In today's interconnected global environment, products, servicesand information can be almost instantaneously transferred from onepart of the world to another. Unfortunately, this rapidtransmission also exists for the spread of diseases and theproliferation of bioterrorist weapons.
That is one of the reasons why, when Biomedical SciencesProfessor Saul Tzipori of the Cummings Veterinary School was givena $25 million government grant last year to research treatmentagainst the use of botulinum toxin as a bioterrorist weapon, hisgoal was to work "as quickly as possible."
"Botulinum is classified as one of the most dangerous, as wellas one of the most accessible, agents of bioterrorism," saidTzipori, who is the school's Division of Infectious DiseasesDirector. "It's therefore one of the highest priorities forresearch. The weapon can be readily manufactured by a toxin that isproduced in the soil. It's extremely toxic, and even tiny amountssprinkled into food or water can lethally poison
people."
The use of botulinum as a biological weapon dates back at least70 years to Japan's occupation of Manchuria, when it was used by aJapanese biological warfare group to poison prisoners.
Although the 1972 Biological and Toxin Weapons Conventionprohibited offensive research and production of biological weapons,it was later revealed to the U.N. that both Iraq and the SovietUnion continued to develop large quantities of botulinum toxin.Thousands of Russian scientists subsequently sold their research onthe toxin to other countries throughout the world after the fall ofthe Soviet Union.
The perceived threat of violence using biological weapons hasintensified in recent years, as a result of Sept. 11 and thesubsequent anthrax attacks. Concern for national security has alsobeen heightened recently due to reports that four of the countrieslisted by the United States as state sponsors of terrorism - Iran,Iraq, North Korea and Syria - are believed to be developingbotulinum toxin as a weapon.
Although the U.S. worked to develop vaccines for the toxinduring World War II, Tzipori said that the creation of an antitoxintherapy is a much more complicated process, requiring a strategy ofapproaching this research project "from several different fronts atthe same time" in order to effectively develop therapies.
"There are seven different types of toxins, and each one wouldrequire a different type of treatment," he said. "We'll be workingwith this grant over seven years to develop therapies for eachpossible type of toxin."
Tzipori earned his B.A. and Ph.D. in veterinary medicine at theUniversity of Queensland, Australia, and had already establishedhimself as a distinguished researcher of infectious diseases whenhe was recruited to the Veterinary School as an assistant professorin 1991.
Soon after, he was made full professor and helped to found theschool's infectious diseases division, which is now one of thelargest and best-funded research organizations at Tufts.
The development of treatment for botulinum toxin in the event ofa bioterrorist attack is the division's latest research project.Tzipori and his research team have also been involved in researchinitiatives to develop therapies for a dangerous virulent strain ofE. coli known as E. coli O157:H7.
They've also worked on doing the same for a diarrhea-causingprotozoan called Cryptosporidium parvum Type I, which infectsindividuals through contact with contaminated food, water or animalfeces and causes severe diarrhea, and can be deadly to individualswith compromised immune systems, such as people with HIV/AIDS.
Tzipori described this disease as "one of the most notoriousopportunistic infections" that complicates AIDS. With the advent ofretroviral therapy in developed countries, he said, the need fortreatment against opportunistic infections such as Cryptosporidiumand other fungal and viral infections will diminish.
"The use of anti-retroviral therapy improves the immune statusand allows individuals to get rid of opportunistic infectionswithout having to treat the infections themselves," Tziporisaid.
In third-world countries in which there is a lack ofantiretroviral therapy coupled with a generally unsanitaryenvironment, however, Cryptosporidium remains a very serious anddeadly disease, especially among children between two months andthree years of age.
Specific research in this area includes a program in Ugandaresearching two microorganisms - Cryptosporidium and Microsporidium- associated with diarrhea, and identifying and controlling themajor sources of contamination that lead to infection.
Although the division is still working on developing treatment,they have recently succeeded in sequencing the genome ofCryptosporidium.
"If we know the genomic makeup, we can then identify moleculartargets such as enzymes important in metabolic pathways or proteinsinvolved in the attachment of cells," Tzipori said. "We'll be ableto identify analogues that are structurally similar and can competewith the infected enzymes."
Whereas treatment for Cryptosporidium is still a work inprogress, treatment for E. coli is available. The problem,according to Tzipori, is to "get it through the various trials toproduction, and then to commercial use."
The National Institute of Health (NIH) gave the researchdivision a million dollar grant to produce the first ten grams oftreatment, which Tzipori plans to test on adult volunteers "toensure the safety and efficacy of the drug before it can be givento children."
The testing process will take approximately eight to ten months,after which Tzipori's team faces the obstacle of finding a companywilling to pick up the treatment for clinical use.
"The trouble with this treatment is that it affects about 2,000children in the United States, and it is a nasty disease, causingkidney failure, dialysis and death, but it doesn't affect a largeenough population for any company to be willing to invest in it,"Tzipori said.
Tzipori noted that The Food and Drug Administration (FDA)encourages ventures in which companies are "not interested" - suchas those involving drugs against rare diseases and/or diseases thataffect very small populations - by subsidizing the production oftreatment.
"We managed to get money from NIH just to test the drug," hesaid. "Hopefully, when we have gained governmental support, we willbe able to attract companies - once they see that they have nothingto lose."
