In March, 2001 a stunning program on NOVA Public Broadcast (NPB) described a breakthrough in cancer research by Dr. Judah Folkman of Harvard Medical School and Boston Childrens Hospital. Dr. Folkman is a surgeon, a research surgeon rather than a conventional molecular biologist. He makes a great deal of that difference and his work documents it. The following discusses the differences between Dr. Folkmans scientific methods and those of the reductionist specialized departments of science, illustrating the similarities between the surgery-based science of Dr. Folkman and British scientific empiricism. It was first developed by Francis Bacon, and applied to Natural History (science) in Britain from Hume to Mill and Darwin. Today it is represented in the semiotics and neo-hermeneutics of C.S. Peirce, L. Jonathan Cohen, Gunther Stent, Patrick Heelan and Thomas Sebeok (Wheeler, 1987). It is possible, from the following, and by inference from the work of Evelyn Fox Keller (Keller, 2000) that Folkman could have made his discoveries without knowledge of the last thirty years of molecular biology. The references to Folkmans science are taken from his statements made on NPB (Linde, 2001) interviews. References to Bacon's scientific empiricism are taken from my articles. (Wheeler, 1998; 2001)
Dr. Judah Folkman is a surgeon-scientist. His research began over thirty years ago studying tumors as organisms holistically rather than their component chemical properties. He knew the more conventional approach in the sciences is reductionist, as in biochemistry and physical chemistry - sometimes defended as applying an Occams Razor simplification. Several biologists like Gunther Stent and James Danielli (Danielli, 1982) had long questioned this, arguing that the properties of organisms are not summations of their chemical components but rather can best be understood holistically (Elsasser, 1982;1986). Gunther Stent calls his approach neo-Kantian and neo-hermeneutic. Patrick Heelans philosophy of science makes the same argument (Heelan, 1983). A similar point was made in the post-modern physics of John A. Wheelers participant-observer (Wheeler, J. 1994) universe, extended by David Bohm into the explicate/implicate order. (Bohm, 1995)
Judah Folkman points out that to become a surgeon involves long years of professional training in studying and experimenting with complete organisms. His research was conducted in hospitals and clinics whose separate departments were based on organs, diseases and treatments rather than on graduate school sub-divisions of research specialties: the study of metastatic organs rather than protein folding enzymes and models. All scientific research is institutionalized and departmentalized but the difference is between departments based scientific disciplines, and clinics based on medical disorders. In the Renaissance when Occam advocated the razor principle of simplification he was criticizing the Thomists of the day. Today Occams Razor supports reductionism: micro is better than macro; nano is better than micro. But under conditions described by Dr. Folkman, it may inhibit the understanding of complex organisms. Jay Forrester many years ago pointed out that highly complex organizations are counter-intuitive. Intuitive solutions, like treating melanoma with menthol, worsen rather than solve.(Forrester, 1969)
Folkman's breakthroughs began in 1961 when he noticed previously undetected properties of tumors as organisms, not aspects of their biochemical component particles. First was the discovery that if tumors were invaded or isolated, cancerous growth was stimulated. Next came the identification of two related behaviors of tumors: angiogenesis and angiostatin: the formation and the inhibition of blood vessels, or capillaries (Kravitz, 1974) . He concluded that tumors grow through angiogenisis, as a property of tumors as organisms and their cells.(Cooke, 2001) Angiostatin is the inhibition of blood vessel production. It is exciting to relive the point when Folkman realized he had discovered something about tumors nobody else had ever before known - and his perception that it might lead to arresting tumor growth.
An analogy: the ancient discovery of fermentation as a property of maize and keeping maize dry prevents fermentation. Dryness as a maize fermostatin.
Having discovered angiogenesis Dr. Folkman believed its angiostatin could be sought and used to fight metastasis.
Fermentation changes maize into a new thing. Yeast, produces fermentation. Applying yeast and moisture to maize turns maize into bread or beer. Under adverse moisture conditions maize may produce ergot, a deadly poison.
The maize analogy illustrates that Judah Folkman might have made his discoveries without any specialized knowledge of advances in the last thirty years of molecular biology. He was a surgeon-scientist who applied a scientific empiricism known since Francis Bacon (Spedding, 1860-68) and especially characteristic of British science - natural history. Bacon made clear that scientific empiricism is not mere trial-and-error, linear, time-determined empiric induction which he rejected firmly. (Wheeler, 1999; Peltonen, 1996) Folkman, like Bacon, sought a hidden, unwritten property of organisms. The evidence was circumstantial (Cooke, 2001) rather than a post-hoc ergo propter hoc form of science. Hume, Kant and J.S. Mill studied it Bacons philosophy of natural history; Darwin and Spencer applied it. Pasturization and Mendelian genetics are familiar examples. L. Jonathan Cohen (Cohen, 1977) and Von Wright (G. Von Wright, 1960) are among the leading recent philosophers of the Baconian approach. More recent is Leonard Hayflicks discovery that e-coli cells are not immortal: they stop reproducing in vitro after a certain number of divisions. (Hayflick, 1967) Several years later a virtual death-dealing cell endostatin, telemerase, was found: a chromosome enzyme tail-snipper that counteracted the Hayflick Limit of fifty or so cell divisions and promised immortality.(Telemerase, 1998)
The most dramatic modern example of discovery that depended on scientific empiricism was the breaking the genetic code. It featured a contrast between reductionist physical chemistry and the systems-theoretic approach of scientific empiricism. The race was won by the counter-intuitive hypothesis of the double helix. On one side was one of the greatest chemists in history, Linus Pauling - Nobel Laureate for discovering of the molecular bond - and the relatively obscure winners, Crick and Watson (Watson, 1968). Paulings work in conventional cause-effect physical chemistry had been watched carefully by Crick and Watson. They, like Pauling himself, were stumped until one day chatting outside a university hall they noticed its spiral staircase. The secret, as with Dr. Folkman, came in a flash. The structure was not linear, as all had assumed, but holistic: a double spiral like two intertwined spiral staircases. The confirmation required intensive microbiology but the discovery itself was Baconian.
Francis Bacons eliminative empiricism is explained in Novum Organum and its applied departmentalization is illustrated in The New Atlantis.(Wheeler, 1991; 1999). His concept was based not on math or physics but on the theory of evidence he developed for the English common law. His model for the large scale organization of scientific research was patterned on the Stuart Chancery where he was Lord Chancellor - The Royal Society was an attempted approximation. Organized research was administratively departmentalized to collect and evaluate evidence using his new systematic logic engine. Bacon applied it to all departments of nature - the secularized laws of nature ( Bacon, F. Valerius Terminus). Natural history was the British name for science well into the 20th century.
Britain s unwritten common law was real; an implicitly phenomenological kind of reality. Bacon recognized its special kind of thingness and developed a reverse Platonism to deal with it scientifically: a Platonism of things rather than words. (Wheeler, 1999). Bacons tri-relative model of Forma, Processus and Schematismus paved the way for Kants phenomenology. (Wheeler, 1999) Hume. J. S. Mill, Darwin and on to Crick and Watson applied Bacons method of discovery through use of stipulated facts and circumstantial evidence to eliminate all but one hypothetical explanation:
The human being cannot know things directly but instead must analyze the phenomena implicit in the noumena that humans do experience. The object of science is progressively finer degrees of phenomenal validity (Bacon, vii, 223, Phenomena of the Universe).
Eliminative, adminicle empiricism was Bacons name for this process of collecting evidence to reject all but one hypothesis. The resulting discovery is not infallible. It is always subject to being supplanted later by new evidence or by a finer and more discriminative interpretation of the evidence.
The fact that Dr. Folkman was a surgeon made his scientific recognition difficult but also was the source of his special scientific insights. In 1961, while conducting medical research in a U.S. Navy lab he stumbled upon the secret of how cancer grows. Before the decade was out, he was forming the theory that would occupy the rest of his professional life. Being a professional surgeon had disadvantages:
The following quotations are statements by Dr. Folkman on NOVA in interviews by Nancy Linde, February 27, 2001:
Surgery has the disadvantage that the training takes so long and is so physically demanding. It's like training for the Olympics practically. There's often little time for any kind of research or scholarly work, and surgeons often do not have any ability to have the very long period of scientific training that basic scientists have. And so surgeons often are ridiculed because they are thought not to be able to do research. Yet many great, interesting, and important advances have come from surgeons.
Medicine also conveyed special scientific advantages:
Clinical medicine has tremendous feedback, so the people who work in it are willing to work night and day. Patients just call you up all the time and say you saved my son's life and all that. Research is the opposite. It's just years of frustration.
You have to live with experiments that don't work and grants that don't get funded. You have nothing to show for it. You've got critics all over, and scientists are sometimes mean to each other; they criticize the ideas in the name of scientific skepticism. It's not an easy life. You know that line, I've been rich, and I've been poor, and rich is better? Well, it's easier to be a physician than to be a researcher. I've been both, and physician is easier.... [I] always thought of it in an amused way, because I knew something that no one else knew, and I had been at the operating table.
But there were comparative disadvantages to being a scientist :
It wasn't the surgeons who were criticizing, it was basic scientists, and I knew that many of them had never seen cancer except in a dish. I knew that they had not experienced what I had experienced. The idea of tumors growing in three dimensions and needing blood vessels in the eye, in the peritoneal cavity, in the thyroid, and many other places, and the whole concept of in situ cancers and tumors waiting dormant -- I had seen all that. So I kept saying the ideas, I think, are right, and it will just take a long time for people to see them.
It is relevant to recall Scott Buchanans plea for a new professional science of medicine. (Buchanan, 1938)
Here is Dr. Folkmans description of his research:
Most research is failure. You go years and years and years, and then every once in a while there is a tremendous finding, and you realize for the first time in your life that you know something that hour or that day that nobody else in history has ever known, and you can understand something of how nature works. (Linde, 2001)
C.S. Peirce (Peirce, 1955, 1958) Ernst Mayr (Mayr, 1982) , Gerald Edelman (Edelman, 1992) and Thomas Sebeok (Sebeok, 1981) are among the leading theorists of the kind of scientific research Folkman conducted. It is like the back-chaining method of medical diagnosis from symptoms - an eliminative process of delving to a root foundation; and then a rising process to a higher adminicle hypothesis. It is semiosis, analogous also to fuzzy set theory (Zadeh, 1973).
The philosophy of science suffers from an ontological version of Whig Historicism. After a discovery is made analysts work backward from it to the events that explain its foundations. Instead what is needed is a retrospective inventology (Wheeler & Wilkinson,1974) that starts from conditions before the discovery and works forward from them. From what was known at the beginning it is possible to follow the hypothesis-eliminating steps that ended with an Ah-Hah discovery. Consider Newtons invention of celestial mechanics - which provided the model for the philosophy of science until the mid-20th century. Decades of the disparagement of Baconian scientific empiricism were based on the classical mechanics model. The irony is that Newton, an avowed Baconian, applied a Baconian approach in his invention of The Calculus. The process he followed in The Optiks was precisely Bacons adminical eliminative empiricism. (Wheeler (1999).
Recall Dr. Folkmans retrospective story. As a youth accompanying his father to provide hospital patients with rabbinical services, he announced his goal of serving people as a doctor, not a rabbi. (Cooke, 2001)
In the 1960's, when Dr. Folkman was an obscure surgeon, the so-called second scientific revolution was being heralded; atomic physics was Big Science and the other sciences lusted after it. The genetic code had been broken; the modern synthesis of genetic and evolutionary Darwinism held great promise.(Edelman, 1992; Rosenfield, 1988) Much was anticipated and more hoped for. Biophysics - as at the Salk Institute - was expected to cure cancer and deliver immortality.
Think science forward from there, forgetting what Judah Folkman later discovered. Here is the young surgeons description of his first discoveries:
It was the early 1960's
....[W]e saw in the isolated organs growing in the glass chambers in the Navy... that the tumors implanted there all stopped at the same size. There should have been a bell-shaped curve like in all biology, but all the same size meant that something was stopping them.
No explanation was immediately apparent:
It took a few years to figure out it was the absence of blood vessels. I had a feeling this is really something important. I didn't have any idea that it would be some 30 years to try to understand the process by which tumors are able to recruit their own private blood supply and just keep going.
Ten years later in 1971 in the New England Journal of Medicine (Folkman, 1971) Dr. Folkman published the first report making four arguments:
One, that the blood vessels in a tumor were new, and the tumor had to recruit them.
Two, that it recruited the vessels by sending out some factor, which we called TAF, tumor angiogenesis factor, because we didn't know what it was that was diffusible. (Diffusion means like, if you put some ink on a table cloth, it travels, but not a long distance.)
Thirdly, we put forward the idea that these diffusible proteins would bring in the vessels.
And fourthly, that if you could turn this process off the tumors should stay as small as they had in the thyroid gland and in the lining of the abdomen that I had seen in surgery, where they are all the same size and tiny but without blood vessels.
Notice the form of reasoning. It is not a set of linear time-determined demonstrations. Dr. Folkman applied a back-chaining process familiar from A/I - Artificial Intelligence. It is the Baconian eliminative process of evidence evaluation that is used effectively in medicine and psychiatry. Interesting examples are the psychiatric counseling programs developed by Roger Gould (Gould, 2001) at UCLA.. Folkmans analysis was like the semiotic empiricism of Sherlock Holmes. Conon Doyle was a practicing physician and gave Sherlock Holmes a method adapted from the diagnostic process of Dr. Joseph Bell, Doyles professor at the Royal Infirmary of Edinburgh. (Sebeok, 1981) Sebeoks treatment of abductive reasoning in the pragmaticism of C.S. Peirce emphasizes Peirces intensive study of medicine. (Sebeok, 1981).
Folkman, using circumstantial evidence, reasoned that pre-cancerous tumors must secrete some mystery factor that stimulates or induces or attracts the formation of new blood vessels. These must convey to the tumor the kind of nutrition which allows, or induces it to grow. The process was not intuitively obvious, it was counter-intuitive (Forrester, 1969). The result was Folkmans counter-intuitive angiogenesis hypothesis: Tumors do not grow larger than the head of a pin without some mysterious capability of attracting blood vessels that will bring them inducers with which they grow into cancers.
It followed that an entirely new way of treating cancer is required : First find a way to block angiogenisis and thereby arrest what facilitates cancer production. To the conventional scientist this was a ridiculous unfounded fantasy and thats what they said: just the sort of thing one might expect from a surgeon.
Twenty-five years later positive results were produced in mus musculus - mice. Today clinical trials have begun with two recently discovered angiogenesis inhibitors, endostatin and angiostatin.
That stage was a long time coming.
I was beginning to wonder whether there would ever be an angiogenic factor. We had spent so many years on it. In general, if you don't find something in four or five years, people say it's not there. In research, there's a very fine line between persistence and obstinacy. You do not know whether if you're persistent a little while longer you'll make it, or whether you're just being obstinate, [and it] doesn't exist. And, of course, you can keep on going, stay with an idea too long -- [that's] called pigheadedness. I was beginning to think we had crossed that line and were spending money and had nothing to show for it.
The second breakthrough:
By about the end of the `70s people began to say, Okay, they are new vessels, we agree. But it's a side effect of dying tumor cells. It's like pus in a wound. When Robert Auerbach came [to our lab] as a sabbatical professor, that was the conventional thinking. But he did the experiment that disproved that as a single, crystal-clear paper. He put live tumor cells in one eye of a rabbit, and he put dying tumor cells in the other, and no blood vessels came to those, only to the live ones. He said they must be live in order to recruit the private blood supply.
The next year, 1984, Folkmans team published in Science their discovery the first angiogenic factor:
That single paper changed a lot of people's thinking.... [It] had great transforming power. Almost overnight many, many, many critics were transformed into competitors, because people began to see that there was a molecule in this field. That was the first; there are now 17..... [T]hat was a great sense of relief,... it actually did exist. It's like sputnik. The U.S. had all the information to put up a satellite, but we didn't until Russia did. Then suddenly we said, Oh you can do it. Once people saw that it was possible [to find angiogenic factors], they began to look and found other ones. ....[T]he watershed year for complete change of thinking amongst scientists was about 1989. By then there were such strong experiments coming from our lab, from Genentec's lab, and from Europe that tumors not only induced new vessels but were angiogenesis-dependent, that most scientists began to accept that. But it took a long time.
NOTE: Angiogenisis is not a thing it is a phenomenon. It is a name; a semiotic sign (Peirce, 1981; Sebeok, 1984; Wheeler, 1999)
The third breakthrough was the big one. Implicit in the first two breakthroughs was a another phenomenon - a process generator - which if observed would deserve a new name: angiostatin - angiogenisis inhibitor - a factor that stopped blood vessel growth. It took a long time.
In 1980 came interferon, in 1981 or 1982 came platelet factor 4. These were the first two. By then we said there are angiogenesis inhibitors.
A felix culpa - fortunate accident - had produced evidence for the third breakthrough:
Don Ingber had the presence of mind to study a curious contaminant rather than simply dispose of it..... He was an M.D., Ph.D. who had come up from Yale and was studying endothelial cells. Every time a new building was being built outside Children's Hospital, funguses would come into the windows, and you'd get contamination of these in the cell cultures. When you got a fungus growing in there, it would turn turbid, and the little dish of cells would all die and float....Don had a set of endothelial cells, and there was a fungus contaminant at one end of the dish. He called me and said you have to come in and see this, because there's something different. The cells were not dying, they were just backing away. He said there's something diffusing, something coming from the fungus that is stopping the endothelial cells. Now, what's important is that anyone else in the lab would have thrown that out. There were signs all over the lab that said if your cell culture becomes contaminated with a fungus, you must throw it out, because if you try to keep it and treat it, it will infect the whole lab. I used to get upset with people who didn't, so Ingber called and said I would like permission to keep this culture. A fungus that contaminated Ingber's cultures lead to the angiogenesis inhibitor known as TNP470.
That led to the isolation of a compound that is today in clinical trial. The whole purification was done by Takeda Chemical Industries, because they are very good at growing funguses. They made the chemical which is today called TNP-470, Takeda neoplastic product #470. It's in clinical trial, and in animal tumors it has a very broad spectrum antitumor effect. It was a little stronger than platelet factor 4 and much stronger than interferon. So that was a purely serendipitous discovery.
Two angiogensis inhibitors - endostatin and angiostatin - were discovered and are now in clinical trials:
"If endostatin or angiostatin should fail, the principles are solid, they've been established over 30 years. They've been replicated over 30 years by laboratories around the world, and other laboratories are making more and more discoveries based on the principles. Demonstrating proof of principle in the clinic that you can control tumors or slow them down or regress them by anti-angiogenic therapy is the hope -- that's what we're working [on] .... So physicians in the next decade may have an arsenal of angiogenesis inhibitors, possibly 10 or 20, and they can combine them and choose among them and add them to other therapies to increase the power of the control that doctors have over cancer.
Judah Folkman and his team had to conduct hundreds of experiments before the scientific community began to accept their unconventional ideas.
Folkmans medical science is an excellent example of post-Newtonian, post-positivist science. Peirce is directly relevant. In "Pragmatism in Retrospect - A Late Formulation," Pierce described his intensive study of two subjects: medicine and Kants Critique of Pure Reason. Peirces realism was an interpretation of words as signs whose relation to their referents was selected by their effectiveness in a Darwinian process. His semiosis was a transitive tri-relative projective-contrajective process interactive between nature, mind and schema - a logical Baconian engine of science-making. Peirces "Critical common-sensism" involved:
* the mutual confirmation of the senses;
* subjecting them to a Kantian critique:
a poly-perceptual lens-like resolution of the differences between sense impressions, as in David Bohms implicate-explicate order, an interpretation of John A. Wheelers participant-observer universe.(Bohm, 1981) Peirce argued that this process works in the brain in a Darwinian reinforcement process (Edelman, 1992) that associates likeness, contiguity and cause: a non-statistical probability like that of Bacon and Skinner. (Skinner, 1957). Roman Jakobson's aphasia studies, based on Luria's experiments, adopted this model. In his capstone, Peirce contrasted his triadic semiotic model with conventional dyadic dynamical models based on Newtonian mechanics. He distinguished between dyadic cause-and-effect dynamical sciences, from his kind of triadic empiricist sciences that employ a tri-relative (semiotic) relation between object, sign and interpretant - the "law of semiosis."(Peirce, 1981) His triad is like Kant's phenomenon, noumen and schematismus, and Bacons Forma Processus and Schematismus, which Kant drew upon. (Wheeler, 1999) It is applicable to the analysis of systemic relations; a quest resumed by Husserl and Merleau-Ponty Heelan, 1983; Sebeok, 1981). Folkmans science is pragmaticist in the Peircean sense.
comments for Harvey Wheeler
NOTE: All references to writings by Francis Bacon are from Spedding, J., etc. (1860-64) The Works of Francis Bacon, Baron of Verulam, Viscount St. Albans, and Lord High Chancellor of England, 15 vols, Brown and Taggard, Boston.
Bacon, Francis, Valerius Terminus, vol VI, pp. 25-76. The first analysis of secularized natural law theory.
Bacon, Francis, (1607) Phenomena of the Universe, vol VII, p 223; his first use of phenomena.
Bohm, David (1981/1995),Wholeness and the Implicate Order, Routledge, London
Cohen, L. Jonathan (1977) The Probable and the Provable, Oxford U.P., London.
Cooke, Robert, (2001), Dr. Folkmans War, Random House, N.Y. pp. 79-80, the ignored 1945 discovery of angiogenesis by Dr. Glen Algire snd Dr. Folkmans conclusions in the 1960's based on circumstantial evidence., p. 81,
Cooke, Robert 2, (2001) op. cit., p. 81 The circumstantial evidence had been accumulating in the back of his mind for half a decade. etc.
Danielli, James; FRS, Founder/editor J. Theor. Bio.; Co-founder/editor, J. Soc. & Bio Structs.; (1982) Constructional Biology, Jour. Soc. & Bio. Structs. Vol 5, #1.
Edelman, Gerald M. (1988) Morphoregulating Molecules. Biochemistry, vol 27, p. 3534.; (1990) Topobiology: Adhesion Molecules in Neural Morphogenesis, Willard B. Rew Memorial Lecture, Harvard Medical School; (1992) Bright Air, Brilliant Fire, Basic Books, p. 47.
Elsasser, W.M. (1982) Biological Theory on a Holistic Basis, Johns Hop. Univ. Dept of Earth and Planetary Sciences, Baltimore; (1984) The Natural Philosophy of Holism, Johns Hop. Univ. Dept. of Earth and Planetary Sciences, Baltimore.
Folkman, Judah (1995) Tumor Angiogenesis, in The Molecular Basis of Cancer, ed. J. Mendelsohn, etc.
Folkman, Judah (1996) Fighting Cancer by Attacking its Blood Supply, Scientific American, September.
Forrester, Jay W. (1969) A Deeper Knowledge of Social Systems, Camb. Alumni Assn, MIT, Cambridge, Mass.
Gould, Roger (2001) www.masteringstress.com.
Hayflick, Leonard (1967) Biology of the Micoplasma, New Your Academy of Sciences, New York, vol 143, Art 1.
Heelan, Patrick A., (1983) Space-Perception and the Philosophy of Science, Univ. of Calif. Press.
Keller, E. F. (2000) The Century of the Gene, Harvard Univ. Press, Cambridge, Mass.
Kravitz, Edward A. etc. (1974) The Chemistry of Synaptic Transmission, Charon Press, Newton, Mass.
Linde, N. (2001) Cancer Warrior, NOVA, NPB, February 27.
Peirce, C.S. (1955) Philosophical Writings of Peirce, ed. Ed. J. Buchler, Dover, N.Y. (1966) Selected Writings, Ed. P.P. Wiener, Dover, Boston.
Peltonen, Markku (1996) ed. The Cambridge Companion to Bacon, Cambridge Univ. Press. Cambridge, cites Malherbe: from a lower certainty to a higher certainty.
Mayr, Ernst (1982) The Growth of Biological Thought, Harvard University Press.
Rosenfield, Isrdael (1988) Neural Darwinism, etc. New York Review, October 9,
Skinner, B. F. (1957) Verbal Behavior, Appleton-Century-Crofts, N.Y. (Roman Jakobson's aphasia studies, based on Luria's experiments, adopted Skinners non-statistical model of probability.
Stent, Gunther (1969) The Coming of the Golden Age, Natural History Press, Garden City, N.Y.; (1981) Cerebral Hermeneutics, J. Soc. & Bio. Structs., vol. iv, #2.; (1989) The Poverty of Neurophilosophy, XXXXX
Telemerase discovery (1998); Nicholas Wade, Science Times, New York Times, November 17.
Von Wright, G. 1960) A Treatise on Induction and Probability, Littlefield, Patterson, N.J.
Watson, James D. (1968) The Double Helix, Atheneum, N.Y.
Wheeler, Harvey (1987) A Constructional Biology of Hermeneutic Structures of Juegment, Jour. Soc. & Bio. Structs. Vol 10, pp 103-194.
Wheeler, Harvey, (1999) Francis Bacons Verulamium etc., Angelaki, iv, 2, 7-26.
Wheeler, John A. (1994) At Home In the Universe, Amer. Inst. of Physics, Woodbury, N.Y.
William of Occam, 14th century philosopher opposed Thomism and advocated simplification - Occams Razor