DU spectrophotometer

DU spectrophotometer

DU Spectrophotometer, National Technical Laboratories, 1947
measuring ultraviolet light absorbed
Inventor(s) Arnold Orville Beckman
Developed National Technical Laboratories
External video
"The Instrument that Made the Ultraviolet Spectrum Visible to Scientists Everywhere", Chemical Heritage Foundation

The DU spectrophotometer or Beckman DU was the first commercially viable scientific instrument for measuring the amount of ultraviolet light absorbed by a substance. This model of spectrophotometer enabled scientists to easily examine and identify a given substance based on its absorption spectrum, the pattern of light absorbed at different wavelengths.[1]:148 National Technical Laboratories (later Beckman Instruments) developed three in-house prototype models (A, B, C) and one limited distribution model (D) before moving to full production with the DU. Introduced in 1941, approximately 30,000 DU spectrophotometers were manufactured and sold between 1941 and 1976.[2][3]

Measuring both the visible and ultraviolet spectra,[4] the model DU spectrophotometer yielded more accurate results, and substantially reduced the time needed to accurately determine the chemical composition of a complex substance from weeks or hours to minutes.[5] The Beckman Ultraviolet-Visible (UV-Vis) DU spectrophotometer was essential to several critical secret research projects during World War II.[6][7] Schmidt credits it with having "brought about a breakthrough in optical spectroscopy".[2] It has been identified as one of the "most essential instruments" of postwar science,[8] and "probably the most important instrument ever developed towards the advancement of bioscience".[9]

Development

The DU was developed at National Technical Laboratories (later Beckman Instruments) under the direction of Arnold Orville Beckman, an American chemist and inventor.[1][10][11][12] Beckman's research team was led by Howard Cary, who went on to co-found Applied Physics Corporation (later Cary Instruments) and become one of Beckman's strongest competitors. Other scientists included Roland Hawes and Kenyon George.[13]

Spectroscopic methods for observing absorption in the visible spectrum were used as early as the 1860s.[14] In 1940, the equipment needed to measure light energy in the visible spectrum could cost a laboratory as much as $3,000, a huge amount.[1]:149 Complicated equipment had to be assembled, and test samples were run through awkward and time-consuming processes to separate them into analyzable components.[11] Further, the spectrum of visible light was not broad enough to enable scientists to examine substances such as vitamin A.[15]

Beckman had already developed a successful pH meter for measuring acidity of solutions. Coleman Instruments had recently coupled a pH meter with an optical phototube unit to examine the visual spectrum (the Coleman Model DM). Rather than depending on a human observer's visual ability, or the development of a photographic plate, to detect wavelengths, phototubes could be used to register and report specific wavelengths. Beckman made it a goal to create an easy-to-use instrument extending into the ultraviolet range.[1]:149–151

Model A

The first prototype Beckman spectrophotometer, the Model A, was created at National Technologies Laboratories in 1940. It used a tungsten light source with a glass Fery prism as a monochromator. An external amplifier from the Beckman pH meter and a vacuum tube photocell were used to detect wavelengths.[11]

Model B

Optical quality quartz crystals

It was quickly realized that the glass prism was not suitable for use with the ultraviolet spectrum, and a quartz prism was substituted instead, resulting in the Model B. In the model B, a tangent bar mechanism was used to adjust the monochromator. The mechanism was highly sensitive and required a skilled operator.[11]

Model C

Three Model C instruments were then built, improving the instrument's wavelength resolution. The Model B's rotary cell compartment was replaced with a linear sample chamber. The tangent bar mechanism was replaced by a scroll drive mechanism,[11] which could be more precisely controlled to reset the quartz prism and select the desired wavelength.[16] With this new mechanism, results could be more easily and reliably obtained, without requiring a highly skilled operator. This set the pattern for all of Beckman's later quartz prism instruments.[11]

Model D

The A, B, and C models all coupled an external Beckman pH meter to the optical component to obtain readouts. In developing the Model D, Beckman took the DC amplifier circuit from the pH meter and combined the optical and electronic components in a single housing, making it more economical.[16] The model D also used a hydrogen lamp as a light source rather than tungsten.[11]

Moving from a prototype to production of the Model D involved challenges. Beckman originally approached Bausch and Lomb about making quartz prisms for the spectrophotometer. When they turned down the opportunity, National Technical Laboratories designed its own optical system, including both a control mechanism and a quartz prism. Large, high optical quality quartz suitable for creating prisms was difficult to obtain. It came from Brazil, and was in demand for wartime radio oscillators. Beckman had to obtain a wartime priority listing for the spectrophotometer to get access to suitable quartz supplies.[11]

The company designed its own hydrogen lamp for the Model D, enclosing an anode in a thin blown-glass window. The instrument's design also required a more sensitive phototube than was commercially available at that time. Beckman was able to obtain small batches of an experimental phototube from RCA for the first Model D instruments. The Model D spectrophotometer, using the experimental RCA phototube, was shown at MIT's Summer Conference on Spectroscopy in July 1941. It was the first model to enter actual production, and only a small number of Model D instruments were sold before it was superseded by the DU.[11]

Model DU

When RCA could not meet Beckman's demand for experimental phototubes, National Technical Laboratories again had to design its own components in-house. With the incorporation of Beckman's own newly developed UV-sensitive phototubes, the Model D became the Model DU UV-Vis spectrophotometer.[11] As he had done with the pH meter, Beckman had replaced an array of complicated equipment with a single, easy-to-use instrument. One of the first "black boxes" used in modern chemical laboratories,[17] it sold for $723 in 1941.[9]

Design

From 1941 until 1976, when it was discontinued, the Model DU spectrophotometer was built upon what was essentially the same design.[9] It was a single beam instrument.[13]:11 The DU spectrophotometers used a quartz prism to separate light into its absorption spectrum and a phototube to electrically measure the light energy across the spectrum. This allowed the user to plot the light absorption spectrum of a substance to obtain a standardized "fingerprint" characteristic of a compound.[1]:151 [18] All modern UV-Vis spectrometers are built on the same basic principles as the DU spectrophotometer.[4]

Use

Beckman DU spectrophotometer in use

The model D and DU spectrophotometer was the first easy-to-use single instrument containing both the optical and electronic components needed for ultraviolet-absorption spectrophotometry.[1]:153 The user could insert a sample, dial up the desired wavelength of light, and read the amount of absorption of that frequency from a simple meter. A series of readings at different wavelengths could be taken without disturbing the sample. Working in both the ultraviolet and the visible regions of the spectrum, the model D produced accurate absorption spectra which could be obtained with relative ease and accurately replicated.[19] The National Bureau of Standards ran tests to certify that the DU's results were accurate and repeatable and recommended its use.[1]:156

The DU spectrophotometer's manual scanning method was extremely fast, reducing analysis times from weeks or hours to minutes. It was accurate in both the visible and ultraviolet spectrums.[4] Advantages included its higher resolution and the minimization of stray light in the ultraviolet region.[9] Although it was not cheap, its price point made it available to most scientists.[8]

Impact

World War II poster encouraged researchers to "Give this job Everything You've got"

Beckman's DU spectrophotometer has been referred to as the "Model T" of scientific instruments. It enabled researchers to perform easier analysis of mixtures of chemicals by quickly taking measurements at more than one wavelength to produce an absorption spectrum describing the complete substance. "This device forever simplified and streamlined chemical analysis, by allowing researchers to perform a 99.9% accurate quantitative measurement of a substance within minutes, as opposed to the weeks required previously for results of only 25% accuracy."[20] Theodore L. Brown notes that it "revolutionized the measurement of light signals from samples".[21]:2 Nobel laureate Bruce Merrifield is quoted as calling the DU spectrophotometer "probably the most important instrument ever developed towards the advancement of bioscience."[9]

Vitamins

Development of the spectrophotometer had direct relevance to World War II and the American war effort. The role of vitamins in health was of significant concern, as scientists wanted to identify Vitamin A-rich foods to keep soldiers healthy. Previous methods of assessing Vitamin A levels involved feeding rats a food for several weeks and then performing a biopsy to estimate ingested Vitamin A levels. In contrast, examining a food sample with a DU spectrophotometer yielded better results in a matter of minutes.[22] The DU spectrophotometer could be used to study both vitamin A and its precursor carotenoids,[23] and rapidly became the preferred method of spectrophotometric analysis.[15][24][25]

Penicillin

The DU spectrophotometer was also an important tool for scientists studying and producing the new wonder drug penicillin.[16] The development of penicillin was a secret national mission, involving 17 drug companies, with the goal of providing penicillin to all U.S. Forces engaged in World War II.[7][26] It was known that penicillin was more effective than sulfa drugs,[26] and that its use reduced mortality, severity of long-term wound trauma, and recovery time.[1]:158 However, its structure was not understood, isolation procedures used to create pure cultures were primitive, and production using known surface culture techniques was slow.[26]

At Northern Regional Research Laboratory in Peoria, Illinois, researchers collected and examined more than 2,000 specimens of molds (as well as other microorganisms).[27] An extensive research team included Dr. Robert Coghill, Dr. Norman Heatley, Dr. Andrew Moyer, lab bacteriologist Mary Hunt,[28][29][30] Frank H. Stodola and Morris E. Friedkin. Friedkin recalls that an early model of the Beckman DU spectrophotometer was used by the penicillin researchers in Peoria.[26] The Peoria lab was successful in isolating and commercially producing superior strains of the mold, which were 200 times more effective than the original forms discovered by Alexander Fleming.[28] By the end of the war, American pharmaceutical companies were producing 650 billion units of penicillin each month.[28] Much of the work done in this area during World War II was kept secret until after the war.[1]:158[7]

Hydrocarbons

The DU spectrophotometer was also used for critical analysis of hydrocarbons in crude oil. A number of hydrocarbons were of interest to the war effort. Toluene, a hydrocarbon in crude oil, was used in production of TNT for military use.[1]:158–159[11] Benzene and butadienes were used in the production of synthetic rubber.[31] Rubber, used in tires for jeeps, airplanes and tanks, was in critically short supply because the United States was cut off from foreign supplies of natural rubber.[1]:158–159[32] The Office of Rubber Reserve organized researchers at universities and in industry to secretly work on the problem.[6] The demand for synthetic rubber caused Beckman Instruments to develop infrared spectrophotometers, which were better suited to measuring wavelengths of hydrocarbons.[1]:159[14]

Enzyme assays and DNA research

Gerty Cori and her husband Carl Ferdinand Cori won the Nobel Prize in Physiology or Medicine in 1947 in recognition of their work on enzymes. They made several discoveries critical to understanding carbohydrate metabolism, including the isolation and discovery of the Cori ester, glucose-1 phosphate, and the understanding of the Cori cycle. They determined that the enzyme phosphorylase catalyzes formation of glucose 1-phosphate, which is the beginning and ending step in the conversions of glycogen into glucose and blood glucose to glycogen. Gerty Cori was also the first to show that a defect in an enzyme can be the cause of a human genetic disease.[33] The Beckman DU spectrophotometer was used in the Cori laboratory to calculate enzyme concentrations, including phosphorylase.[34]

Arthur Kornberg worked with Severo Ochoa, learning the process of enzyme purification of aconitase, and then spent six months in 1947 at the Cori laboratory, "the most vibrant place in biochemistry at that time", before returning to the National Institutes of Health (NIH) in 1948. He too used the DU spectrophotometer.[35]

"The enzyme could be assayed in a few minutes by coupling it to isocitrate dehydrogenase and in measuring the NADH formed using the Beckman DU spectrophotometer, an instrument that transformed biochemistry."[36]

Kornberg and Bernard L. Horecker used the Beckman DU spectrophotometer for enzyme assays measuring NADH and NADPH. They determined their extinction coefficients, establishing a basis for quantitative measurements in reactions involving nucleotides. This work became one of the most cited papers in biochemistry.[36]:115 Kornberg went on to study nucleotides in DNA synthesis, isolating the first DNA polymerizing enzyme (DNA polymerase I) in 1956 and receiving the Nobel Prize in Physiology or Medicine with Severo Ochoa in 1959.[37]

The bases of DNA absorbed ultraviolet light near 260 nm.[16] Inspired by the work of Oswald Avery[38] on DNA, Erwin Chargaff used a DU spectrophotometer in the 1940s in measuring the relative concentrations of bases in DNA.[39]:260, 290–302 Based on this research, he formulated Chargaff's rules.[40] In the first complete quantitative analysis of DNA, he reported the near-equal correspondence of pairs of bases in DNA, with the number of guanine units equaling the number of cytosine units, and the number of adenine units equaling the number of thymine units. He further demonstrated that the relative amounts of guanine, cytosine, adenine and thymine varied between species. In 1952, Chargaff met Francis Crick and James D. Watson, discussing his findings with them. Watson and Crick built upon his ideas in their determination of the structure of DNA.[40]

Biotechnology

Ultraviolet spectroscopy has wide applicability in molecular biology, particularly the study of photosynthesis.[41] It has been used to study a wide variety of flowering plants and ferns[42] by researchers in departments of biology, biology, plant physiology and agriculture science as well as molecular genetics.[43]

Particularly useful in detecting conjugated double bonds, the new technology made it possible for researchers like Ralph Holman and George O. Burr to study dietary fats, work with significant implications for human diet.[44] The DU spectrophotometer was also used in the study of steroids[23][45] by researchers like Alejandro Zaffaroni,[46] who helped to develop the birth control pill, the nicotine patch, and corticosteroids.[47]

Later models

Beckman Model DK1 Ultraviolet Spectrophotometer

The Beckman team eventually developed additional models, as well as a number of accessories or attachments which could be used to modify the DU for different types of work. One of the first accessories was a flame attachment with a more powerful photo multiplier to enable the user to examine flames such as potassium, sodium and cesium (1947).[13]:11[48]

In the 1950s, Beckman Industries developed the DR and the DK, both of which were double-beam ultraviolet spectrophotometers. The DK was named for Wilbur I. Kaye, who developed it by modifying the DU to expand its range into the near-infrared.[13] He did the initial work while at Tennessee Eastman Kodak, and later was hired by Beckman Instruments.[49] The DKs introduced an automatic recording feature. The DK-1 used a non-linear scroll, and the DK-2 used a linear scroll to automatically record the spectra.[49]:21

The DR incorporated a "robot operator" which would reset the knobs on the DU to complete a sequence of measurements at different wavelengths, just like a human operator would to generate results for a full spectrum. It used a linear shuttle with four positions, and a superstructure to change the knobs. It had a moving chart recorder to plot results, with red, green and black dots.[13] The cost of recording spectrophotometers was substantially higher than non-recording machines.[23]

The DK was ten times faster than the DR, but not quite as accurate.[13] It used a photomultiplier, which had introduced a source of error.[49]:21 The DK's speed made it preferred to the DR.[13] Kaye eventually developed the DKU, combining infrared and ultraviolet features in one instrument, but it was more expensive than other models.[49]

The last DU spectrophotometer was produced on July 6, 1976.[50]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Thackray, Arnold; Myers, Jr., Minor (2000). Arnold O. Beckman : one hundred years of excellence. Philadelphia, Pa.: Chemical Heritage Foundation. ISBN 978-0-941901-23-9.
  2. 1 2 Schmidt, Werner (2005). "Introduction to Optical Spectroscopy". Optical spectroscopy in chemistry and life sciences (PDF). Weinheim: Wiley-VCH. pp. 1–11. ISBN 3-527-29911-4. Retrieved 14 March 2016.
  3. ↑ Browne, Malcolm W. (November 10, 1987). "After Decades, Inventor's Work Is Still Felt in the Laboratory". The New York Times. Retrieved 9 March 2016.
  4. 1 2 3 Buie, John (July 13, 2011). "Evolution of UV-Vis Spectrophotometers" (PDF). Lab Manager. pp. 24–25.
  5. ↑ "In Memoriam: Arnold O. Beckman (1900 – 2004)". News and Views. The Scripps Research Institute 4 (18). May 24, 2004. Retrieved 10 March 2016. The spectrophotometer improved biological assays from a process that took weeks and achieved 25 percent accuracy to one that took minutes and achieved 99.9 percent precision.
  6. 1 2 "Beckman Infrared Spectrometer". Rubber Matters: Solving the World War II Rubber Problem. Chemical Heritage Foundation. Retrieved 19 March 2016.
  7. 1 2 3 Sneader, Walter (2005). Drug Discovery: A History. Chichester: John Wiley. p. 294. ISBN 978-0-470-35929-7. The drug exceeded all expectations, but the public were not told since penicillin was classified as a US military secret.
  8. 1 2 "Beckman DU UV-Vis Spectrophotometer and Power Supply". Chemical Heritage Foundation. Retrieved 10 March 2016.
  9. 1 2 3 4 5 Simoni, Robert D.; Hill, Robert L.; Vaughan, Martha; Tabor, Herbert (December 5, 2003). "A Classic Instrument: The Beckman DU Spectrophotometer and Its Inventor, Arnold O. Beckman". Journal of Biological Chemistry 278 (e1). Retrieved 15 December 2015.
  10. ↑ Gallwas, Jerry (2004). "People: Arnold Orville Beckman (1900–2004)". Analytical Chemistry 76 (15): 264 A. doi:10.1021/ac041608j.
  11. 1 2 3 4 5 6 7 8 9 10 11 Belser, Karl Arnold. "Arnold Orville Beckman" (PDF). Karl Belser. Retrieved 10 March 2016.
  12. ↑ Jaehnig, Kenton G. "Finding Aid to the Beckman Historical Collection 1911–2011 (Bulk 1935–2004 )". Chemical Heritage Foundation. Chemical Heritage Foundation Archives. Retrieved 30 October 2015. Click on 'Beckman Historical Collection Finding Aid' to go to full document.
  13. 1 2 3 4 5 6 7 Brock, David C.; Gallwas, Gerald E.; Manning, Robert J. (February 19, 2002). "Interview with Robert J. Manning". Center for Oral History, Chemical Heritage Foundation. pp. 8–14.
  14. 1 2 Morris, Peter J. T.; Travis, Anthony S. (2002). "The role of physical instrumentation in structural organic chemistry in the twentieth century". In Morris, Peter J. T. From classical to modern chemistry : the instrumental revolution. Cambridge: Royal Society of Chemistry in assoc. with the Science Museum. pp. 57–84. ISBN 978-0-85404-479-5.
  15. 1 2 Rosenfeld, Louis (1997). "Vitamine—vitamin. The early years of discovery". Clinical Chemistry 43 (4): 680–685. Retrieved 17 March 2016.
  16. 1 2 3 4 Smutzer, Gregory (October 15, 2001). "Spectrophotometers: An Absorbing Tale". The Scientist. Retrieved 6 March 2014. The DU spectrophotometer was extensively used in the mass production of penicillin.
  17. ↑ "Visible Proofs: Forensic Views of the Body". National Institutes of Health. Retrieved 14 March 2016.
  18. ↑ Jarnutowski, R.; Ferraro, J. R.; Lankin, D. C. (1992). "Fifty years of commercial instrumentation in absorption spectroscopy, part II. Landmark instruments in UV/vis". Spectroscopy 7: 22–24, 26.
  19. ↑ "Beckman DU Spectrophotometer". National Museum of American History. Retrieved 6 March 2014.
  20. ↑ "Arnold O. Beckman". Massachusetts Institute of Technology. Retrieved 6 March 2014.
  21. ↑ Brown, Theodore L. (2009). Bridging divides : the origins of the Beckman Institute at Illinois. Urbana: University of Illinois. ISBN 978-0-252-03484-8. Retrieved 11 December 2014.
  22. ↑ Mark, Andrew (September 21, 2007). "Leading the way in chemical instrumentation". Laboratory News. Retrieved 6 March 2014.
  23. 1 2 3 Krige, John; Pestre, Dominique, eds. (2003). Science in the twentieth century. London: Routledge. p. 725. ISBN 1-134-40686-X. Retrieved 14 March 2016.
  24. ↑ Sebrell, W. H.; Harris, Robert S. (1954). The Vitamins: Chemistry, Physiology, Pathology. New York: Academic Press. p. 89. Retrieved 14 March 2016.
  25. ↑ Cartwright, Anthony C. (June 28, 2015). The British Pharmacopoeia, 1864 to 2014: Medicines, International Standards and the State. Farnham, Surrey & Burlington, Vermont: Ashgate Publishing, Ltd. ISBN 978-1-4724-2032-9. Retrieved 17 March 2016.
  26. 1 2 3 4 Friedkin, Morris E. (1995). "Growing up in the golden era of intermediary metabolism". Protein Science (Cambridge University Press) 4 (2): 311–325. Retrieved 14 March 2016. The research was part of a national mission: to make penicillin available to all of our forces and by secrecy to prevent its use by Germany and Japan. Within a year, 17 drug companies were working on penicillin.
  27. ↑ Klaus, Abby. "Penicillin: "The Miracle Drug"" (PDF). Illinois Government. Retrieved 14 March 2016.
  28. 1 2 3 Markel, Howard. "The Real Story Behind Penicillin". September 27, 2013. PBS Newshour. Retrieved 6 March 2014.
  29. ↑ Kelly, Norman V. (April 20, 2013). "We called her 'Moldy Mary'". Peoria Historian. Retrieved 14 March 2016.
  30. ↑ "Our View: Penicillin: Another bit of area history deserving notice". Journal Star. October 7, 2010. Retrieved 14 March 2016.
  31. ↑ Henglein, F. A.; Lang, R.F. (1968). Chemical technology (1st English ed.). Oxford: Pergamon Press. ISBN 978-0-08-011848-2. Retrieved 15 March 2016.
  32. ↑ "Rubber Matters". Chemical Heritage Foundation. Retrieved 19 March 2016.
  33. ↑ Smeltzer, Ronald K. (2013). Extraordinary Women in Science & Medicine: Four Centuries of Achievement. The Grolier Club.
  34. ↑ Cori, Carl F.; Illingworth, Barbara (July 15, 1957). "The prosthetic group of phosphorylase". Proceedings of the National Academy of Sciences 43 (7): 547–552. Bibcode:1957PNAS...43..547C. doi:10.1073/pnas.43.7.547. Retrieved 17 March 2016.
  35. ↑ Kornberg, Arthur (January 5, 2001). "Remembering Our Teachers". The Journal of Biological Chemistry 276: 3–11. Retrieved 17 March 2016.
  36. 1 2 Exton, John H. (2013). "Arthur Kornberg". Crucible of science : the story of the Cori Laboratory. New York: Oxford University Press. pp. 112–122. ISBN 978-0-19-986107-1.
  37. ↑ Kresge, Nicole; Simoni, Robert D.; Hill, Robert L. (2005). "Arthur Kornberg's Discovery of DNA Polymerase I". J. Biol. Chem. 280 (46). Retrieved 15 March 2016.
  38. ↑ Avery, Oswald T.; MacLeod, Colin M.; McCarty, Maclyn (February 1, 1944). "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types - Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III" (PDF). Journal of Experimental Medicine 79 (2): 137–158. PMID 19871359. Retrieved 10 March 2016.
  39. ↑ Hunter, Graeme K. (2000). Vital forces the discovery of the molecular basis of life. San Diego: Academic Press. ISBN 978-0-12-361810-8. Retrieved 17 March 2016.
  40. 1 2 Board on Physics and Astronomy, Division on Engineering and Physical Sciences (2006). Instrumentation for a better tomorrow : proceedings of a symposium in honor of Arnold Beckman. Washington, D.C.: National Academies Press. ISBN 978-0-309-10116-5.
  41. ↑ Sandage, Alan (2004). Centennial history of the Carnegie Institution of Washington. 4. Cambridge: Cambridge University Press. p. 127. ISBN 978-0-521-83078-2.
  42. ↑ Ludlow, C. Joseph; Wolf, Frederick T. (April 1975). "Photosynthesis and Respiration Rates of Ferns" (PDF). American Fern Journal 65 (2): 43. doi:10.2307/1546309. Retrieved 17 March 2016.
  43. ↑ Sarkar, Sahotra (2001). The philosophy and history of molecular biology : new perspectives. Dordrecht: Kluwer Academic. p. 54. ISBN 978-1-4020-0249-6. Retrieved 17 March 2016.
  44. ↑ Holman, Ralph T. (1997). "ω3 and ω6 Essential Fatty Acid Status in Human Health and Disease". In Yehuda, Shlomo; Mostofsky, David I. Handbook of essential fatty acid biology biochemistry, physiology, and behavioral neurobiology. Totowa, N.J.: Humana Press. pp. 139–182. ISBN 978-1-4757-2582-7. Retrieved 17 March 2016.
  45. ↑ Weisbart, Melvin (1973). Isolation and purification of hormones. New York: MSS Information Corp. p. 47. ISBN 978-0-8422-7107-3. Retrieved 17 March 2016.
  46. ↑ Kornberg, Arthur (2002). The golden helix : inside biotech ventures. Sausalito, Calif.: University Science Books. p. 62. ISBN 978-1-891389-19-1. Retrieved 17 March 2016.
  47. ↑ Pollack, Andrew (March 6, 2014). "Alejandro Zaffaroni, Entrepreneur on Biotech Frontier, Dies at 91". The New York Times. Retrieved 17 March 2016.
  48. ↑ Gardiner, Kenneth (1956). "Flame photometry". In Berl, Walter G. Physical Methods in Chemical Analysis (3 ed.). New York: Academic Press. pp. 219–290. ISBN 978-1-4832-5563-7. Retrieved 17 March 2016.
  49. 1 2 3 4 Gallwas, Gerald E.; Thackray, Arnold; Kaye, Wilbur I. (February 27, 2002). "Interview with Wilbur I. Kaye". Center for Oral History, Chemical Heritage Foundation.
  50. ↑ Beckman, A. O.; Gallaway, W. S.; Kaye, W.; Ulrich, W. F. (March 1977). "History of spectrophotometry at Beckman Instruments, Inc". Analytical Chemistry 49 (3): 280A–300A. doi:10.1021/ac50011a001. Retrieved 14 March 2016.

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