16 ChemMatters, FEBRUARY 2007 http://chemistry.org/education/chemmatters.html

ChemHistory

Imagine you are a 15-year-old returning home fromschool, and you are met at your front door by two offi-cials instead of your parents. You are arrested andthen told to say good-bye to your family, but huggingis not allowed. The armed officials take you to a facility

for a quick physical exam. Afterward, you are sent to anisolated peninsula named Kalaupapa, bounded by verticalcliffs 2,000 feet high and surrounded by a deep ocean.Separated from your family and friends, you are banishedhere for the rest of your life not for what you did but forwhat you have: leprosy!

Your only escape from a lifetime sentence to thiscolony of exiled souls, damned by disease, rests in thehands of a young chemist named Alice Ball. She was thefirst to discover a chemical key that offered millions of suf-ferers the hope of being set free from their medical exile.

The most cursed placeon earth

Jack London called it “the most cursed place onearth” and “the pit of hell” after taking a tour of the colony.Three sides of the peninsula were ringed by jagged, razor-sharp lava rock, making landings impossible. The fourthcliff rose as a two-thousand-foot wall so sheer that wildgoats tumbled from its face.

For 80 years, beginning in 1866, the Hawaiian andlater the American governments forcibly removed morethan 8000 men, women, and children to the remote andinaccessible Kalaupapa settlement on the Hawaiian islandof Molokai. The following is an except from The Colony byJohn Tayman:

Under a law to prevent the spread of lep-rosy, persons suspected of having the diseasewere chased down, arrested, subjected to a cur-sory exam, and exiled. Armed guards forcedthem into the cattle stalls of inter-island shipsand sailed them 58 nautical miles east of Hon-olulu, to the brutal northern coast of Molokai.There, they were dumped on an inhospitableshelf of land of the approximate size and shapeof lower Manhattan, which jutted into the Pacificfrom the base of the tallest sea cliffs in the world.It was, as Robert Louis Stevenson would write,“a prison fortified by nature.” In the early days ofthe colony, the government provided virtually nomedical care, a bare subsistence of food, andonly crude shelter. The patients were judged tobe civilly dead, their spouses granted summarydivorces, and their wills executed as if they werealready in the grave. Soon thousands were inexile, and life within this lawless penitentiary

Alice A. Augusta BallYoung Chemist GaveHope to MillionsBy Paul Wermager and Carl Heltzel

Kalawao main street (on the east side of Kalaupapa) during itsearly years.

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ChemMatters, FEBRUARY 2007 17

came to resemble that aboard acrowded raft in the aftermath of ashipwreck, with epic battles eruptingover food, water, blankets, andwomen. As news of the abject mis-ery spread, others with the diseasehid in terror from the government’sbounty hunters, or violently resistedexile, murdering doctors, sheriffs,and soldiers who conspired to sendthem away.Some tried to escape, only to fall to their

death from the cliff. Others were swept out tosea by the relentless currents.

Back on the mainland, public health andlaw officials rounded up thousands of peopleto be sent to other isolation centers acrossAmerica: North Brother Island (New YorkCity), a locked building next to San Fran-cisco’s City Pest House, Louisiana LeperHome (near New Orleans), Penikese Island inBuzzards Bay (Massachusetts), and Seattle’sDiamond Point.

LeprosyHansen’s disease (renamed after the

Norwegian physician, Gerhard Hansen, whofirst identified the causative bacillus,Mycobacterium leprae) was the scourge ofmankind for centuries. Its contagious, disfig-

uring, and seemingly incurable traits terrifiedpeople across every continent. Fear and igno-rance of the disease closely paralleled theearly days of the AIDS epidemic. Former U.S.Surgeon General Dr. C. Everett Koop noted ina 1989 visit to Kalaupapa, “AIDS is the mod-ern-day leprosy.” The difference betweenthem is that AIDS is caused by a virus, andleprosy is caused by a bacterium.

Leprosy is a chronic disease that affectsthe skin, peripheral nerves, mucus mem-

branes in the respiratory tract, and eyes. It isknown to affect people of all ages from new-borns to the elderly. It is most common inwarm, wet areas in the tropics and subtropics.

Although the disease is known to be con-tagious, the exact mechanism of transmissionof leprosy is unknown. It was thought thatdirect contact between someone with the dis-ease and a healthy person was the only waythe disease spread. Some believe that it maybe spread via the respiratory route. M. lepraewas the first bacterium that was discovered tocause disease in humans. Its size and shaperesembles tubercle bacillus, the pathogenresponsible for tuberculosis.

Though rare in the United States, the disease still surfaces in parts of Texas andLouisiana. Worldwide, there are about600,000 new cases of leprosy reported eachyear.

Early treatmentsDown through the ages, desperate physi-

cians and researchers had tried numeroustreatments to combat the horrible disease,including surgery, diet, X-rays, mercury,arsenic, antimony, copper, dyes, strychnine,

and other esoteric concoctionsadministered as ointments or injec-tions. All failed to cure the disease.

Only one natural substanceseemed to offer relief and improve-ment to some patients suffering fromHansen’s disease.

Chaulmoogra oilSince the 14th century in China and even

earlier in India, chaulmoogra oil was usedwith moderate and inconsistent success tolessen the effects of Hansen’s disease.Obtained from the seeds of the chaulmoogratree, or Taraktogenos kurzii, healers adminis-tered chaulmoogra oil orally or applied it as anointment. One reason for the limited effective-ness of early chaulmoogra treatments resultedfrom a botanical mix-up.

Taraktogenos is from a Greek wordmeaning “confused” and refers to the earlierconfusion between it (the true chaulmoogra)and two other genera, Hydnocarpus or Gyno-cardia, (both false chaulmoogras). The falsechaulmoogra oil lacked several of the essen-tial chemicals found in the true oil. Becausemost of the commercial chaulmoogra on themarket before 1900 was false chaulmoogra,unsuspecting physicians and patients oftenexperienced varying and disappointing resultsfrom chaulmoogra.

Chaulmoogra oil was first introduced toHawaii in 1879 but failed to gain widespreaduse because of its unreliable therapeuticeffects. Physicians and researchers continuedto be frustrated but were also intrigued by themystery of why some patients showedremarkable improvements with chaulmoograoil, while others did not. Originally, the oil wasapplied topically to leprous areas but externalapplication had only limited value in treatingthe disease. An oral remedy was more effec-tive but had an extremely nauseating effect onthe patient. Furthermore, plain chaulmoograhad a bitter, disagreeable taste thus patientswere very reluctant to take it long term.

Scientists around the world searcheddiligently for an effective way to administerchaulmoogra oil as an injection. Earlyattempts with injectable forms of chaul-moogra failed because the oily drug was vir-tually insoluble in water, and so it was painfulwhen injected and created abscesses(lumps). We now know the active con-

stituents of chaul-moogra oil arechaulmoogric acidand hydnocarpic acid.These drugs aresolids in their purifiedstate and their rela-tively long, nonpolarhydrocarbon chainsrender them waterinsoluble.

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The disfigured hands of a patient with Hansen’s disease.

Enter AliceDr. Harry T. Hollmann was the catalyst

who brought the chaulmoogra problem to itschemical solution by selecting the right prob-lem solver: Alice Ball. As Assistant Surgeon atKalihi Hospital in Hawaii where new Hansen’sdisease patients were sent, Dr. Hollmann hadrefused to give up on chaulmoogra’s promise.He’d been a physician at the federally fundedLeprosy Investigation Station when it openedat Kalaupapa in 1909. In his 1922 medicalarticle, he explained how it all began:

“I interested Miss Alice Ball, M.S.,an instructress in chemistry at the Col-lege of Hawaii in the chemical problemof obtaining for me the active agents inthe oil of chaulmoogra. After a greatamount of experimental work, Miss Ballsolved the problem for me by makingthe ethyl esters of the fatty acids foundin the chaulmoogra oil, employing thetechnique herewith described.”

Alice’s solution to the problem involvedpreparing the ethyl esters of the fatty acidspresent in the oil. An ester can be preparedfrom a carboxylic acid by reacting it with analcohol, usually in the presence of anotheracid as a catalyst. An alcohol has an -OH func-tional group, and a carboxylic acid functionalgroup has the general formula -COOH, or-CO2H. The ethyl ester of an acid is formedusing ethanol as the alcohol.

The straight, untreated oil consists of avariety of different esters with very high mol-ecular weights and are highly viscous. Vis-cosity is a measure of a substance’sresistance to flow. A thick liquid like honey ishighly viscous, whereas gasoline is not.Patients described the injections of chaul-moogra oil as burning like fire, and the vis-cous oil moved visibly through the skin like asnake slithering under a sheet. Alice’s ethylesters reduced the viscosity of the bioactivecompounds in the oil. The active acids them-selves are solids, and as mentioned previ-

ously, are not water soluble. When formulat-ing a drug, water solubility is a highly desir-able property for the obvious reason that, ifsoluble, a drug can make its way through thebody (which is mostly water). Many of today’sdrugs are in their salt form. You can preparethe salt of a carboxylic acid by treating it witha base such as sodium hydroxide.

The sodium salts of chaulmoogric andhydnocarpic acids would be water soluble. Butbecause of their size, they would act likesoaps and could cause the undesirable sideeffect of hemolysis (breakdown of red bloodcells) when injected.

It often takes a hero to rescue us fromdesperate times and desperate situations. Inthis case, our heroine was a remarkable youngfemale chemist. Alice Augusta Ball accom-plished what many researchers, chemists, and

pharmacologists working in some of theworld’s most sophisticated and well-equippedlaboratories had been unable to do. At the ageof 24, Alice discovered the first preparation ofa water-soluble, injectable form of chaul-moogra oil for the treatment of leprosy.

Her early yearsAlice Ball was born on July 24, 1892, in

Seattle, WA, to African-American parents.Alice grew up around chemicals. Her grandfa-ther, J. P. Ball, Sr., was a famous photogra-pher and one of the first African Americans inthe United States to learn the art of daguerreo-type (early photographic images were devel-oped on silver-coated glass or copper plates).She probably helped out in the family photogallery, mixing fresh developers and preparing

photographic plates. Her father, mother, andaunt were also photographers.

Alice first came to Hawaii in 1903. Sheaccompanied her family, including her grand-father, who was suffering from arthritis andseeking comfort in Hawaii’s warm climate. In1904, her grandfather died in Honolulu, andshe moved back to Seattle with her family.She attended Seattle High School and earnedexcellent grades, especially in the sciences. Inher four years at the University of Washing-

18 ChemMatters, FEBRUARY 2007

R OH +

O

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alcohol carboxylic acid ester

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NaO R+ H2O+NaOH

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Forming an ester from an alcohol and a carboxylic acid. R and R’ represent two different hydrocarbon groups.

Forming the ethyl ester of chaulmoogric acid

Forming the sodium salt of a carboxylic acid.

Structure of a typical soap.

ChemMatters, FEBRUARY 2007 19

ton, Alice earned two degrees: pharmaceuticalchemistry (in 1912) and pharmacy (in 1914).Before departing to Hawaii for graduateschool, Alice copublished with her pharmacyinstructor a 10-page article “Benzoylations inEther Solution” in the prestigious Journal ofthe American Chemical Society.

After one year of graduate study, AliceBall graduated on June 1, 1915, with her mas-ter’s degree in chemistry from the College ofHawaii (later renamed the University ofHawaii). Her master’s thesis involved the iden-tification of the active constituents of kavaroot. She was the first woman and the firstAfrican American to graduate with a master’sdegree from the college. Alice was also thefirst Black female instructor in the college’schemistry department from 1915 to 1916.

Triumph of spiritReflecting on the tremendous obstacles

and oppressive discrimination that Alice—andall African Americans—faced during thisperiod of history, makes her achievementseven more outstanding. Following the CivilWar, the corrosive Jim Crow laws and theinhumane attitudes they engendered made lifehumiliating and treacherous for Blacks.

We don’t know the setbacks or disap-pointments that Alice experienced in herresearch because no record of her daily workexists. We do know that she taught chemistryclasses and chemistry labs during the day soshe probably conducted the chaulmoograexperiments in her free time. Because shesolved the chaulmoogra puzzle rather quickly—between 1915 and early 1916—we can pre-sume she possessed a brilliant insight andpersistent work ethic.

At the height of her accomplishment, butbefore she could publish her research, Alicetragically became ill. She returned home toSeattle and died on the last day of December1916, at the age of 24. The cause of her early

demise remains unknown becauseher death certificate was altered.

A 1917 newspaper article inthe Honolulu Pacific CommercialAdvertiser may offer a clue: “Whileinstructing her class in September1916, Miss Ball suffered from chlo-rine poisoning.” During this time,ventilation hoods were not amandatory safety feature in labora-tories.

After her untimely death, Dr.Arthur L. Dean, a chemist and Pres-ident of the College of Hawaii, car-ried on Alice’s pioneering work. Alaboratory at the College began pro-ducing large quantities of the new injectablechaulmoogra to supply the numerousrequests for their preparations from all overthe world.

Sadly, Alice never lived to witness theresults of her discovery. In 1918, a Hawaiiphysician reported in the Journal of the Amer-ican Medical Association (JAMA) that 78patients of Kalihi Hospital were released byboard of health examiners after being treatedby chaulmoogra injections. During the fouryears between 1919 and 1923, no newpatients were exiled to Kalaupapa. As late as1936, the Philippine Journal of Science notedthat Hansen’s disease patients treated withchaulmoogra continued to be paroled fromthat country’s Culion Leper Colony.

But like the ebb and flow of life, joy gaveway to sadness as patients began relapsingand ships once again returned to Kalaupapawith their human cargo. It appeared that thedevious bacterium had developed a resistanceto Ball’s chaulmoogra. Some speculated thatpatients who returned to their old homes werereinfected by dormant spores in their environ-ment. Whatever the cause, the disease beganto reclaim old patients and destroy new lives,but with nothing better to offer patients,chaulmoogra remained the standard of careuntil the sulfones (Sulfa antibiotics) weredeveloped in the 1940s.

The injectable form of chaulmoogra oildeveloped by Alice Ball gave hope to thehopeless for almost two decades that one daythey would be reunited with their loved ones.Some say it also offered a new form of hopeto the world. Governments and researchersdon’t like to waste their time and money onhopeless causes. Ball’s chaulmoogra showedthat Hansen’s disease was no longer hope-less. Increased funding for research resulted

in the development of the sulfones and othereffective treatments for Hansen’s disease.

The Governor of Hawaii issued a procla-mation on February 29, 2000, declaring it“Alice Ball Day.” On the same day, the Univer-sity of Hawaii honored its first woman gradu-ate and pioneering chemist with a bronzeplaque mounted at the base of the lone chaul-moogra tree on campus. In December 2006,the Board of Regents of the University ofHawaii honored Alice’s work and memory withits Regent Medal of Distinction (posthumouslyconferred).

Hopefully, the world will not forget AliceAugusta Ball and how this young African-American chemist, researcher, and instructorovercame impossible odds and racial andgender discrimination to give hope to the mil-lions of banished and forgotten victims ofHansen’s disease.

Paul Wermager is a freelance writer based inHonolulu, Hawaii, and Carl Heltzel is the editor ofChemMatters.

Young girls during the early years at Kalaupapa.

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Kalaupapa National Historical Park was established in 1980.Kalaupapa is still home for many surviving Hansen’s diseasepatients.

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