When Eugene Goldwasser launched the project that would become his life’s work, he thought it would only take a matter of months. Since the early 20th century, biologists had predicted that a hormone they named erythropoietin must exist to promote the production of red blood cells when the body was running low. But in 1955, nobody had found it. Working at the University of Chicago after World War II, Goldwasser was challenged by his mentor, Leon Jacobson, to find erythropoietin, or Epo as it would come to be known.
“Very few biochemists were foolhardy enough to commit themselves to working on this seemingly intractable protein,” wrote Goldwasser, who passed away last week at the age of 88. “My thought was that any reasonably good biochemist ought to be able, in a relatively short time, to purify a hormone with a measurable biological effect.”
It took 22 years. But the purification of Epo, and the hormone’s eventual commercialization as the drug Epogen, ended up being one of the most significant discoveries of its time. A godsend for people struggling with anemia, either directly or as a consequence of kidney failure, cancer, or AIDS, Epo has helped millions of patients avoid blood transfusions that were once a regular part of their disease. A less savory use of Epo, as a performance-boosting drug, led to widespread controversy in the Tour de France in the late 1990’s. The billions of dollars made off of Epogen, and the legal and political battles over that windfall, also made it an important landmark (for better and worse) in the early days of the biotechnology industry.
Goldwasser himself was the recipient of almost none of that fortune, having failed to pursue a patent on the hormone when his purification experiments finally reached fruition in 1977. For him, the pursuit of Epo was pure basic science, and the potential for clinical application, never mind the money to be made off that translation, was a low priority. In a 1996 essay for the journal Perspectives in Biology and Medicine (not online, sadly), Goldwasser wrote about how he was so unconcerned with patenting his discovery, he forgot that he had even tried until discovering an unanswered disclosure form in his files decades later.
“After submitting the form I promptly forgot about it, since nothing was ever done about filing for a patent,” Goldwasser wrote. When the hormones was eventually patented and sold by the company Amgen, Epo brought them well over a billion dollars a year in revenue.
Even in the midst of this boom, Goldwasser was more interested in the scientific history of Epo than its profitability and legal wrangling. The 1996 essay is a gripping narrative of a scientific hunt, riddled with pitfalls and obstacles that Goldwasser and his collaborators were forced to navigate in order to grab hold of the elusive Epo. The biggest obstacle was the hormone itself, which is so effective in promoting red blood cell production that it is only secreted for brief periods and in very small amounts to produce millions of cells. As Merrill Goozner, author of “The $800 Million Pill,” wrote: “the amount of Epo needed to produce that lifetime supply could be dried and formed into a tablet no larger than an aspirin.” Finding such an ephemeral factor and then gathering a quantity large enough to study and replicate it was a gargantuan task, despite Goldwasser’s early confidence.
When Goldwasser began his search, scientists weren’t even sure which organ secreted Epo. So they started with a crude experiment: removing different organs from rats and injecting them with a salt known to induce red blood cell production. When the kidneys were removed, the salt had no effect, leading the researchers to believe they had found their organ (another clue was the anemia often seen in people with chronic kidney disease).
The next step was to find and purify Epo. The obvious place to look was in the blood itself, where over 200 different proteins were candidates for the target hormone. But because Epo is only around when the body needs to produce more red blood cells, Goldwasser and colleagues looked for anemic animals that would presumably be cranking up production of the hormone to compensate. Gathering enough blood plasma from these animals was a problem – rabbits and sheep were tried, but neither could provide enough material for more than a handful of experiments. Years of visiting Chicago-area slaughterhouses and collecting blood plasma from anemic sheep yielded only 200 micrograms of pure Epo – about as much as a dash of salt.
But the project was saved by an unlikely hero: urine. Because Epo was produced by the kidneys, trace amounts would turn up in the urine, so Goldwasser set about the unforgiving task of collecting as many samples as possible of the fluid. The crucial bounty of urine was contributed by a Japanese scientist named Takaji Miyake, who was studying a population of anemic patients in Japan. In 1975, he brought Goldwasser a unique present: 2,550 liters of urine, dried and presented in an elaborately decorated package, according to Goozer’s book.
From that supply, Goldwasser’s laboratory was able to generate a whopping 8 milligrams of pure human Epo, 40 times the amount they purified from the sheep plasma. While still a very small sample – enough to fit in a single test tube – it was enough for Goldwasser and scientists at CalTech to determine the amino-acid sequence of the hormone. Using that code, scientists at the newly-established company Applied Molecular Genetics (now known as Amgen) then found the gene in human DNA, and successfully cloned it, placing it into hamster ovary cells to generate an endless supply of the hormone. Clinical trials of the hormone in anemic patients were an overwhelming success, and the drug Epogen officially came to market in 1987.
The story from there is one of business, politics, and law that would take more than a blog post to explain (Goozer’s book summarizes it vividly in a chapter devoted to Epo’s discovery and commercialization). Goldwasser, while occasionally called upon to give depositions in the many legal battles that ensued over the valuable drug, returned to the less glamorous world of the laboratory, where he continued studying the function of Epo for the rest of his career. Though he lamented that he didn’t receive more of the financial rewards of his discovery, if only to fund the continued work of his laboratory, Goldwasser wrote with great humility about the unexpected benefits of his basic research – and the need for more public funding of such work.
“The enormous clinical success of Epo still astonishes me. The improvements of the quality of life of the thousands of chronic renal disease patients on dialysis who no longer need frequent transfusions, who feel better and are more productive due to their increased red cell mass, cannot be easily calculated,” Goldwasser wrote in the 1996 essay. “It is a particularly impressive example of how basic research can pay a dividend that could not be anticipated at the start, and it is a pity that the lesson still has not been learned by those who control public funding of science.”
[More obituaries are appearing, from the New York Times, the Chicago Tribune, the Los Angeles Times, and Merrill Goozner. A memorial service will be held at the University of Chicago’s Rockefeller Chapel on Monday, January 24th at 4pm.]
Goldwasser E (1996). Erythropoietin: a somewhat personal history. Perspectives in biology and medicine, 40 (1), 18-32 PMID: 8946758