Leading the way in chemical instrumentation

One company, Beckman Coulter, Inc. can claim to have contributed more to this field than most competitors. Andrew Mark looks at what it has achieved.

Dr Beckman with pH meter

The Chemical Heritage Foundation is currently compiling a list of 50 chemical laboratory instruments that changed the twentieth century. Of the 67 nominations, one company, Beckman Coulter, stands out as the major contributor with 17 instruments listed – more than double any other company.

It all began in 1934, when Dr Glen Joseph, a chemist and school friend of Dr Arnold O. Beckman, needed a rugged instrument to measure the acidity of citrus products quickly, directly and accurately. At that time researchers still relied on colour-change reactions like the litmus test, and the only instrument measurements available were cumbersome, requiring a benchtop of equipment using fragile, thin-walled glass electrodes. Dr Beckman came up with a pH meter with thicker-walled electrodes. When the electrodes were placed in the sample, a simple battery was produced. The weak current was proportional to the hydrogen-ion concentration – that is, the acidity or sourness of the sample, this current was amplified by two vacuum tubes so that the signal could be measured on a dial.

The pH meter was the first instrument to apply electronics to direct chemical measurement, and started a revolution in scientific instrumentation. To control the pH meter, Dr Beckman then designed a new precision helical potentiometer, the Helipot. This was widely used during the Second World War in top-secret radar equipment. Beckman’s experience of measuring small electrical currents with the pH meter also provided the basis for monitoring the performance of the first US nuclear reactors.

This was quickly followed by the first competitor – a similar device, the Coleman pH Electrometer. Coleman went on to adapt the electronics of the Electrometer to provide the readout for a simple visible range spectrophotometer. After a series of prototypes, Dr Beckman brought out his own design in 1941 – the famous Beckman Quartz Spectrophotometer.

Baby in oxygen tent with a Beckman oxygen analyser in use

The Model D was the first to incorporate the electronics of the pH meter within the spectrophotometer itself, but the greatest leap came in 1942 when an improved detector, a UV phototube, was incorporated. This Model DU spectrophotometer was the first with full UV capability and integrated electronics, enabling the detection of a broad range of organic and biologically significant molecules. The DU became indispensable for chemical research, allowing investigators to answer new questions in molecular biology, speeding up the pace of research.

The DU had particular impact in the area of vitamins. By the early 1940s researchers knew that vitamin A was an important dietary substance. However, to analyse its content in food, researchers had to feed rats one foodstuff for several weeks and then perform a biopsy. The DU allowed vitamin A levels to be measured directly within minutes. During the Second World War the DU helped identify other important vitamins and assess their content in foods. In 1946, Erwin Chargaff used it to develop the first quantitative micro method for the complete analysis of DNA. The results were used by Watson and Crick in the determination of the double helix structure of DNA.

World War II provided the context for Beckman to develop spectrophotometers further. The USA was cut off from sources of natural rubber, so developing a synthetic source for military tyres was a priority. The US Office of Rubber Reserve approached Beckman’s National Technical Laboratories, to secretly manufacture a powerful infrared spectrophotometer to help chemists with this work. Based on a design supplied by Shell Development, the company manufactured the IR-1 spectrophotometer which helped ensure that a reliable source of synthetic rubber was manufactured for the war effort. It also helped chemists to develop other vital materials, including aviation fuel and explosives.

In 1940 the US government asked Dr Linus Pauling, one of the twentieth century’s greatest chemists, to create an instrument to measure the partial pressure of oxygen in the atmospheres of submarines and high-altitude aircraft. Pauling created an oxygen analyser, in which a delicate glass dumbbell, suspended on an invisible quartz fibre, would twist according to the presence of oxygen. To help manufacture his secret instrument quickly, he turned to Dr Beckman, a former colleague at the Californian Institute of Technology. With Beckman’s aid, hundreds of analysers were produced, and in 1955 the Beckman Mark II Atmospheric Analyser was fitted in the US nuclear submarine fleet.

Another use was found for the analyser, which marked Beckman’s entry into the clinical instrumentation field. Premature babies placed in incubators often went blind because their retinas were damaged by too much oxygen. Doctors used the Beckman oxygen analyser to establish safe levels and resolve the problem.

After the war, scientists turned to investigating life’s basic building blocks. By 1950, Chargaff had discovered that pairs of the four building blocks of DNA appeared in equal amounts but that the amounts differed between species, implying that the sequence was the chemical language of genetics.

Three years later, James Watson and Francis Crick used Chargaff’s findings in their hunt for the chemical structure of DNA. The double helix they identified explained Chargaff’s results and gave new life to the field of molecular biology. Researchers sought to unravel the chemistry of DNA further and to understand its processes. This required an array of powerful new instruments with the first commercial development of an amino acid analyser, automated protein sequencers and a peptide synthesiser. Other new instruments included ion exchange chromatography, paper and capillary electrophoresis, automated DNA sequencers and SNP genotyping systems.

One of the most significant instrumentation developments in understanding the genetic code was the ultracentrifuge, which enabled DNA to be extracted from cells and purified without being damaged. The first analytical ultracentrifuge, the Model E, was developed in 1947 by Edward Greydon Pickels. It was used to first isolate the polio virus, and also enabled Caltech scientists Meselson and Stahl to confirm in 1958 how DNA replicates.

Spinco, the company that Pickels co-founded, was acquired by Beckman in 1955 and the technology became one of the company’s core focuses. Also in the 1950s, Pickels abandoned the schlieren optics he had used in the Model E in favour of a UV absorption optical system, enabling DNA to be studied at one-thousandth of the concentration of previous work.

Subsequent improvements included incorporation of a laser light source to increase the concentration range accessible for measurement, refrigeration, and most recently a high-torque drive system. The latter accelerates and brakes in half the time of conventional drives, delivering higher-speed g-forces with larger volumes. As well as promoting research in molecular biology, the ultracentrifuge aided progress in the understanding of cellular processes by enabling minute quantities of enzymes and other proteins to be isolated and studied.

New instruments and technologies are continually being devised, improved and automated – giving rise to the phrase ‘simplify, automate and innovate’ and the company continues to explore other technologies to aid this. For example, in 1997 Beckman acquired the Coulter Corporation and became Beckman Coulter.

Wallace Coulter had advanced clinical diagnostics and medical research in the 1950s by devising and patenting the Coulter Principle – an electronic, automated method of counting and sizing microscopic particles. This eliminated the need for labour-intensive and, often inaccurate, manual counting of blood cells and became the foundation of Coulter Corporation. Today, the Coulter Principle is relied upon to count and size a myriad of microscopic particles in both medical and industrial applications. The company also introduced automated platelet counts and new statistical blood parameters, as well as automated sample handling, to further reduce labour and improve clinical diagnosis. Later, Coulter developed systems for analysis of cells by flow cytometry and pattern-recognition microscopy. Coulter was also an early pioneer in monoclonal antibodies, which have proven to be extremely potent in the diagnosing and treatment monitoring of cancer, lymphoma and leukaemia.

pH meter with lemons Dr Beckman: ‘If Dr. Joseph hadn’t come in with his lemon juice problem, chances are I never in the world would have thought about making a pH meter’

Although Wallace Coulter invented the Coulter Principle, Joseph Coulter Jr, was a co-inventor of its early implementations. The two brothers shared Dr Beckman’s appreciation of electronic technology and acted on their belief that science should serve humanity. They combined their strengths to improve and provide a broad range of automated instrumentation for both clinical diagnostics and medical research. During the last few years, Beckman Coulter has developed bio robotic systems to automate high-throughput drug screening and the first capillary electrophoresis-based system for automated glycoprotein analysis (P/ACE), with kits to speed up the separation and quantification of highly polar pharmaceuticals, proteins, chiral isomers and basic compounds.

The company continues to expand its research base. Most recently it has signed an agreement for Althea gene expression technologies and acquired the Agencourt Bioscience Corporation, gaining technology for nucleic acid sampling. Sequencing the human genome was simply the next rung on the research ladder after Watson and Crick identified the DNA helix. Understanding the sequence, the proteins it encodes and how that all relates to the biology of a cell and the body itself – and monitoring the processes – are the next challenges. Beckman Coulter is already working on the new tools that will be required for that continuing discovery.

Chemical Heritage Foundation (USA) Nominations 1934  Beckman Acidimeter: First application of electronics to direct chemical measurement 1935 Beckman Model G pH meter: First commercial/general-purpose chemical instrument to utilise electronics 1941  Beckman Model DU Spectrophotometer: First commercial UV-Vis spectrophotometer 1942  Beckman IR-1 Spectrophotometer: First production IR spectrophotometer used in top-secret synthetic rubber and aviation fuel programmes during World War Two for multi-component analysis of C4 isomers 1943  Beckman Oxygen Analyser Models P and D2: First instrumental measurement of the partial pressure of oxygen 1947  Spinco Model E Analytical Ultracentrifuge: First analytical centrifuge to find wide use in science; used to first isolate the polio virus and to confirm the structure of DNA 1950  Spinco Model L Ultracentrifuge: First commercial preparative ultracentrifuge 1953  Spinco Model R Paper Electrophoresis System: First integrated system to separate and quantify serum proteins for clinical diagnostic use 1954 Beckman Model DK-2A UV-Vis-NIR: Early, widely used UV-Vis-NIR spectrophotometer 1956  Model A Coulter Counter: First automated cell counter; changed medicine by increasing the speed and accuracy by which blood counts are made 1958 Beckman Model 120 Amino Acid Analyser: First commercial amino acid analyser 1963 Beckman FT-IR 520 Spectrophotometer: First far-infrared FT-IR spectrophotometer 1968 Beckman Glucose Analyser: First application of a one-minute rate measurement to a clinical chemistry analysis 1970 Beckman Models 800 and 890 Protein Sequencers: First automated protein sequencers 1971  Beckman Peptide Synthesis: First commercial product to enable the synthetic duplication of the structures of important peptides 1978 Beckman Astra: First clinical chemistry analyser to incorporate rate kinetic first-order reactions for one-minute assays of substrates 2000  Beckman P/ACE System 2000 Capillary Electrophoresis: First fully integrated capillary electrophoresis system with auto-sampler and temperature control

By Andrew Mark. Andrew is Marketing Communications Manager for Beckman Coulter UK. He is a biologist by discipline and originally joined Beckman Coulter to specialise in particle characterisation. He is currently a UK technical expert to the ISO committee on particle characterisation methods.