Garrod and Thomson, and why they made the screening for inborn errors of metabolism possible

I'm currently preparing a lecture on Personalized Medicine, of course with the impact of mass spectrometry in mind. I have always been fascinated by the history of science, and in particular, the vision of the postulate working without the benefit of today's tools and technology. I decided to indulge my fascination, just this once...

In my preparation for my lecture, it occurred to me that more than 12 million babies per year benefit from screening programs for inborn errors of metabolism, the foundational work for which was undertaken more than a century ago by two contemporaries, who might never have even met each other.

Of course, the methodologies for the screening programs were developed much later by such innovators as Millington, Chase and Roe; but the notion that a disease could be transferred via a monogenetic route was first mooted by A.E. Garrod in 1908. In his landmark Croonian lectures of June that year, he reported his observations of the patterns of heredity in certain disorders. Notably, he spotted the family traits in alkaptonuria patients, their dark urine being easy to spot, though not openly discussed in public! In his subsequent book "Inborn Errors of Metabolism" - a term still used today in metabolic medicine - he said:

"the progress of chemical physiology is teaching us that behind a superficial uniformity there exists a diversity which is no less real than that of [physiological] structure, although it is far less obvious".

The striking part of this statement is that it could equally have been written today by some leader in metabolomics, proteomics, etc. Garrod realised that during the progression of any disease, there must surely be some small chemical difference between a healthy person, and an ill one. Although he was unable to prove it, Garrod also understood that the chemical differences are likely to be as a result of disease progression, via an alternative metabolic pathway or accumulated metabolite, rather than necessarily the cause of the outward clinical condition.

As Garrod was a Medic-Scientist, I don't know if he ever met J. J. Thomson, who was principally a physicist, but he would likely have heard of him receiving his Nobel Prize for Physics in 1906. Both men worked in England at this time, at a time when there was more scope for cross-disciplinary curiosity in the scientific community, compared with today's ultra-specialized focus. However, Thomson was clearly influential and an excellent mentor, as 9 of his research assistants (including his son) also received Nobel prizes in chemistry or physics for their respective contributions.

Thomson, of course, is most famous for his work in separating ions, a process which defines a mass spectrometer. His apparatus used a large magnet to deflect a beam of gas-phase ions, and their deflection was indicated on a photographic plate. His work, and that of one of his researchers F. W. Aston, who realised atoms of the same element could have different masses (isotopes), gave the experimental underpinnings for the theoretical treatment of subatomic theory which was also gathering interest at this time.

It is interesting to think of the truly significant building blocks that were needed for this foundation science to make large-scale population screening by mass spectrometry possible. The invention in the 1950s by Wolfgang Paul of non-magnetic quadrupoles for selecting ions was key, as was the invention of microprocessors in the 1970s. The invention of tranputers and improvement in CPU design in the 1980s allowed mass spectrometers to control and acquire data simultaneously.

Electrospray ionisation, developed in the 1960s, and initially ignored, owing to the huge amount of work the vacuum systems had to do (1mL/minute of water becomes 1.25L/minute of water vapour at STP, and much higher volume in the vacuum of a MS) was rediscovered in the 1980s by Fenn's work measuring proteins (rewarded by a share of the Nobel Prize in 2002). Later in that decade, various efforts were made to interface HPLC with mass spectrometry, this required even more processing power. Gradually, as thermospray ionisation was replaced by electrospray ionisation, and vacuum system became more reliable, lower-priced and with higher capacity, the development of mass spectrometers accelerated.

By the 1990s, mass spectrometers no longer needed large control panels to control them, nor a team of physicists to operate them. They could be deployed to tackle real problems, and even become instruments of routine use. They were being manufactured, as opposed to being custom-built, which meant that they could become validated in a routine clinical laboratory.

Just as it is difficult for us to conceive of the enormity of the concepts first discussed by Garrod and Thomson, without the tools and retrospective view that we have, it would have been impossible for them to imagine where we are now. Thousands of mass spectrometers are routinely used Worldwide in healthcare laboratories to screen, diagnose, direct treatment, or to measure circulating drug levels. I expect the future will change how we deploy mass spectrometry in a clinical environment. Already mass spectrometers have been designed to be used in-vivo to aid the surgeon. Microbial typing can be done more quickly and at lower cost using a mass spectrometer than traditional techniques, whilst removing subjectivity. I believe that soon, we will each have a biochemical phenotype/genotype map in each of our medical records, something that can be monitored periodically to detect disease subclinically.

Garrod and Thomson may have been working 70 miles apart, but one hundred years after some of their work, their contributions, and those of many others including those mentioned here, have been unified in the benefit of millions of people every year.

(Footnote: It is not my intention, nor to my benefit to reduce the huge contributions of notable founders of neonatal screening. I mentioned Roe, Millington and Chase here, but I could equally add the pioneering work of Guthrie and so many others. This article is to remind or to inform people of the sizeable contributions of Garrod and Thomson)