Editor's note: We are pleased to present the eighth installment in our series, The League of Imaginary Cats. Read more about the Series in our accompanying editorial, and use the navigation links at the top right to catch up.

1957

He is writing.

He is tired. He is always tired these days, but still he must write. So much has been written already, but there is so much more to say...

So tired.

And it is all about him, it is always about him, I, I, I, me, me, mine. It is I, it is always I, it is all about him. What is true and what he wants to be true and what he remembers to be true are one thing, and three things, and nothing.

Will history be kind?

1945

The old man is dead.

What does this mean for him? Can he now, at long last, put right the wrong? Does he no longer have to suffer injustice?

It means that he can tell the truth; hidden these many years, out of –

What?

Respect? Fear?

Uncertain memory?

No, he cannot countenance that. This is what he remembers; this is how it was. The compound that wasn’t a compound.

Not-heparin. Heparphosphatide.

But heparin, nonetheless.

And it was his.

Truth. He will write his truth.

1937

Best’s cronies have been at it day and night. Gordon Murray has been doing experiments – on people! They say the new heparin is purer, and safer; they infused some poor unsuspecting soul for two hours. Two hours!

But it works. He can’t deny it. If the blind are not seeing, the lame at least are walking.

1929

Charles Best is building a lab at the School of Hygiene in Toronto. Not so much a lab as a processing plant, truth be told.

He visits his former boss in the halls of the Institute. Not long for retirement now, he hears; and they might write that perspective of theirs. How he, Jay McLean, was the inspiration behind heparin, how he discovered it out of his desire to be famous.

It’s gone now, the project. Gone for good and the greater good. Out of the lab, and out of the country. This is a good thing, he thinks, of course it is. It could save lives in Sweden, the rest of the world, if Best and the Connaught Farm can only find a better, cheaper source than the livers of dogs.

When he visits Toronto the smell and the arrangement of flasks and tubes tells him it’s not degraded cephalin; not his heparphosphatide, his antithrombin, his heparin. What then, is this substance they are making and using to inhibit coagulation?

It is his heparin.

It must be his heparin.

1922

He reads the paper, with his former boss’s name and with his unmistakable style. He thinks that this is not heparin. Not what he knows as heparin, anyway. There is no nitrogen, and it is not soluble in fat. It is the complete opposite of heparin, but it has the same effect on the blood of dogs.

He is not an author on this paper. He is mentioned, in that he found something in a sample once. But they’ve named it heparin.

It should have been his to name, this heparphosphatide.

1918

Perhaps he shouldn’t have written it up before he was ready. But there is something interesting there, in the fraction he wasn’t working on. Something that stopped blood clotting.

1916

Knowing exactly what went on, and who did what, is difficult. Who is a reliable witness?

---

Heparin

Blood is a remarkable substance.

A liquid that carries nutrients, waste products and the ever-vigilant cells of the immune system around the body, blood rapidly turns into a solid when it leaves its veins and arteries and becomes exposed to bodily tissues or the air outside. This process of solidification – clotting, or coagulation – is executed and controlled by a complex set of reactions and interactions primarily involving the enzyme thrombin and the surface of platelets. The 'coagulation cascade' was first elucidated and described in the 1960s, but remains an active area of research to this day.

As with any biological process, coagulation can and does go wrong. If one of the factors in the cascade is missing, or inactive, or present only at very low levels, then you end up with a bleeding condition such as von Willebrand Disease or haemophilia. If, on the other hand, your blood clots where it shouldn't – while still in the veins and arteries – then you have a thrombotic condition. Depending on where the clot forms and what it does next this can manifest as deep-vein thrombosis, a pulmonary embolism, a stroke or a myocardial infarction (heart attack). These are all pretty serious events and will cause you a great deal of grief – if they don't kill you immediately.

Fortunately, in the past 20 or 30 years we have been able to develop some fairly astounding treatments for thrombotic conditions, and if we can identify somebody as being at risk of a thrombotic event we also have a pretty good chance of stopping it happening (or if we're too late for that, stopping it happening again). For example, if you have a heart attack a cardiologist will be able to open the blocked artery, either by physically pushing aside or flattening the blockage (and sometimes leaving a stent in place to ensure it remains open). The clot itself – whether in the heart or in the brain – might be dissolved pharmacologically using the 'clot-busting' enzyme tissue plasminogen activator.

Antiplatelet drugs, such as aspirin and clopidogrel, stop platelets sticking together and making things worse. Anticoagulants, on the other hand, are drugs that stop clots forming by preventing thrombin from working. These include warfarin and similar agents, bivalirudin, the new oral anticoagulants (apixaban, dabigatran, rivaroxaban, edoxaban and betrixaban), and heparin and its derivatives. Heparin, a natural product, was the first effective pharmacological anticoagulant, and is the basis for low molecular weight heparins and the synthetic fondaparinux. All these antithrombotic drugs are effective in differing ways in differing indications, and have saved or improved countless lives. And there's a story behind each one.

Warfarin, famously, was developed by Karl Link as a rat poison in Depression-era America. It was trialled as a medical anticoagulant to treat heart attacks and strokes after a marine tried (and failed) to commit suicide with it, and became famous when US President Dwight D Eisenhower was treated with it in 1955. Bivalirudin is a synthetic version of the anticoagulant used by medicinal leeches, and the new oral anticoagulants were all designed through now-classical drug discovery pathways to directly inhibit a specific target in the coagulation cascade.

Produced naturally by basophils and mast cells, heparin is one of the oldest drugs in widespread clinical use. But oddly enough, what we know today as heparin is not the compound originally given the name.

In 1916, Jay McLean was a medical student who had saved up enough money to do just a year's research with William Howell, a professor of physiology at Johns Hopkins Medical School in Baltimore. Howell suggested McLean demonstrate that the observed procoagulant (i.e. it promoted clotting) activity of liver cephalin, a fat-soluble phospholipid first isolated from the brain of dogs, was due to cephalin itself and not a contaminant. This was basic biochemistry that would have made a nice little project for a student. But while working on this, McLean accidentally discovered a fat-soluble anticoagulant activity in liver extracts that induced bleeding in dogs – which were commonly used as experimental animals in this field. McLean made a note of this, mentioned it to Howell, and left the lab when he ran out of funds. He returned later, but to work on coagulation rather than anticoagulation – as he thought this would be more important in a time of war.

Howell himself did continue, however, and working with another medical student by the name of L Emmett Holt, in 1918 isolated a different fat-soluble phospholipid anticoagulant, calling it "heparin" (after ηπαρ, Greek for "liver") to indicate its origin.

But if you read Wikipedia, you'll find that heparin is described as having "the highest negative charge density of any known biological molecule". Which to a biochemist sounds very odd indeed, if heparin is a fat-soluble compound. This is a conundrum because highly charged (ionic) compounds are not soluble in lipid (fat). You can try it if you like – stir a teaspoon of salt into a cup of olive oil and see how far you get. So what we know as heparin today cannot be what McLean saw in 1916, nor what Holt and Howell named in 1918.

Can it?

As it turns out, no, it can't. Holt and Howell kept tinkering with dogs' livers and in 1922 presented an aqueous (that is, water-soluble) extraction protocol for heparin. This heparin, further refined with an improved protocol published in 1926, was a polysaccharide (a sugar-based molecule), not a phospholipid, and decidedly not soluble in fat.

Although he didn't patent it, commercialization of Howell's heparin began in 1924. It remained contaminated with impurities however, and caused unpleasant side effects such as headache, fever and nausea. Howell retired in 1931 and didn't do any further research on heparin; the task of making it medically useful fell to Charles Best, who had already contributed to the the Nobel Prize-winning discovery of insulin. And in 1937 Best and colleagues infused a human patient with essentially pure heparin (from cow liver) for two hours, with no ill effects. After that, heparin passed into widespread use as a preventative anticoagulant in surgery and for treating myocardial infarction, deep-vein thrombosis and pulmonary embolism; anywhere, essentially, where an unwanted blood clot might form.

So what of our medical student, McLean? In 1939 he began experimenting with heparin to prevent arterial thromboses associated with endocarditis – although both his patients died from the infection. He had better luck using it to treat gangrene. But the funny thing is, after Howell died in 1945, McLean started publicly proclaiming that he, not Howell, was the true discoverer of heparin. This is despite his failure to isolate anything like what we know as heparin today (or even in 1945).

Some still want to credit him with the discovery of heparin, but is this is pushing matters too far? There may be some mileage in saying that McLean inspired Howell to change the direction of his research (but then again there might not), and in that case McLean may be thought of as the impetus behind the discovery. As James Marcum (according to the Heparin Science website, http://www.heparinscience.com/) puts it slightly more diplomatically, a scientific discovery

“is seldom made by an individual in isolation but often occurs in a community of scholars and their intellectual history or traditions”

But by that logic we might credit Paul Morawitz, who described the action of leech anticoagulant on thrombin in 1905, or John Berry Haycraft who identified the anticoagulant nature of leech saliva in 1884, or even Huang Ti, who wrote about venous thromboembolic disease in the 27^th century before Christ.

McLean sat down to write his own version of events, presumably to explain why he considered himself the discoverer of heparin. Rather inconveniently, he died in 1957, before he could complete his version of the history of heparin. His unfinished account ends

“When I demonstrated new batches to him in vitro, and be became satisfied that it did actually inhibit the coagulation of the serum-plasma test mixture as well as whole blood in vitro, we planned the first in vivo experiment with a dog and administered the heparin intravenously.”

The 'heparin' that was not, it would appear, heparin as we know it.