymer. Unmodified DLGs can also be attached on a solid support by using reactive polystyrene that bears epoxy functionalities. [27] For both approaches, AFM studies revealed that the resulting nanomaterials displayed monolayered homogeneous surfaces.

Biology Biocompatibility

In order to enter the real world of industrial applications such as drug and gene delivery, biomaterial and tissue engineering, bioimaging or biosensing, polymers should display a number of crucial properties that we believe DGLs exhibit. Indeed, it was demonstrated that DGLs are readily soluble in water at least up to 60 g/L in water, [12] are stable under sterilization conditions, [28] and are partially degradable under the action of endogenous peptidases. [29] In addition, these biomacromolecules are non-immunogenic [30] and carry low cytotoxicity (i.e. IC50 values on Hep2 cells of 16.8, 13.2, and 13.9 µg.mL -1 from second-to fourth-generation DGL, respectively), [31] in comparison with other polycationic polymers (e.g. about 90% viability for DGL G3 versus less than 50% viability for hyperbranched PEI at a same concentration of 12.5 µg.mL -1 on HeLa cells). [32] As a result, DGLs already attracted the interest of multiple research groups during the last quinquennium, and found numerous applications in the biomedical field, where the ability of the arborescent polymers to display multiple functionalities has been exploited. Selected examples are presented below.

Biocide

Because polycationic polymers are known to possess inherent antibacterial activities that result from the binding to the microorganisms' cytoplasmic membrane and to their subsequent disruption, native DGLs have been considered as potential antibiotics. The interactions between DGLs and Gramnegative bacteria (i.e. Erwinia carotovora) were studied by Cottet et al. using capillary electrophoresis, with reported binding affinities in the micromolar range, and binding stoichiometries that decrease with increasing DGL generation (i.e. from 10.2 x 10 6 to 1.1 x 10 6 for DGL G2 to G4, respectively). [33] Moreover, a fast bacteriolytic activity of the second-generation DGL G2 was observed against Erwinia carotovora under low salt conditions. [34] This observation is interesting since Gram-negative bacteriadue to a largely impermeable cell wall -are more resistant to antibiotics than Gram-positive bacteria.

Although it is obvious that native DGLs display a small therapeutic window with respect to their antibacterial activity/cytotoxicity balance, one can now envisioned chemical modifications of DGLs, such as for example the quaternization of the free nitrogen atoms or the reduction of the charge density via the introduction of PEG chains, in order to improve both their biocide properties against Gram-negative bacteria and their cytocompatibility. [35] Drug and gene delivery

Several obstacles such as fast degradation, low penetration through membranes, or low selectivity for target cells, often hinder the efficient delivery of bioactive molecules, including peptides or proteins. Sideratou et al. reported the efficient complexation of insulin with native and guanidine end-functionalized DGL G2, through electrostatic interactions between the partners at physiological pH. [36] The protection against enzymatic degradation as well as the retardation of insulin release in simulated intestinal fluid, which were found to be positively related to the number of guanidine end-groups, open interesting perspectives in the delivery of insulin to systemic circulation through oral administration. A therapeutic drug can also be covalently attached to a cationic dendrigraft, to obtain small-sized nanoparticles with strong penetrability in cells and tissues. However, small-sized nanoparticles are hampered by their fast systemic clearance and limited tumour retention. To address this issue, Gao et al. decorated a third-generation DGL G3 with multiple anticancer doxorubicin (Dox) motifs, was itself conjugated on the surface of large-sized gelatin nanoparticles. [37] Once in tumour microenvironments, high concentrations of the gelatin-degradating enzyme MMP-2 induced a shrinking event towards small-sized DGL-Dox conjugates. Such a multistage approach permits therefore to take advantage of both the enhanced retention properties of large-sized nanoparticles, and the tumour penetration of small-sized nanoparticles. To further improve the tumour targeting, an additional arginine-glycine-aspartic acid ligand, which is well-known to very efficiently bind the overexpressed α v β 3 integrin receptors on neo-vessel endothelial cells, can also be introduced on the nanotherapeutics' surface. [38] In contrast to drug-based medicine, gene therapy targets the molecular cause of a disease instead of healing its consequences. It was demonstrated that positively charged amino groups of DGLs can interact with negatively charged phosphates of nucleic acids to yield polyplexes that protect the genetic material against DNAse I attack, and promote its cellular uptake via endocytosis or endocytosislike mechanism. [31] Regarding their plasmid DNA (pDNA) and silencing RNA (siRNA) internalizing properties in Hep2 cells, DGLs can be ranked as follows: G3 > G4 ≥ G2, with a higher effectiveness than the commercial transfection reagent Lipofectamine 2000. However, unmodified DGLs displayed disappointing transfection capabilities, which may results from their cytotoxicity at the high concentrations required in nucleic acid delivery experiments. Gene expression could be significantly boosted by the introduction of PEG chains on the dendrigrafts. For both DGLs G2 and G3, an increase in the covalent PEGylation extend resulted in an increase (i.e. up to four times) in gene pEGFP-N2 expression in HEK 293 cells, as well as a decrease of the polyplexes' cytotoxicity (e.g. at 200 µg.mL -1 , from 83±3% to 92±7% cell viability with a second-generation native DGL and a second-generation DGL-PEG, respectively). [39] These PEG chains can also be further labeled with known ligands for membrane proteins, thereby rendering gene vectors with targeting properties. For example, PEGylated DGL G3 was decorated by Jiang et al. (who are certainly the most active research group in the field of drug/gene/probe delivery using DGLs -A/N) with the short peptide EPRNEEK that is known to bind laminin receptors expressed on the blood-brain barrier and on cerebral glial cancer cells. [40] The resulting nanoparticles DGL-PEG-EPRNEEK were able to deliver in vivo a siRNA against survivin, which is an apoptosis inhibitor protein. In glioma-bearing mice, the untreated groups exhibited an early death as a function of time (i.e. 50% survival at 34 days), while DGLs-PEG/survivin groups showed no prolonged survival time, which was only increased in G3-PEG-EPRNEEK/survivin groups (i.e. 50% survival at 41 days). However, the expression of target receptors on normal cells and tissues is inevitable, which may lead to side effects of the nanoparticles. Some intrinsic characteristics of the tumour microenvironment can be exploited towards enhanced tumour/background accumulation ratio. Jiang et al. showed that the variation of the extracellular pH could be used to activate/inactivate a receptor-mediated endocytosis by conjugating the shielding molecule diethylenetriaminepentaaceticacid (DTPA) to the transferin membrane protein-targeting peptide HAIYPRH via a pH-sensitive hydrazone bond. [41] Under normal conditions (pH 7.4), the resulting G3-PEG-HAIYPRH-hydrazone-DTPA nanoparticle was not able to deliver a pDNA encoding for the green fluorescent protein, whereas the nanoparticle was considerably absorbed in tumor acidic environment (pH 6.5). In addition, the non-hydrolysable G3-PEG-HAIYPRH-DTPA/pDNA ensemble was inactive against transferin-expressing cells in acidic conditions, demonstrating therefore the pH-activated detachment of the shielding molecule.

Then, combining gene and drug delivery may be regarded as a potential strategy for achieving enhanced therapeutic activities. Using the previously described vector G3-PEG-HAIYPRH, it has been shown that Dox as a chemotherapeutic drug to kill tumor cells, and anti-VEGF (i.e. vascular endothelial growth factor) as a gene to inhibit tumor angiogenesis, both synergically promoted a remarkable extend of median survival time in treated glioma-bearing mice (i.e. twice as long in comparison untreated animals). [42] Another level of sophistication can be added to the former nanoparticle approach by replacing the targeting ligand by an activatable cell-penetrating peptide that is dual-triggered by the pH and MMP-2. [43] The resulting nanotherapeutics displayed a superior efficiency against glioma as a result of both tumor targeting and internalization functions. This last example certainly describes one of the most elaborated DGL-based nanotherapeutics to date.

Imaging

Early detection and monitoring is essential to the successful treatment of many diseases including cancer and neurodegenerative diseases. Therefore, imaging agents should display high affinity, selectivity for targeted tissues or cells. Various strategies involving DGLs have been reported in the literature towards bioimaging:

• The coupling through a PEG linker of a conventional Gd(III)-pentetic acid complex. When associated with a neuroectodermal tumour-specific ligand (i.e. chlorotoxin), the precise detection of glioma located behind the blood-brain barrier was possible by magnetic resonance imaging. [44] • The delivery of a green fluorescent protein-encoding plasmid. When associated with a peptidic ligand for the low-density lipoprotein receptor-related protein (i.e. angiopep), the nanoparticles permitted the visualisation by fluorescence microscopy of SH-SY5Y cells, which are a model of dopaminergic neurons in Parkinson's disease. [45] At the same concentration, the DGL-based nanoparticles showed higher cellular uptake and gene expression compared to the PAMAM-based equivalent. In addition, they exhibited no apparent cytotoxicity against the cell line.

• The non-covalent absorption of DGLs on superparamagnetic iron oxide nanoparticles. When associated with a peptidic ligand for α v β 3 integrin receptors (i.e. RGD), the nanoparticles permitted in vivo magnetic resonance imaging of living mice bearing HepG2 tumors. [46] • The coupling with an organic fluorophore (i.e. Bodipy) through a hydroxysuccinimide-amine reaction for the 3D localization of DGL/DNA complexes in mice by CT scanning. [47] In some cases, the optical signal may also be turned on by desired events, such as a pH-dependant electron transfer between the fluorophore and a quencher, [48] or the separation of the fluorophore and a quencher upon enzymatic cleavage. [49] Such approaches minimize the background signal for increased specificity and sensitivity of the images.

In most cases, the probes were associated with oligonucleotides and/or drugs for a concomitant diagnostic and therapeutic action. In a very recent example, Guo et al. decorated a third-generation DGL with two aptamers (i.e. a nucleolin-specific binding aptamer, AS1411, and a cytochrome c aptamer) for targeting, and a fluorophore (i.e. Cy 5.5) for imaging. Dox was intercalated into a DNA duplex containing an ATP aptamer, which was subsequently condensed by DGL to form a theragnostic nanoparticle (Figure 5). [50] This elegant system has demonstrated to not only selectively accumulate in the mitochondria of HeLa cancer cells, but also to generate a distinct near-infrared fluorescence signal in the tumor region and to promptly release the loaded Dox in virtue of the high concentrations of ATP in mitochondria.

Tissue engineering

Tissue engineering aims at the regeneration of damaged or dysfunctional tissues ands organs through the use of polymeric scaffolds that promote cell adhesion and/or deliver growth factors. In the context of regenerative medicine for peripheral nerve, DGLs were identified to be superior to linear poly-L-lysines of similar molecular weights in promoting nerve cell adhesion, suggesting that nerve cells adhered more efficiently to the dendritic-coated poly(glycolic acid) fibres. [51] In addition, DGL G4, in association with a poly( -caprolactone) membrane, was also an effective nanoreservoir for the nerve growth factor; the resulting biomaterial being able to induce the full vascularization and innervation of a tooth in vivo. [52] Biosensing

In a biosensing purpose, a third-generation generation DGL G3, immobilized on plasma activated polypropylene filters, was reported to be an efficient capture agent for concentrating bacteriophage MS2, allowing the quantification of the model virus in large volumes of water. [53] This approach relies on the non-covalent interactions that take place between positively charged dendrigrafts and the negatively charged surface of the viral particles. It is interesting to note that, since DGLs and bacteria also displayed high affinities based on electrostatic interactions [33], this approach could be extended to the detection and/or removal of pathogenic bacteria from contaminated waters. Recently, Vial et al. envisioned that a DGL might be able to mimic the highly basic protamine, a heparin neutralizing protein. Heparin is a polysulfated glycosaminoglycan (GAG) that is extensively administered to patients as an intravenous anticoagulant, and its quantification in clinical settings is highly desirable in order to prevent thrombophilia or bleeding disorders. It turned out that DGLs were able to form multi-ligand complexes with a poly-anionic fluorescent peptide, leading to the decrease of the optical signal that can be restored upon the introduction of heparin, in a typical indicator-displacement regime (Figure 6). [54] This simple system allows -for the first time -the detection and the quantification of the anticoagulant in human blood at clinically relevant levels. In the same conditions and at comparable molecular weight, LPL was not able to bind the anionic probe, highlighting therefore the importance of the dendritic topology for a strong association event between the binding partners when working in complex media. Remarkably, the highly concentrated circulating protein serum albumin (i.e. about 40 grams per litre of blood), which was reported to display dissociation constants with DGLs in the micromolar range, [55] did not seem to interfere with the sensing process, therefore highlighting the tremendous affinity of dendrigrafts for heparin. Also, depending on the loading of the indicator on the receptor, various GAGs induced an increase or a decrease of the optical signal as they displace the indicators from the receptor or they compact the indicators on the receptor' s surface, respectively. [56] This unique feature allowed the blind identification of various GAGs by linear discrimination analysis with a level of accuracy of 100%.

Conclusion

Here, we deliver a digest of the diverse research works that involved the newcoming poly-L-lysine dendrigrafts so far. The ambition of this minireview is a better exposure of these macromolecules, with the objective that they will eventually realize their full potential. Although DGLs have been reported in some biological studies to be superior to other linear or dendritic cationic polymers, their ability to actually respond to medical needs has still to be demonstrated. This includes clinical data, and imposes collaboration with physicians/medical researchers for potential clinical translations. In this biomedical context, the attractiveness of these macromolecules relies on their: (i) straightforward, robust and green synthesis on a multi-gram scale, (ii) strong positive electrostatic potential and conformational elasticity for highly efficient interactions with biologically relevant anionic species, (iii) chemical flexibility for further functionalization to implement desirable properties, and (iv) biodegradability, low toxicity and non-immunogenicity. Given these features and the success met so far by poly-L-lysine dendrigrafts, we believe that they are promising next-generation biopolymers for real-world applications.

Table of Content

Figure 3 :

 3 Figure 3: From left to right: snapshots of the first-to fourth-generation DGLs G1-G4 from microsecond MD simulations. Blue dots highlight the positively charged nitrogen atoms at physiological pH.Adapted with permission from ref.[16], copyright: 2017 American Chemical Society.

Figure 5 :

 5 Figure 5: (A) Schematic illustration of the G3-based theragnostic nanoparticle (Dox/Mito-DGL) structure, and the mechanism of mitochondria-targeting drug release triggered by ATP; (B) timedependent in vivo fluorescence images of subcutaneous HeLa tumor-bearing mice after i.v. injection of Dox/duplex-Cy5.5, Dox/Mito-DGL (no AS1411) or Dox/Mito-DGL; (C) change in the relative tumor volume (V/V0) upon different treatments (Dox/Mito-cDGL is obtained by replacing the duplex in Dox/Mito-DGL by a non ATP-responsive duplex). Data are means ± SD (n = 6), ***P < 0.001 compared to other groups using a one-way ANOVA. Adapted with permission from ref. [50], copyright: 2017 Royal Society of Chemistry.

Figure 6 :

 6 Figure 6: Schematic representation of the indicator-displacement assay using a DGL-fluorescent indicator complex (top), and application to the sensing of heparin (HP) from heparinized human blood samples (bottom). Adapted with permission from ref. [54], copyright: 2015 Royal Society of Chemistry.

Figure 8 :

 8 Figure 8: Graphical Abstract

Table 1 :

 1 Selected physico-chemical properties of DGLs G1-G4 (with the corresponding references[12,13,16]).

		G1	G2	G3	G4	Ref.
	Molecular Weight (g.mol-1)	-	11800 32100 88800 [12]
	Degree of polymerisation	8	48	123	365	[12]
	Branching ratio (%)	-	12	24	23	[16]
	Polydispersity index	1.20	1.38	1.46	1.36	[12]
	Hydrodynamic radius (nm)	0.77	1.40	2.14	3.00	[13]
	Number of peptidic bonds	7	41	92	280	[16]
	Number of isopeptidic bonds	0	6	30	84	[16]

Acknowledgment

This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Université de Lyon, and the Université de Montpellier.