UvA-DARE (Digital Academic Repository) Citation analysis of the scientific publications of Britton Chance in ISI citation indexes

development of physical methods to probe it appear to be the connecting thread of the lifelong research of Britton Chance. Furthermore, we generate the journal map and co-authorship map to show the broad scope of research topics and collaborators and the high impacts of the scienti¯c oeuvre of Britton Chance ranging from physics, engineering


Introduction to Britton Chance
, one of the most outstanding scientists in the world in the 20th century, had been a legendary¯gure in the history of science. He was famous for his enthusiasm in sailing due to his family tradition, which brought him the rare experience of catching a big, over 400 lb blue marlin in Caribbean Sea, an Olympic Gold Medal for 5.5 m boat sailing in 1952, and a couple of world championships of sailing in 1960s. However, his talent, enthusiasm and fame were far more distinguished in science. As a teenager, he invented an optoelectric device for ship autosteering, which was later tested satisfactorily for large commercial ships such as the Texas Sun and New England Star in 1930s. Along with these testing trips, he was admitted to the Trinity College of Cambridge University in late 1930s under the mentorship of Glenn Millikan, the son of the Nobel Laureate Robert A. Millikan, who measured the charge of the electron. Eventually, he graduated with two PhDs, one in Physical Chemistry from the University of Pennsylvania in 1940, and one in Physiology from the University of Cambridge in 1942. His PhD thesis was on developing a fast mini stop-°ow device for measuring the kinetics of enzymatic reactions. With such a device, he achieved the¯rst experimental, quantitative demonstration of the existence of Michaelis-Menten enzyme-substrate complex in early 1940s. He was also highly skillful with circuits and electronics. From 1941From -1946, he was recruited to the Radiation Lab in MIT for developing advanced radar systems including anti-aircraft radar SCR584 and airborne radar bomber sight used for¯ghting against Nazi during World War II. He quickly rose to be a member of Steering Committee of the Radiation Lab, leading a large group of physicists with over 200 people. His group taught Presper Eckert how to make key circuits and overcome some technical problems for ENIAC, the world 1st general purpose electronic digital computer at the University of Pennsylvania in 1946. From 1940s till 2010 except a couple of short term leaves, he stayed in the Johnson Research Foundation, Department of Biochemistry and Biophysics at the University of Pennsylvania for seven decades. From 2006 to 2010, he spent half a year annually in research institutions in Asian countries and regions such as Singapore, Mainland China and Taiwan to conduct research and education, helping the development of biophotonics in those places.
His eight decades of scienti¯c research (1926-2010) culminated into numerous scienti¯c discoveries and technological inventions. He had advanced many frontier research¯elds at the time with both the development of new methods/devices and their applications to key biological questions. Apart from the aforementioned enzyme kinetics studies with his mini stop-°ow device, in 1950s, Chance invented the dual-wavelength spectrophotometer which has been widely used for studying turbid biological samples around the world until today. He applied this instrument to extensive investigations on the electron transport in mitochondrial respiration, redox cofactors and metabolic control mechanisms. In 1960s, he¯rst discovered the electronic tunneling process in biological systems. In 1970s, he identi¯ed hydrogen peroxide released by the respiratory chain in mitochondria. From 1970s to early 1980s, he developed the 3D cryogenic redox scanner for imaging tissue redox state and its heterogeneity at submillimeter resolution. In the 1970-1980s, he was also a key player in developing in vivo 31 P-NMR spectroscopy for bioenergetics studies and using X-ray spectroscopy to elucidate the structure-function relation of biomolecules. Since late 1980s, Prof Chance and his collaborators had founded the¯eld of biophotonics by developing in vivo NIR spectroscopy and imaging methods, mainly based on hemoglobin absorption, time-resolved spectroscopy, photon di®usion, etc. These methods have been widely applied in both laboratory and clinic studies for the measurement of blood oxygenation, volume, and°ow, brain activities, muscle functions and cancer detections and diagnosis. The new research directions he developed during the last decade of his life includes developing novel molecular beacons for cancer diagnosis and therapy, predicting cancer aggressiveness by redox scanning, and developing an oral optical metabolometer to detect nutritional status in human subjects. The latter two directions completed the circle of his scienti¯c research since 1950s by utilizing intrinsic optical signals from mitochondria. Among many honors and awards 1

Scientometric Analysis
To commemorate a great scholar and carry on his/ her legacy to future generations, scientometric analysis can be used in addition to anecdotal stories. Scientometric analyses have been utilized to evaluate the achievements of scholars, 2 and usually these scholars have a focus within a speci¯c¯eld. Here we employed several tools to evaluate the scienti¯c contribution of Britton Chance whose career spanning multiple disciplines. Our analysis was based on a dataset downloaded from the ISI Citation Indexes in April, 2013. Articles, reviews and proceeding papers were included with no meeting abstracts. We obtained 1023 publication records in total from 1945 to 2013 including 1236 authors in 266 journals with 17,114 citations.
Publication periods. We try to correlate the annual publication pro¯le of Chance with his research activities. In these 67 years between 1945 and 2012 (age 32-97), average of 15.3 papers were published with 255 citations annually. Note that these numbers underestimate his published manuscripts, because many of his manuscripts were published in places not indexed by ISI Citation Indexes yet. His publications during his graduate studies were not covered by ISI. Moreover, during the time before World War II ended in 1945, he worked in the area of electronic engineering in a secret mission at Radiation Laboratory, thus, most of his works were not published in academic journals. Figure 1 shows the annual number of published manuscripts from 1945-2012. At a glance, there are seven periods of Gaussian distributions over the whole time, and each one seems to represent roughly main subjects of his works. The publications of these periods went up and down, and we found that, for quite a few occasions, the publications of new ideas changed the research direction of Chance and boosted his publication records.
The¯rst Gaussian period (1945)(1946)(1947)(1948)(1949)(1950)(1951)(1952)(1953)(1954)(1955)(1956), peak at 1952) includes a number of applications of the micro stop-°ow method to enzyme-substrate kinetics [3][4][5] and the development of dual beam spectrometer 6 enabling the study of turbid biological samples. With those apparatuses, Chance was active himself in several areas as well as he helped many other research works in various¯elds of physiology, chemistry, biochemistry, enzymology, etc. In 1947, Chance was the¯rst to identify catalase compound I as an intermediate in the reaction of hydrogen peroxide and catalase. 7 In 1955, he published a landmark paper series with G.R. Williams on respiratory enzymes in oxidative phosphorylation. [8][9][10][11] Chance¯nally set his life work into the mitochondrial biochemistry.
The second period (1957-1968) contains a peak at 1959 with the key publications of Chance's lifelong work on metabolic control mechanisms. [12][13][14][15][16][17] The function of mitochondrial energy metabolism was well understood by the kinetic experiments of substrate and products relationships using the double beam spectrometer. The peak at 1959 also came after the¯rst observation of mitochondrial NADH°uorescence 18 by him and Baltsche®sky in 1958 and coincided with the¯rst observation of tissue NADH°uorescence 19 by Chance and Jobsis in 1959. Chance et al. published in 1962 the¯rst in vivo observation of NAD(P)H°uorescence and redox state from the brain and kidney. [20][21][22] As we can see with his work on NADH°uorescence, Chance started with mitochondria followed by tissue and in vivo studies. This group of papers laid down a milestone for bioenergetics research and Chance's later work on the translational and clinical studies. From 1962-1968, Chance continued mitochondrial bioenergetics research on Complex I to IV with optical spectrometers and°uorometers of cytochromes and NADH. His publication peaked again in 1966 coinciding with another landmark discovery by him and DeVoult on the¯rst experimental observation of quantum mechanical electron tunneling in biological system. 23 The importance of this work was recognized later on by a conference of the Royal Society on quantum catalysis in enzymes in 2005. 24 During the valley of 1967-1968, Chance and coworkers identi¯ed oxidized°avoproteins (Fp including FAD) as another source of intrinsic°uorescence from mitochondria, [25][26][27] which contributed to another rebound of publications in the following years.
The 3rd broad period of Chance publication curve from 1969-1977 appears to have the 2nd largest publication peak with studies ranging from NADH,°avoproteins, cytochoromes, calcium uptake to hydrogen peroxide generation. The use of oxidized°a voproteins together with NADH makes the in vivo measurement of redox status (Fp/NADH or Fp/ (FpþNADH)) possible by the°uorescence spectroscopy and imaging. Therefore Chance et al. developed this idea and technologies into translational researches by inventing NADH°uorometery,°y ing spot technology and cryogenic NADH/Fp redox scanning, etc. Still now, these are the only°u orescence signals used clinically, mainly for cancer detection. Chance wrote in his unpublished autobiography regarding the importance of his discovery of the°uorescence of NADH and Fp from mitochondria both in vivo and ex vivo: \. . .This was perhaps the most important discovery of my career because, for the¯rst time, we could obtain optical signals from living mitochondrial tissues. A series of papers, exploring this discovery in the liver, kidney, adrenal gland, and brain, opened a new eld of metabolic research. . .." Indeed, since 1950s Chance kept publishing on NADH and °avoproteins throughout the rest of his life. The work on NADH and°avoproteins, along with his other research work including the studies on cytochromes, 28-30 discovery of the calcium uptake by mitochondria and its e®ects on bioenergetics, 31 discovery of hydrogen peroxide generation by mitochondria, 32 etc., really drove the publication of Chance onto a new level in the subsequent years until late 1970s, with about 20 papers annually.
The 4th period in 1978-1981 is only 4 years, and it is the beginning of three important new directions of publications. The¯rst direction of new publications marked the beginning of Chance's e®ort in developing 31 P-NMR techniques for bioenergetics studies in organs and human body. [33][34][35][36] Chance funded himself to make an NMR machine for studying phosphorous energetics in human subjects including his own leg in vivo. 33,37 The second new direction of publications was about the chemiluminescence 38-40 emitted by the lipid peroxidation process in biological systems, which was the continuation of the interest of Chance on metabolism, redox reactions and free radicals. Chance published his studies on chemiluminescence from late 1970s to mid 1990s. He and coworkers probably provided one of the early experimental evidences for the generation of singlet oxygen in biological processes. [41][42][43] The third source of new publications was the studies 44-48 by Chance and Power et al. using synchrotron radiation X-ray spectroscopy to illustrate structure-function relation for biomolecules including cytochrome oxidase, myoglobin, glyoxalase, etc.
The 5th period of Chance publication (1982-1989) has the highest peak in 1987 with an annual publication of 32 papers. That was on average two papers per three week at the age of 74. That was the period when Chance and Leigh et al.  51 which made it possible to measure scattering and absorption coe±cients in biological tissue. This paper was revolutionary for optical¯elds because it gave birth to the di®usive biomedical photonics.
The last two Gaussian periods of Chance publication (1990-1999 and 2000-2010) are truly optical and more translational periods of Chance's work. Chance, as a founding father of modern biophotonics, had collaborated with A. Yodh and a number of researchers since 1990s to develop NIR spectroscopy and imaging, including time resolved spectroscopy, photon di®usion tomography (PDT), phased array and their biomedical applications to study brain (fNIR), muscle and various diseases such as breast cancer. [52][53][54][55][56][57][58][59][60][61][62][63] Chance et al. also integrated NIR spectroscopy/imaging with magnetic resonance imaging. 58 his temperature jump method that could dissect chemical reactions even more¯nely than Brit's stopped°ow approach, he publicly regretted not being able to share the honor with Britton Chance" (Gottfried Schatz, 2011 http://www.med.upenn.edu/biocbiop/ chance/symposium/schatz/schatz talk.html). For Britton Chance, this was also a period with important new discoveries that were nothing short of importance compared to his¯rst experimental demonstration of the existence of Michaelis-Menten enzyme-substrate complex. He and his coworkers developed the dual-beam spectrometer for biological studies and characterized the electron-transport chain and bioenergetic process in mitochondrial oxidative phosphorylation. They discovered the°uorescence of NADH and°avoproteins from mitochondria and translated these methods to tissue in vivo with many clinical applications. They also discovered the electron-tunneling in biological systems, and ident-i¯ed the calcium uptake and hydrogen peroxide generation by mitochondria. In 1974, Britton Chance was awarded the US National Medal of Sciences. The¯rst leveling phase L1 corresponds to 1973-1976. The third rising R3 phase from 1976 to 1996 includes the original development of phosphorous NMR and di®usive optical spectroscopy and imaging methods, with a slope similar to that of rst phase, followed by the leveling phase L2 from 1997-2001 with over 1500 citations per year on average. The rising phase R4 is from 2002 to 2012 with a slope of 30 citations per year higher than that of R1 and R3.
HistCite analysis. Figures 3 and 4 show the citation analysis results from HistCite TM for top 30 papers with the highest global citations and local citations, respectively. The local citations refer to the citations only by the papers published by Chance himself. The citation relationships among these papers are displayed in these two¯gures. The detailed paper information and the number of citations are also listed in the order of publication years from the oldest to the latest.
For global citation analysis, there are six papers cited by over 1000 times. The No. 1 highest cited paper 76 is a review by Chance et al. in 1979 on hydrogen peroxide metabolism in mammalian organs, with nearly 4000 citations. The fourth highest cited paper 77 is also about hydrogen peroxide, i.e., its generation by mitochondria, general  For local citation analysis, three of the top six highest globally cited papers remain in the top six. They are two papers on respiratory chain/oxidative phosphorylation 8,78 and one on time-resolved optical spectroscopy. 51 The other three ranked within the top six locally cited are all on respiratory chain/ oxidative phosphorylation. 10,80,81 Among the top 30 locally most cited papers, 4 papers are about enzyme assay and kinetic studies, 1 about dual beam spectrometer, 16 about mitochondrial respiration and redox state, 1 about calcium ion uptake by mitochondrion, 5 about NIR imaging and spectroscopy (biophotonics), 4 about in vivo 31 P-NMR. It appears that the studies on mitochondrial metabolism and the related development of optical techniques are most-often cited by Chance himself. From the LCS map (Fig. 4) we can see that these work form the center of the citation tree, with biophotonics and NMR bioenergetics as side lobes linked to the center. This relationship indicates mitochondrial metabolism as a central basis of Chance research rationale and a long-term pursued research goal. During the last 20 years of his life, Chance appeared to have diversi¯ed his research and moved away from this research focus by developing new techniques such as in vivo NIR spectroscopy and imaging. Nevertheless, these new methods, although with many novel applications beyond mitochondrial metabolism, are important for probing and understanding about tissue metabolism.
Diversity of research¯elds and collaborators.  Fig. 5), we can see that the research of Chance covered multiple disciplines ranging from physics, engineering, biology to medicine. Figure 6 provides more detailed information about the top 19 journals with most publications from Chance. Impressively there are 92 papers in Journal of Biological Chemistry, 37 in PNAS, 27 in Nature and 16 in Science. Figure 7 is the coauthor map showing all coauthors with more than 1 publication with Chance. The size of sphere is proportional to the number of papers. We can see S. Nioka, J. S. Leigh, A. Yodh as the top 3 coauthors with the most coauthored papers with Britton Chance.

Discussion and Summary
Note that all the above analysis and discussion are based on the 1023 records collected by ISI citation database in April, 2013. Our own collection of Britton Chance's publication record, which is still an ongoing process, showed over 1500 manuscripts. We may perform additional analysis on this database once it is complete. This may provide a more complete picture about his research activity. Furthermore, considering the tremendously diversi¯ed multi-disciplinary research conducted by Britton Chance, we can only cover some major research topics we are familiar with. The scientometric methods we used have a limited number of angles of perspectives. It is highly possible we fail to disclose many interesting or meaningful connections among the research publications by Chance and his research activities.
In summary, we have presented the¯rst scientometric analysis on a world preeminent scholar Britton Chance, whose research spanned multiple disciplines from physics, engineering, biology to medicine. We try to understand the pro¯les of his annual publications and citations by correlating them with his research activities. We have also summarized some key research areas that Britton Chance had focused and exerted great impact on. Among the diversi¯ed research studies Chance had conducted, metabolism and the development of physical methods to probe it appeared to be the central thread that connected all the dots. We also note that Chance had many excellent collaborators from very diversi¯ed¯elds of science throughout his life, and that had enabled him to make such a great amount of publications with tremendous impact on science.