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From a new method of drug design to an antiviral agent for herpes, Gertrude Elion's works totally transformed the world of drug development.

Hosted by: Michael Aranda

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Sources:
https://jwa.org/womenofvalor/elion
https://www.youtube.com/watch?v=kamweFBx0iU
https://www.nobelprize.org/prizes/medicine/1988/elion/biographical/
https://www.nobelprize.org/prizes/medicine/1988/press-release/
https://www.pharmaceutical-journal.com/news-and-analysis/infographics/a-history-of-aspirin/20066661.article?firstPass=false
https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html

https://www.ncbi.nlm.nih.gov/pubmed/3538499 or https://journals.sagepub.com/doi/abs/10.1177/074823378600200201?journalCode=tiha
https://www.annualreviews.org/doi/abs/10.1146/annurev.pa.33.040193.000245
https://www.who.int/medicines/publications/essentialmedicines/en/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135445/
http://theoncologist.alphamedpress.org/content/11/9/961
https://www.cell.com/trends/pharmacological-sciences/fulltext/0165-6147(83)90404-2
https://www.nature.com/articles/18790
https://science.sciencemag.org/content/244/4900/41.long
https://theoncologist.alphamedpress.org/content/4/2/0i.short
https://www.cancer.org/cancer/cancer-in-children/types-of-childhood-cancers.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091383/

Image Sources:
https://commons.wikimedia.org/w/index.php?sort=relevance&search=Gertrude+B.+Elion&title=Special:Search&profile=advanced&fulltext=1&advancedSearch-current=%7B%7D&ns0=1&ns6=1&ns12=1&ns14=1&ns100=1&ns106=1#/media/File:Nci-vol-8236-300_Gertrude_Elion.jpg
https://wellcomecollection.org/works/eq42gqut#licenseInformation
https://en.wikipedia.org/wiki/Mercaptopurine#/media/File:Mercaptopurin_ball-and-stick.png
https://en.wikipedia.org/wiki/Aciclovir#/media/File:Aciclovir_ball-and-stick.png
https://en.wikipedia.org/wiki/Zidovudine#/media/File:Zidovudine-3D-balls.png
https://wellcomecollection.org/works/gk2w4hjf#licenseInformation
https://commons.wikimedia.org/wiki/File:Sir_James_W._Black.png

(Intro)

Back in 1944, scientists were only just beginning to suspect that DNA was our genetic material.  That's the year Gertrude Elion first started studying nucleotides, the chemical building blocks that form DNA.  Over the next five decades, Elion became a leading expert on nucleotides and her outside-the-box thinking led to methods that totally transformed the world of drug development, including life-saving therapies we still use today.

Gertrude Elion was born in New York City, in 1918, the daughter of Eastern European immigrants.  The year she finished high school, she watched her grandfather succumb painfully to cancer.  His death inspired her to study chemistry in college and eventually earn a Master's degree.  There weren't a ton of research jobs available during the Great Depression, particularly for a woman, but after World War II broke out, she scored a position in the lab of a guy named George Hitchings. 

Hitchings had this idea that if you could understand a biological process, you should be able to use that information to design chemicals to disrupt that process.  This idea might seem obvious now, but that's just because it's how we like to develop drugs today.  At the time, this rational approach to drug design, as it came to be called, was new and pretty radical.

See, in the mid-1940s, most of the drugs that were avialable were either based on plant compounds that people had been using for millennia, like aspirin, or they'd been discovered by accident, like penicillin, but Elion and Hitchings wanted to take a more deliberate approach, and there were two key reasons why nucleotides seemed like a good place to start.

1) All cells need them to divide, since dividing means doubling your DNA and DNA needs nucleotides, and 2) Certain bad cells like cancer, parasites, and bacteria divide way faster than healthy cells.  This makes them especially hungry for nucleotides.  If you had a way to exploit this hunger, you might be able to fight all those things.

The problem was, nobody knew much of anything about how cells make or use nucleotides.  One of Elion's first assignments at her new job was to start figuring all of this out, so she synthesized a bunch of chemical analogs that were similar to nucleotides, or things that cells needed for making nucleotides.  The idea was to see what cells would do with these imposter compounds.  

Some of the analogs had key chemical differences that made cells unable to use them like normal nucleotides.  They were a biochemical dead end and they would gum up the works, essentially blocking a cell's ability to make DNA or RNA, which is exactly what Elion and Hitchings were looking for in a drug, but they had to make sure it wasn't too toxic to people.

The first breakthrough came in 1951 when Elion synthesized 6-Mercaptopurine, or 6-MP.  It's one of those dead end molecules and it's especially good for stopping out of control immune cells.  It was a huge step forward in treating childhood leukemia and it opened the door to new ideas for treating cancer in general.  In testing 6-MP and related molecules, Elion started to piece together that different cell types and cells from different species responded differently to some analogs and that's the key to making drugs like these work.

Once she found a promising lead, she would design slightly different compounds to try to exploit some of those differences.  Her approach to synthesizing them was novel as well.  On top of that, she was among the first to follow what happened to drugs in the body and use that information to design drugs that were more specific, less toxic, and more effective.

All of these approaches in combination led to lots of new discoveries about nucleotide metabolism and they led Elion to treatments for an incredibly diverse set of problems, including malaria, gout, tissue rejection, and autoimmune diseases.  Later in her career, she showed that it was possible to develop highly effective drugs for viral diseases.  

In the 1960s, most of the research world, including Hitchings, her partner, believed that since viruses use human cells to replicate, it would be impossible to develop a drug that would disrupt viral replication without harming the human host, but Elion proved them wrong in a big way.  She connected the dots between several studies, some hers, some from another lab, and realized that modified nucleotides could block viral replication.  She followed the lead and developed Acyclovir.  It's a compound that interferes specifically with a nucleotide making enzyme from the herpes virus, but not the human version of that same enzyme, and this work paved the way for AZT, the first effective anti-retroviral drug in the fight against HIV and AIDS.  In fact, it was scientists from Elion's research team who developed AZT after her official retirement.

Not only are AZT, 6-MP, and other drugs Elion helped develop still in use today, the World Health Organization counts them among the safest, most effective drugs available, but beyond the drugs themselves, it was Elion and Hitchings' contributions to the process of drug discovery that had the greatest impacts.  Once they showed that their process worked, that you could rationally build drugs from scratch, other drug companies around the world starting using it, and that's what earned them a Nobel Prize.  Elion and Hitchings, along with co-awardee James Black, received the Nobel Prize in Medicine in 1988 for their contributions to the field of drug development.

It's rare that a half-century of toil earns such recognition, but no one can argue that it's not well deserved and as long as we continue to use the drugs she designed, Elion's contributions will continue to improve the lives of people everywhere.

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