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Case File: Mystery of the Black Death

Clues and Evi­dence

For a dis­ease-caus­ing microor­gan­ism to infect the human body there must be a gate­way or por­tal through which it enters into human cells. The plague bac­teri­um works this way, hijack­ing the white blood cells sent to elim­i­nate it. Trav­el­ing inside the white blood cells to the lymph nodes, the bac­te­ria break out and attack the focal point of the human immune sys­tem. Dr. Stephen O’Brien felt that the mutat­ed CCR5 gene, delta 32, may have pre­vent­ed the plague from being able to enter its host’s white blood cells.

Eyam pro­vid­ed O’Brien an ide­al oppor­tu­ni­ty to test this the­o­ry. Specif­i­cal­ly, Eyam was an iso­lat­ed pop­u­la­tion known to have sur­vived a plague epi­dem­ic. Every­one in the town would have been exposed to the bac­teri­um, so it’s like­ly that any life-sav­ing genet­ic trait would have been pos­sessed by each of these sur­vivors. “Like a Xerox machine,” says O’Brien, “their gene fre­quen­cies have been repli­cat­ed for sev­er­al gen­er­a­tions with­out a lot of infu­sion from out­side,” thus pro­vid­ing a viable pool of sur­vivor-descen­dents who would have inher­it­ed such a trait.

Know­ing who died and who lived through the ear­ly years of the plague is some­what prob­lem­at­ic. Deaths among the gen­er­al Eng­lish pop­u­la­tion were not record­ed in the 14th Cen­tu­ry — the height of the Plague — and most com­mu­ni­ties did not begin record­ing parish reg­is­ters until around 1538. For­tu­nate­ly, Eyam began keep­ing a parish reg­is­ter in 1630. Thus his­to­ri­an John Clif­ford began by exam­in­ing the reg­is­ter, not­ing every­one who was alive in 1665, the year the plague came to Eyam. He searched for evi­dence of life through the year 1725 — mar­riages, bap­tisms, buri­als that took place years after the plague had left the vil­lage. Delet­ing the names of those lost dur­ing the plague peri­od, he was able to deter­mine who the sur­vivors were.

DNA sam­ples could only be col­lect­ed from direct descen­dents of the plague sur­vivors. DNA is the prin­ci­pal com­po­nent of chro­mo­somes, which car­ry the genes that trans­mit hered­i­tary char­ac­ter­is­tics. We inher­it our DNA from our par­ents, thus Eyam res­i­dent Joan Plant, for instance, may have inher­it­ed the delta 32 muta­tion from one of her ancient rel­a­tives. Plant can trace her moth­er’s lin­eage back ten gen­er­a­tions to the Black­well sib­lings, Fran­cis and Mar­garet, who both lived through the plague to the turn of the 18th cen­tu­ry. The next step was to har­vest a DNA sam­ple from Joan and the oth­er descen­dants. DNA is found in the nuclei of cells. The amount is con­stant in all typ­i­cal cells, regard­less of the size or func­tion of that cell. One of the eas­i­est meth­ods of obtain­ing a DNA tis­sue sam­ple is to take a cheek, or buc­cal, swab.

After three weeks of test­ing at Uni­ver­si­ty Col­lege in Lon­don, delta 32 had been found in 14% of the sam­ples. This is a genet­i­cal­ly sig­nif­i­cant per­cent­age, yet what, real­ly, did it mean? Could the vil­lagers have inher­it­ed delta 32 from else­where, res­i­dents who had moved to the com­mu­ni­ty in the 350 years since the plague? Was this real­ly a high­er per­cent­age than any­where else? To find out, O’Brien assem­bled an inter­na­tion­al team of sci­en­tists to test for the pres­ence of delta 32 around the world. “Native Africans did not have delta 32 at all,” O’Brien says, “and when we looked at East Asians and Indi­ans, they were also flat zero.” In fact, the lev­els of delta 32 found in Eyam were only matched in regions of Europe that had been affect­ed by the plague and in Amer­i­ca, which was, for the most part, set­tled by Euro­pean plague sur­vivors and their descen­dents.

Mean­while, recent work with anoth­er dis­ease strik­ing­ly sim­i­lar to the plague, AIDS, sug­gests O’Brien was on the right track. HIV, the virus that caus­es AIDS, tricks the immune sys­tem in a sim­i­lar man­ner as the plague bac­teri­um, tar­get­ing and tak­ing over white blood cells. Virol­o­gist Dr. Bill Pax­ton at the Aaron Dia­mond AIDS Research Cen­ter in New York City noticed, “the cen­ter had no study of peo­ple who were exposed to HIV but who had remained neg­a­tive.” He began test­ing the blood of high-risk, HIV-neg­a­tive indi­vid­u­als like Steve Crohn, expos­ing their blood to three thou­sand times the amount of HIV nor­mal­ly need­ed to infect a cell. Steve’s blood nev­er became infect­ed. “We thought maybe we had infect­ed the cul­ture with bac­te­ria or what­ev­er,” says Pax­ton. “So we went back to Steve. But it was the same result. We went back again and again. Same result.” Pax­ton began study­ing Crohn’s DNA, and con­clud­ed there was some sort of block­ing mech­a­nism pre­vent­ing the virus from bind­ing to his cells. Fur­ther research showed that that mech­a­nism was delta 32.

Sci­en­tists study­ing HIV first learned about the gate­way-block­ing capac­i­ty of the CCR5 muta­tion in 1996. Sev­er­al drug com­pa­nies, then, quick­ly began explor­ing the pos­si­bil­i­ty of devel­op­ing phar­ma­ceu­ti­cals that would mim­ic delta 32 by bind­ing to CCR5 and block­ing the attach­ment of HIV. Pre­vi­ous meth­ods of treat­ment inter­fered with HIV’s abil­i­ty to repli­cate after the virus has already entered a cell. This new class of HIV treat­ment, called ear­ly-inhibitor — or fusion-inhibitor — drugs seek to pre­vent the virus from ever attach­ing at all. These phar­ma­ceu­ti­cals are still in rel­a­tive­ly ear­ly stages of devel­op­ment, but cer­tain­ly stand as a hope­ful new method of approach­ing HIV treat­ment.

Orig­i­nal arti­cle: http://www.pbs.org/wnet/secrets/case_plague/p_clues.html


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