(The opinions and views expressed in the commentaries and letters to the Editor of The Somerville Times belong solely to the authors and do not reflect the views or opinions of The Somerville Times, its staff or publishers)

By Ian Halim

In biology, little things make big things happen. Take, for instance, the spike protein that projects from the virus that causes COVID-19. Despite a length measured in mere billionths of a meter, it is this spike that allows the virus to attach to our cells and infect them, much like a mosquito extending its long snout to prick us. The spike protein is also the target of the COVID vaccine. Indeed, the mRNA COVID vaccine gives our body instructions so that we can make copies of the protein, get to know it, and thereby recognize the peril when confronted with the actual virus. Virtually everything that happens in living things, in fact – the action of drugs, the genetic information encoded in our DNA, even the flexing of our muscles – is thanks to tiny machine-like structures within us. And the power of penicillin – the first antibiotic, and the subject of this essay – arises from its tiny patterned structure too.

One of the early explorers of the microscopic structures and shapes within us was the English chemist Dorothy Crowfoot Hodgkin. It was her fascination with complex patterns of all kinds, both in chemistry and art, that gave her the passion to uncover these tiny structures – including the penicillin molecule.

In the spring of 1928, as a young woman just about to start college, Hodgkin found herself amidst the magnificent ruins of an ancient city said to have been founded by Alexander the Great. She was visiting Jerash, in Jordan, at the invitation of her archaeologist parents. In her unpublished memoirs, quoted by her biographer Georgina Ferry, she describes arriving at a “great triumphal arch on the open hillside” that looked down upon the ancient ruins, and finding it, “one of the most beautiful places on earth.”

In Jerash that summer, she became ensnared by the patterns in the mosaics on the floors of the Byzantine churches, volunteering for the painstaking work of drafting scaled-down copies, representing each tile with a dot of bright blue, pink, or green paint. From these points of color arise larger shapes and images, like in a pointillist painting, forming interlacing patterns of curves and angles, adorned with ancient Greek text –patterns echoing the geometry of intricate chemical structures.

Returning to study at Oxford, first as a college student, and later as a researcher with her own laboratory, Hodgkin grew more and more captivated by the complexity of microscopic structures. Ultimately, she devoted her work as a chemist to a method called X-ray crystallography – leading teams of scientists that uncovered key biomolecules, not just penicillin, but also cholesterol, insulin, and vitamin B12.

The science of X-ray crystallography is powerful, heady stuff. When an X-ray strikes a crystal, that crystal distorts the incoming radiant energy – a little like a glass prism bending visible light and breaking it into rays the colors of the rainbow. Those distortions in the X-ray beams can be captured in a kind of special photograph. And from those peculiar distortions, imprinted on that image, a scientist may back-calculate the tiny internal structure of the crystal that led to those distortions – almost as a shadow or silhouette betrays a person’s shape. Tiny negatively charged particles called electrons within the crystal’s microstructure cause these distortions, betraying themselves and thus the crystal’s inner composition.

Even as a girl, Hodgkin was fascinated by chemical puzzles, spending “many happy hours” analyzing minerals with a professional prospecting kit given to her by a family friend who was a soil scientist. Later, she would use X-ray crystallography to solve chemical puzzles of a much more demanding sort. In a 1974 interview, Hodgkin recalled that as a young student she had, “a somewhat fantastic dream, in which I imagined myself walking about among the trees and picking the atoms off the trees like great birds.” She was seeing, in her vision, how she would one day probe complex molecules, “of which the structures were still unknown.”

In 1942, during World War II, when the US and the UK were working together to mass produce penicillin for the war, Hodgkin obtained crystals of the drug. Penicillin had only been discovered in 1928, and scientists at the time were still debating its structure. She and her team used penicillin crystals based on three different metals, and then studied how each distorted X-rays differently.

Within any crystal, penicillin-based or otherwise, every microscopic unit is repeated in the same configuration over and over–like the flowers in a wallpaper pattern, but in three dimensions. Crystals of table salt, for instance, are made up of microscopic cubes. X-ray crystallography was a revolutionary force that broke open new frontiers in our understanding of such structures. Two of the first crystals resolved, both in 1913, using this method, were table salt and diamond. But penicillin is a much larger molecule with a more complex structure – and so a much more difficult problem.

That problem is a very consequential one too. The secret as to why penicillin works can only be answered from its microstructure. The drug’s life-saving, bacterial-killing active ingredient is a loop of atoms known as the beta lactam ring. It is this ring that kills bacteria. And not just in penicillin. About half the antibiotics we use today kill bacteria in the same way, relying upon that same, tiny ring shape, embedded within the antibiotic’s molecular structure. So, despite being less than one billionth of a meter wide, the beta lactam ring is a central part of the technology of modern medicine – the thing that makes many antibiotics go, like the transistor in a computer, or the engine in a car. Although, unlike the car engine or transistor, penicillin and its beta lactam ring are originally products of nature, made by the Penicillium mold for its own defense, and only later harnessed by scientists to make copy-cat antibiotics that imitate penicillin and work in the same way.

And we now understand very well how that beta lactam ring works. When bacteria are bombarded by penicillin, they confuse that tiny ring with the building material they use to make their cell walls. Without those cell walls, the tiny living organisms cannot survive, divide, or reproduce. Penicillin mucks up the works. Like a bricklayer reaching for something that looks like a brick only to find that it is a trick brick of foam that sticks to his fingers, the bacterial cells are confused, mistaking penicillin for their own cell-wall-building materials. Their tiny machinery for making cell walls is disturbed, leaving them unable to make or maintain their life-sustaining bacterial “skin” or shell. Once this cellular machinery has been disrupted, bacteria die.

The power of the beta lactam ring is that it imitates the precursors that bacteria use to make their cell walls. Bacteria use a special enzyme to turn these cell wall precursors into finished walls. But instead, penicillin tricks this enzyme and binds to it, locking it up and making it useless. This ties up bacteria’s wall-making kits, preventing them from maintaining and building their cell walls – like the imaginary bricklayers with trick-bricks stuck to their fingers that I described.

Without the ability to make and remake their cell walls, bacteria die. It’s Armageddon for the little bugs trying to get us. The downside of antibiotics is that they usually kill off some of the good bacteria in our guts too, and they can also leave behind the bacteria that are most impervious to their powers – bacteria that are harder to control with antibiotics. This is the problem of antibiotic resistance.

But it is the delicate structure of the penicillin molecule that gives the drug its great power – the structure that Hodgkin helped uncover, with her stupendous X-ray vision. For her work on penicillin and other important biomolecules, in 1964 she was awarded the Nobel Prize in Chemistry. At the Nobel banquet that year, she thanked the committee for “the great happiness” bestowed upon her. While she recognized it was not realistic to wish a Nobel for everyone in the banquet hall, she nevertheless expressed her hope that the scientists of the Swedish Academy, at least, should enjoy the same honor, recalling an Arabic saying she’d learned, to use when one is congratulated: “May this happen also to you.” It is a feature of great happiness that it yearns to be shared.

Physician-scribe and Bagel-Bard-at-large Ian Halim writes about how medicine relates to everything from ethics to botany – aiming to make science accessible to the widest possible audience. Ian earned his PhD in Greek & Latin literature and his MD, both at Columbia University in The City of New York. He now lives in Pittsburgh, where he will begin a sabbatical in July.