Emil Fischer

Chapter 1 · Too Stupid for the Family Business

Euskirchen, and a reagent that made a career

1852 – 1875 · Euskirchen · Bonn · Strasbourg

Hermann Emil Fischer was born at Euskirchen near Cologne in October 1852, the only son of a prosperous merchant.

His father wanted him in the business and tried him in it. Fischer's own account is that his father concluded he was too stupid to be a businessman and had better be a student — a judgement Fischer repeated with some relish for the rest of his life.

He wanted to study physics; his father insisted on chemistry as more useful. He went to Bonn and then, in 1872, to the new German university at Strasbourg, where he worked under *Adolf von Baeyer*.

In 1875, aged twenty-two, he discovered *phenylhydrazine*.

That compound is the key to everything he did afterwards, and it is also what killed him. Sugars are extremely difficult to work with: they are syrupy, reluctant to crystallise, and hard to purify or identify. Phenylhydrazine reacts with a sugar to form an *osazone* — a beautifully crystalline derivative with a sharp melting point and a characteristic crystal form.

Suddenly a sugar could be *handled*: purified by recrystallisation, identified by melting point, and distinguished from its near relatives.

It is also seriously toxic, causing chronic damage to blood, liver and kidneys, and it is a skin sensitiser. Fischer handled it for decades. It ruined his health permanently, producing eczema and gastrointestinal illness that troubled him from his forties on.

He followed Baeyer to Munich, and in 1882 began the work on sugars.

“To use a picture, I would say that enzyme and substrate must fit one another like a lock and key.”

— Emil Fischer, Berichte der deutschen chemischen Gesellschaft (1894)

Why this matters

Phenylhydrazine made the sugars tractable by turning syrups into crystals with sharp melting points — and it destroyed Fischer's health over four decades.

You have the father's verdict and the reagent. What would you ask him?

Ask Fischer

• “Did your father really think you too stupid for business?”
• “Why are sugars so hard to work with?”
• “What does phenylhydrazine do for you?”
• “Did you know what it was doing to your health?”
• “Would you rather have done physics?”

Chapter 2 · Sixteen Sugars, and Which Is Which

Working out glucose in the dark

1884 – 1894 · Erlangen · Würzburg · Berlin

Glucose has the formula C₆H₁₂O₆, and so do fifteen other sugars. They differ only in the *three-dimensional arrangement* around four carbon atoms, each of which can be arranged in two ways — two to the power of four, sixteen possibilities.

Fischer set out to determine which arrangement belonged to which sugar, and did it with no way of seeing a molecule at all.

His tools were three. *Synthesis*: build sugars from simpler compounds and see what you get. *Degradation*: take a sugar apart one carbon at a time, by known reactions, and see what remains. And *optical rotation*: a solution of a sugar rotates the plane of polarised light by a characteristic amount, and mirror-image molecules rotate it by equal amounts in opposite directions.

The reasoning is a chain of eliminations. If sugar A on degradation gives the same product as sugar B, they must share a certain feature. If synthesising by a route that must produce a particular arrangement gives you sugar C, then C has that arrangement. Each experiment removes possibilities until one remains.

It took about a decade, and by 1894 he had assigned structures to glucose, fructose, mannose, galactose and the rest, and synthesised several from scratch.

All of it rested on van 't Hoff's proposal of 1874 that carbon's four bonds point to the corners of a tetrahedron — which makes a carbon with four different groups attached exist in two non-superimposable mirror-image forms, like a left and a right hand.

That is *chirality*, and it is the fact the next chapter depends on.

He received the Nobel Prize in Chemistry in 1902 for this work and for the purines.

Why this matters

Fischer determined the three-dimensional arrangement of sixteen sugars by synthesis, degradation and polarised light, without any means of observing a molecule.

You have sixteen possibilities and no way to look. What is your question?

Ask Fischer

• “How do you determine a shape you cannot see?”
• “What does polarised light tell you about a sugar?”
• “Why are there exactly sixteen?”
• “What does it mean for a molecule to be left-handed?”
• “How long can you follow a chain of eliminations?”

Chapter 3 · The Yeast That Refused

1894, and the evidence behind the lock and key

1894 · Berlin

This is the experiment, and it is worth stating exactly, because the lock-and-key model is usually presented as a helpful picture and it is in fact a conclusion forced by a result.

Fischer had pairs of sugars that are *mirror images* of one another — identical in every chemical respect. Same formula. Same bonds. Same melting behaviour in most cases. Same reactions with every ordinary reagent. The only difference is the arrangement in space, as a left hand differs from a right.

He tested them against yeast preparations.

One member of the pair was *fermented completely*. The other was *left entirely alone* — untouched, unconsumed, as though it were not there.

No ordinary chemistry can distinguish these two substances. They react identically with acids, with bases, with oxidising agents. Yet a yeast preparation consumes one and refuses the other absolutely.

The only property that differs is *shape*. Therefore the agent in the yeast — the enzyme — must be discriminating on shape, which means it must have a shape of its own that one sugar fits and the other does not.

Fischer stated it in 1894: enzyme and substrate must fit one another, to use a picture, like a lock and its key.

That explains enzyme *specificity* — why an enzyme acts on one substance and refuses its near neighbours, which is the defining property of enzymes and the reason a cell can run thousands of reactions independently.

What he did not know is what the enzyme *is*. He assumed some kind of organised substance. That an enzyme is itself a *protein* was proved by James Sumner, who crystallised urease in 1926 — seven years after Fischer's death, and from the very class of molecule Fischer had spent his later years taking apart.

Why this matters

Two sugars identical in every chemical respect, one fermented and one refused, leave shape as the only possible explanation — which is why lock and key is a conclusion, not an image.

You have the pair of mirror images and the yeast. What would you ask?

Ask Fischer

• “How different are the two sugars, really?”
• “Why does shape have to be the explanation?”
• “What did you think an enzyme was made of?”
• “Why does specificity matter to a living cell?”
• “Was 'lock and key' meant literally?”

Chapter 4 · The Peptide Bond

Proteins as chains, and eighteen units built by hand

1899 – 1907 · Berlin

After the sugars Fischer turned to *proteins*, the other class of molecule living things are mostly built from, and the harder problem.

It was known that proteins yield amino acids on hydrolysis. What was not known was how the amino acids are joined, or whether a protein is a definite molecule at all — some held that proteins were colloidal aggregates rather than molecules with a fixed structure.

Fischer established that the amino acids are joined in *chains*, linked by a specific bond formed between the amino group of one and the carboxyl group of the next, with the loss of water. He named it the *peptide bond*.

And then he proved it in the only way he trusted: by *building* them. Working with Ernest Fourneau and others, he synthesised peptides of increasing length — a dipeptide, then longer, eventually reaching an octadecapeptide of *eighteen* amino acid residues in 1907.

That was an extraordinary technical achievement with the methods available, and it settled the argument. If you can build a chain of eighteen amino acids by known reactions and it behaves like a small protein, then proteins are chains of amino acids.

His governing principle throughout was that a substance is understood only when it can be *built*. Argument about structure, he held, is worth nothing beside a synthesis.

He also worked out the structures of the *purines* — the family including uric acid, caffeine, theobromine, adenine and guanine — and synthesised many of them. Adenine and guanine are two of the four bases of DNA, though nobody knew that yet.

He drove his students extremely hard, ran a very large laboratory, and was not much loved for it.

Why this matters

Fischer settled whether proteins are definite molecules by synthesising a chain of eighteen amino acids — proof by construction rather than by argument.

You have the chain and the eighteen units. What is your question?

Ask Fischer

• “What exactly is a peptide bond?”
• “Why build a chain rather than argue for one?”
• “What made eighteen units so difficult?”
• “What are the purines, and why did they matter?”
• “Were you as hard on your students as they said?”

Chapter 5 · Two Sons, and the End

War work, loss, and a model that had to be softened

1914 – 1919 and after · Berlin

Fischer's health was failing. Decades of phenylhydrazine had left him with chronic gastrointestinal illness and eczema, and he was in increasing discomfort.

When the war came in 1914 he was drawn into it. He organised German chemical resources for the war effort, working on food substitutes and on the supply of raw materials as the blockade tightened. He signed the *Manifesto of the Ninety-Three*, the declaration by German intellectuals defending the German conduct of the war and denying atrocities in Belgium — a document most of its signatories later regretted and which did lasting damage to German science's international standing.

He knew Fritz Haber, and was aware of the chemical weapons programme. His attitude to it was uncomfortable; his own war work was on supply rather than weapons.

He lost *two of his three sons*. One died of typhoid on service in 1916; another, aged twenty-five, took his own life in 1917 after the brutality of military training. His wife Agnes had died in 1895 after seven years of marriage.

The defeat, the loss of his sons, his ruined health and a diagnosis he understood came together. He died in Berlin on 15 July 1919, aged sixty-six. It is generally accepted that he took his own life.

His lock-and-key model has since been *softened* rather than replaced. Daniel Koshland proposed *induced fit* in 1958: the enzyme is not a rigid lock but adjusts its shape as the substrate arrives, and the substrate adjusts too, so that the fit is achieved rather than pre-existing.

That is a genuine correction, and it leaves the essential claim standing. Specificity is a matter of shape, and Fischer proved it with two sugars and a yeast preparation.

Why this matters

The lock-and-key model was corrected by induced fit rather than replaced: the enzyme flexes, but specificity is still a matter of shape.

You have the war, the sons and the model that was softened. What would you ask?

Ask Fischer

• “Why did you sign the Manifesto of the Ninety-Three?”
• “What did the war take from you?”
• “How would you answer induced fit?”
• “What did you make of Haber's work?”
• “Would you have handled the phenylhydrazine differently?”

What Fischer changed

Every school explanation of why an enzyme acts on one substance and ignores another is Fischer's, and the phrase is still his. What makes it a good idea rather than a lucky one is the evidence it came from: two sugars differing only as a left hand differs from a right, and a yeast preparation that consumed one and refused the other. He also determined the structures of the sugars and the purines, and established that proteins are chains joined by the peptide bond.

A debate that continues

The lock-and-key picture is too rigid and was corrected by Koshland's induced-fit model in 1958; and Fischer never knew that an enzyme is itself a protein, which Sumner proved in 1926, seven years after his death.

Keep exploring — ask Fischer

• “Which structure took you longest to settle?”
• “Is building a thing the only way to know it?”
• “What would you have done with X-ray crystallography?”

Related lives

• August Kekulé — Who Gave Carbon Four Hands
• Søren Sørensen — Who Gave Acidity A Number
• Paul Berg — Who Joined Two Genomes, Then Called a Halt
• Rosalind Franklin — The Dark Lady of DNA

Related themes

Enzymes and specificity · Proteins and amino acids · Carbohydrates