I imagine that many readers of this blog are scientists, and might see engineers as pragmatic problem solvers who prefer solid solutions over elegant ones. You are probably right, and I say this as an engineer. But, there is one more thing that engineers do well. They do things at scale.

 

Let me introduce you to the engineering of science, or the art of replicating, streamlining and scaling up a scientific process. When a candidate medical drug has shown initial promising results, one is faced with the challenge of repeating the trick on a larger population. Manual synthesis only gets you so far, and scaling from the milligrams required for in-vitro to the hundreds of grams required for clinical trial quantities poses a formidable challenge even to seasoned researchers. One struggles to even imagine at this point scaling a laboratory process to produce kilograms and even tonnes of the substance, as pipettes are replaced with pipes and dishes with baths. Scaling production is an engineering problem and it is where engineers can help out.

 

The engineering of science is not a solitary hobby, and engineering is more a mindset than a degree classification. Usually, multidisciplinary teams of engineers, physicists, doctors, architects, chemists and other subject matter experts come together to take an idea out of a lab and into the real world. The process is painstaking and can take years. It also requires a mindset shift, from seeking to understand every aspect of a problem in detail to understanding how the problem can be solved given real-world constraints, be it funding, physics or volatile chemicals. And, engineers tend to be quite practical about how they approach this.

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A good example is the establishment of a penicillin manufacturing plant by Imperial Chemical Industries at Trafford Park in May 1942. The history of penicillin is mostly associated with Alexander Fleming’s discovery in September 1928. He left a petri dish with Staph bacteria in his lab at St Mary’s Hospital in London open to the elements while visiting his country home. Coming back, he found that a blue-green mould had grown on the dish and killed the bacteria surrounding it. Fleming and his graduate student verified the antibacterial properties of the mould, testing it on diphtheria bacillus (it worked), typhus (it didn’t) and Haemophilus influenzae, which scientists later learned causes pneumonia and not influenza. He published the results in a paper in 1929. His work appears to have been cited eight times over the following ten years.

 

The story would have ended there, were it not for the chemist Ernst Chain, who was tasked by the doctor Howard Florey at the Dunn School of Pathology to study natural antibacterial agents. Collaborating across disciplines before it was cool, a team of distinguished scientists, chemists and doctors came together to try to produce useful quantities of penicillin and find its medical properties. The team included Ethel Florey, Howard’s wife and a fellow doctor, who was instrumental in developing treatments and Margeret Jennings, a PPE graduate who studied penicillin toxicity in white blood cells. Florey obtained a £6,000 grant from the Medical Research Council to study penicillin for five years. The team quickly managed to grow more blue-green mould using bedpans, but discovered to their dismay that marmite did not make the mould secreting penicillin any faster. Nevertheless, they discovered that the mould could be filtered through parachute silk and dissolved in amyl acetate to prevent it from denaturing, extracted again with sodium hydroxide and freeze-dried to get rid of excess water. This team was nothing if not ingenious.

 

Having obtained pure penicillin, the doctors set to work. Penicillin was found to be extremely effective at killing harmful bacteria in a petri dish, and apparently not toxic to mammals. The many months of refining production processes also meant that the team now possessed hundreds of milligrams of useful penicillin. In May 1940 they proceeded to inject eight mice with streptococcus bacteria, and four with 10mg or 5mg of penicillin. The penicillin mice survived, and the untreated mice did not. This was the start of a revolution.

 

Even though they were reported in the Lancet, the results did not cause much interest at first, but after another team at Columbia replicated the production process and treated two human patients, the “Roquefort mould” miracle cure made it into the New York Times. This was, after all, a time when bacterial infections routinely killed patients. But Florey needed a difficult case to show that penicillin truly was a miracle, and not simply non-toxic. In February 1941, Florey attempted to treat Constable Albert Alexander of the Oxford police force, who unfortunately had both staph and streptococcus infections. The treatment was highly effective and Constable Alexander quickly improved. The doctors were however again woefully short of useful penicillin, and even though they only required 100-200mg per day, and recovered some from the patient’s urine, they still ran out and the patient sadly relapsed and died. Florey resolved to overcome production limits and made a trip to the United States to exchange ideas, returning with a better mould filtration system and contacts at American medical companies. These included a little-known maker of citric acid called Pfizer, whose engineers realised that mass-production of penicillin would change the world.

 

The original penicillin factory was hosted in the animal autopsy room at the Dunn School of Pathology at the University of Oxford, and the final production line involved an ingenious emulsification setup involving a bathtub, steam-heated dustbins, and assorted dairy equipment, including several milk churns and a milk cooler. This MacGyver-style process did, unfortunately, create an ever-present mist of the amyl acetate solvent - a paint solvent and occasional narcotic - meaning scientists could only spend short stints in the production facility. This setup barely passed safety practices for 1941, let alone 21st century health and safety standards.

 

Faced with a promising drug but without the means of making enough of it, Howard turned to Imperial Chemical Industries (ICI) and a smaller firm, Kemball, Bishop and Co, based near where I live in East London. In September 1942 ICI sent 200 (British) gallons, or 900 litres, of “mould filtrate”, that had to be further filtered and purified, but that side-stepped amyl acetate-induced highs at the Dunn School production line and proved to be the first in a series of deliveries by a major chemical company. The accelerated rate of penicillin production allowed Ethel to successfully treat 172 patients, many on death’s door, and convince sceptical Oxford doctors that Penicillin truly was a miracle cure.

 

Further production improvements were made by Pfizer in the US in early 1943. Engineers there re-tooled citric acid-producing submerged fermentation vessels to instead produce penicillin. The Chemical Engineer John McKeen convinced Pfizer’s board to let him start up fourteen 28,400l tanks (7,500 US gallon) tanks. He bet that the submerged fermentation technique, where fermentation happens in fully enclosed vats, would work for penicillin production. He literally bet the company on this gamble, as Pfizer, then a small company, risked bankruptcy from this manoeuvre. But it paid off. By the end of 1943, the company had produced 45 million units of penicillin, enough to give every Allied soldier on D-day their own dose of the miracle cure. Apart from making Pfizer the company we know today, this story shows the transformative effect that good engineering can have on science. From its humble beginnings in a petri dish, Penicillin has been credited with saving over 500 million lives.

 

Penicillin’s break-through only happened through the collaboration of many doctors, scientists, engineers and technicians. Although the drug always showed promise, it was as “temperamental as an opera singer” according to John Smith, Factory Manager at Pfizer. And it required the imagination of chemists and engineers to produce, extract and purify stable penicillin at useful quantities. Good engineering made the science possible, as scientists later developed the concept of antibiotics as a type of medication. This in turn expanded our understanding of fungi, human cells and microbes and their complex interactions. Had we stopped at that single paper in 1929, Sir Fleming would have missed out on 4,500 citations.

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