Alice Ball (1892-1916) developed the first truly effective treatment for leprosy (Hansen’s disease), but you likely haven’t heard of her. In fact, after her tragic early death, a colleague continued her work and published her findings without giving her credit until another colleague called him out. Even then, it took decades before the University of Hawaii (UH)(then known as the College of Hawaii), where she conducted her groundbreaking work, honored her contributions, despite Ball being the university’s first Black chemist, researcher, and teacher as well as the first woman to earn a master’s degree from UH (in 1915). 

I’m going to start by telling you an overview of Bell’s story, but I’m not going to stop there. I’m going to then go deeper into the science of what she did and found because, well, biochemistry! But more importantly, because she deserves to be remembered for more than just being “forgotten.” Yes, Alice Ball was all those firsts. Yes, she was treated grossly. And these things are really important to call attention to – especially as huge inequities continue to this day. But Alice was more than that. She was a great scientist. And that deserves to be recognized too. 

How often do you see articles headlined “So-and-so becomes the 89th consecutive White man to become a professor at some prestigious institution”? Instead, we’re told about so-and-so’s research. Yet, when we hear about Black scientists, it’s usually because they’re the firsts to hold various positions. I think it’s important to acknowledge that they’re the first because it shines light on just how unequal academia and STEM in general is, but it’s also important not to just treat these Black scientists, who’ve likely worked twice as hard as their White colleagues to get there, as token minorities or historical footnotes or, even worse, proof that “all’s good now – move along, no systemic racism to see here”. I’m so tired of hearing people make excuses for the horrendous actions of White male scientists telling us to focus on the great science they did, while the great science being done by Black scientists (who haven’t done horrendous things) is only mentioned as an afterthought. So, I’m gonna tell you about both.

Ball was born in Seattle in 1892 and received degrees in pharmaceutical chemistry and pharmacy from the University of Washington before pursuing a masters in chemistry from UH. A Hawaiian public health officer, Dr. Harry Hollman, learned about her master’s thesis work extracting the active chemical from awa roots and approached her with a proposition. For years, the oil from chaulmoogra trees had been used as an ointment to treat leprosy, but with limited success. Hollman asked her to work on extracting the active components in the oil to create an injectable medicine. Ball was successful and her work revolutionized leprosy treatment, allowing patients to be discharged from hospitals and released from leper colonies. This treatment would remain standard until the advent of new drugs in the 1940s. https://bit.ly/30Cvx1T 

Despite the unquestionable value of Ball’s work, she almost didn’t receive any credit for it.  After she died before the chance to publish her work, the president of the college, Arthur Dean, continued her work, publishing it without crediting her. (he made a minor tweak, adding an extra step that didn’t seem to really offer any benefit). The techniques she developed became known as “Dean’s method” until 1922, when Dr. Hollman wrote an article exposing the true story, and referring to the method as “Ball’s method”. https://bit.ly/3cZLSAq 

And it wasn’t until 2000 that UH memorialized her with a dedication plaque at the base of the campus’s sole chaulmoogra tree, largely due to the detective work and advocacy of Paul Wermager, a retired Science/Technology Reference Department Head at UH, and colleagues (and Dean still has a whole building named after him….just sayin’…). In 2007, UH awarded Ball a posthumous Medal of Distinction, and they later announced a scholarship in her honor. In 2000, Hawaii declared February 29 as Alice Ball Day and she receives a lot more attention in Hawaii than most places https://bit.ly/30CEF6I 

But I’m hoping more places will start paying attention to her – I was really excited to hear that there’s a new short film about Alice Ball, titled “The Ball Method” that’s going to be released on Amazon Prime in August. It’s written and directed by Dag Abebe, who actually got help from Paul Wermager https://bit.ly/3hj0RZD 

There’s something especially ironic about Ball being “forgotten” for a disease whose victims society basically tried to forget – before Ball, patients with leprosy were usually shunned to leper colonies, and stigma around leprosy continues to this day (yes, leprosy is still a thing, infecting 

over 200,000 people and attacking their skin, nerves, eyes, & limbs). https://bit.ly/3hz0xGi The stigma is deep-seated. People originally thought it was a curse, but then in 1873, a Norwegian doctor named Gerhard Hansen, discovered the bacterium that causes it, Mycobacterium leprae. The disease got the name Hansens disease, and it now had a cause, but still no effective treatment. 

The treatment Ball developed was by no means perfect, and when sulfone antibiotics came along in the 1940s (initially injected and then swallowed) it was quickly replaced. And then that was later replaced by a multi-drug therapy in the 1970s-80s, to get around the problem of drug resistance. So, the treatment Ball developed isn’t used today, but it was used widely in the 1920s-30s and it likely saved lives (and “life” since it allowed leprosy patients to live at home instead of isolated in colonies) and sure as hell beat the previous standard of care.

Chaulmoogra oil had been used in traditional Indian and Chinese medicine for years, isolated from chaulmoogra (Hydnocarpus wightianus) trees. It was often applied as an ointment to the characteristic sores of leprosy patients. But it had limited success and could cause even more irritation. 

Some scientists thought – well, maybe if we could get it inside the body? They tried to get patients to drink it but it was so disgusting that, if they even managed to suppress their gag reflex and swallow it, the patients would just puke it right back out. So doctors tried injecting it. That didn’t work so well either. Totally not the same thing, but imagine someone injecting aloe vera gel under your skin. Instead of just nicely getting blended in with all of your other bodily fluids, the oil would collect in bumps and blisters around the injection site – as if the ones caused by leprosy weren’t enough…

What was going on? It’s “oil” about the oil. You know that saying about oil and water not mixing? Well, it’s true, and it’s due to their chemical makeups. Chemical molecules are made up of atoms (think the individual hydrogens and oxygen in water). And those atoms link together to form molecules by sharing pairs of negatively-charged subatomic particles called electrons. In neutral molecules, the electrons are balanced out by positively-charged protons, but if the spread of the electrons is uneven, even if the molecule is neutral overall there can still be partly-positive & partly-negative regions. Water’s a great example of this phenomenon called “polarity” – oxygen hogs the electrons it shares with the hydrogens, making it partly negative and the hydrogens partly positive. And opposites attract so water molecules stick to one another, which is why you get cool things like surface tension that lets insects walk on water. 

Water will also stick to other partly- or fully-charged things. We call those things “hydrophilic” and water will surround them with a water coat, welcoming them into the water network and thereby “dissolving” them, so hydrophilic things tend to be water-soluble. But water won’t stick to things that don’t offer any charge to stick to. Such electrostaticaly neutral molecules are called “hydrophobic” and they’re excluded by the water network. Instead of being dissolved, they’re left to hang out with other hydrophobic things. 

Oil is one of those hydrophobic molecules. Water doesn’t want to hang out with it. And, since our bodies are like 3/4 water, this made administering chaulmoogra oil quite challenging… Doctors could inject it all they wanted, but the watery body fluids weren’t gonna let it join them. So researchers realized they were gonna have to get creative and go straight to the source – the “active ingredients.”

“Chaulmoogra oil” is actually a mix of different oils. All oils are characterized by being hydrophobic and having long hydrocarbon chains. One of the first things scientists scientists noticed when they characterized the oils in “chaulmoogra oil” was that there were rings at the ends of the chains, which is weird. 

There are 2 main oils of this end-ringed type in “chaulmoogra oil” – chaulmoogric oil & hydnocarpic oil (which is just like chaulmoogric oil but its chain is 2 carbons shorter) as well as some other oils. Ball had to come up with a method to separate these different oils (a process called fractionation) and then to convert them into a more soluble form. It only took her a year.

To do this she started by treating the oil with a strong base to isolate the fatty acid salts. Basically, in the oil form there are several chains held together by an “end-cap” molecule called glycerol and if you add something like NaOH you can remove that endcap glycerol to give you the individual chains as fatty acid salts. And then you can add an acid to neutralize the base and get the “free fatty acids” which is much less viscous (gooey) than the oils. This, combined with dissolving it in various alcohols and letting it recrystallize over and over allowed her to get pure fatty acids.

But now she needed to make them less “salty” – the fatty acid forms have a carboxylic acid group (-(C=O)-OH) at the end of their fatty chain (hence the name). This can deprotonate (give up a proton, H⁺) to form a carboxylate (-(C=O)-O⁻). This negatively-charged carboxylate is neutralized by hanging out really close to a positively charged cation like a sodium cation (Na⁺ ) and this combo is a salt. Doctors were worried that this salt form might cause a problem called hemolysis – basically if the salts got into blood cells, the surrounding fluid would try to dilute the salt by sending in some of their water, leading the blood cells to burst. Or at least that’s what I think they’re referring to as their reasoning for going for the esters… https://bit.ly/3dYom8h 

An ester is where you stick something other than an H onto the end of a carboxylate, and ethyl tells you there are 2 carbon/hydrogen groups stuck on. To convert the fatty acids into their ethyl esters, she used ethyl alcohol (aka ethanol). I’m not gonna go too into the details (check out the figure if you’re interested), but basically this let her add a chemical “cap” onto the charged part of the salt that makes it non-charged but still polar and soluble (and injectable) and without all that sodium. (note: from what I could find it looks like the salt form was used too, so I guess that hemolysis wasn’t an issue – sorry I’m trying, but it means digging through a bunch of old papers, some of which I don’t have access too)

Ethyl esters of chaulmoogra oil were actually first purified by Power in 1905 & first manufactured by Bayer and Company in 1908 under trade name “antileprol” – but there wasn’t enough for actual clinical trials. Until Ball came along and figured out a more scalable method. Dean & Hollman used Ball’s method to purify lots of the ethyl esters and then performed a clinical trial to show that it was effective. Thanks to Ball, patients were allowed to get “paroled” from leper colonies.

As for “how” it works – it seems to have something to do with biotin. Biotin is a little carbohydrate (sugar) chain that looks a bit like hydnocarpic acid and is important for bacterial metabolism (making and breaking molecules). And so it might confuse the bacteria. But I can’t find much other than this 1973 paper, so I’m not gonna try to speculate https://bit.ly/2B8VHOY but if you know more, please let me know!

Part of the reason it was hard to find info is that once they found antibiotics that worked better, this chaulmoogra oil stuff was largely forgotten. And, sadly, so was Alice Ball. Although the particulars of Alice’s story are unique, she is far from alone in the multitudes of women scientists, especially women of color, who have been forgotten or ignored by history. Let’s help shine light on the lives of these amazing women and prevent their stories from being buried.

If you want to learn more about all sorts of things: #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0

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