Poisoning the Poison

A new biologic could save the thousands of people killed by pesticides every year.

By | October 1, 2007

In the year 2000, hospitals in six Turkish cities were flooded by 2,000 students with poisoning symptoms after eating hazelnuts. Fortunately, nobody died. The nuts had been stored for a long time in a grain depot disinfected with an organophosphate (OP) pesticide.

The problem of pesticide poisoning is most acute in developing countries, where workers mix OP pesticides and spray fields without using gloves, goggles, or protective clothing, and then enter sprayed areas without waiting a safe interval. Despite using only 25% of the world's pesticides, these countries are home to 99% of pesticide-related deaths.

It's not just a problem in the developing world: In 1998 in California, all 34 workers fell ill after returning to weed a crop sprayed with an OP pesticide without waiting the recommended 48 hours. One was hospitalized. (Eating food treated with OPs is, of course, not nearly as harmful as swallowing heavily contaminated nuts or walking in newly-sprayed areas.)

A 2005 report on the International Workshop on Secure Access to Pesticides in conjunction with the Annual Congress of the International Association for Suicide Prevention, Durban, South Africa, estimated that there were 3 million cases of pesticide poisoning resulting in as many as 300,000 deaths per year, more than 100,000 of them in China. There's another risk: In rural areas, a significant percentage of people attempting suicide (up to 90%, in Malaysia) use pesticides, and close to 80% of all pesticide-related attempted suicides use OPs. This is a situation that needs some kind of a solution. Enter the military.

OPs are also used as nerve gases such as Sarin, of the infamous Tokyo metro attack. In this context, OPs act as powerful pesticides for people. OPs are cholinesterase inhibitors, interfering with the transmission of signals between nerve cells. Molecularly, all OPs are generally quite similar. Before the first Gulf War, Saddam Hussein converted the Muthanna, Iraq, pesticide factory into a production unit for the OP nerve gases Sarin, Tabun, and VX. The US military currently deploys an atropine-2PAM (2-pyridine aldoxime methylchloride) combination for preexposure prophylaxis and postexposure therapy for OP nerve agents. (Some of you may recall Nicolas Cage stabbing himself in the heart with a syringe-full of antidote after being exposed to Sarin in the 1996 movie, "The Rock"). But this combination has various undesirable side-effects, such as breathing and vision problems.

So researchers are turning to butyrylcholinesterase (BChE), a naturally occurring protein found in human blood that counters the anticholinesterase activity of organophosphates, including those used for agriculture, biowar, and bioterror. Before, BChE could be recovered only in microgram amounts from human blood, but in September 2006 the Annapolis, MD-based biotech PharmAthene was awarded a contract of up to $213 million from the Department of Defense for production of kilogram quantities of recombinant human butyrylcholinesterase (rHuBChE) from the milk of transgenic goats. (I have no ties to PharmAthene, financial or otherwise.)

Preliminary in vivo research suggests that the product's biochemical properties are similar to HuBuChE (Chem Biol Interact, 363:157-8, 2005). Material from PharmAthene does not mention its potential for prophylactic treatment of pesticide workers and for treating poisoned people. The basic mechanism is generic, however, so if the product works against OP nerve gases, could it not also protect people against poisoning from OP pesticides?

Could the benefits be even bigger? New research presented in April at the 8th International Conference on Alzheimer's and Parkinson's Diseases in Salzburg, Austria, from the Hebrew University of Jerusalem, in collaboration with PharmAthene, showed that rBChE dramatically suppresses the formation of intermediary fibrils, believed to play a crucial role in the development of the neurotoxic amyloid plaques that occur in patients with Alzheimer disease. Anticholinesterases are already being used in treating Alzheimer disease; rBChE could be more effective.

In my view, the potential of rHuBChE for prevention and treatment of accidental or intentional exposure to OP pesticides, and of Alzheimer disease, is likely to produce tangible benefits far outweighing its putative military use. It'll take time and money to test the product's effectiveness against pesticides and plaques, and there are obvious challenges associated with making it available to the millions who would need it in developing countries. But wouldn't all that be worth it if it worked?

Jack Woodall is former director of the Nucleus for the Investigation of Emerging Infectious Diseases in the Institute of Medical Biochemistry at Brazil's Federal University of Rio de Janeiro. jwoodall@the-scientist.com


Avatar of: Brian Hanley

Brian Hanley

Posts: 11

October 30, 2007

Since butyrylcholinesterase is a large protein, it has potential for generating an immune reaction when administered exogenously. The recombinant version will match the sequence of most people well enough, but there is variation in sequence in proteins produced in people. Additionally, sometimes the presence of a self protein in unusually large quantities can result in the expansion of B cells against that protein as well. There is also the possibility that administration by one route could lead to a reaction, while administration by another would not, or be much less likely to do so. The fraction of human population likely to have this occur is low, but not zero. If it does happen, there is potential for generating an autoimmune disorder in those people, and having them lose all functional butylcholinesterase completely. \n\nThe effect of such an auto-immune reaction would be minor under normal conditions. Normally, it would cause the appearance of unusual sensitivity to certain muscle relaxants, which is a benign problem. This is a problem that anesthesiologists in the developed world would mostly catch and be able to handle. However, for field workers in developing nations if this occurred it would render them even less capable of dealing with pesticides than they were in the first place. \n\nThis method of helping field workers would still be a good one I think. It can save lives, and perhaps prevent neurological deficits from occurring due to subacute exposures. I know that there is nothing perfectly safe and on balance it is probably overwhelmingly positive. \n\nHowever, there could be problems in some people. It may be worth noting that in some groups (most likely farther removed genetically from the human reference sequence source) due to critical sequence differences (that cause no change in enzymatic activity) the incidence could be higher than in the population as a whole. \n\nIt might be worth considering taking a look at the sequence of this enzyme (and that of other enzymatic therapies) in the ethnic subgroups performing field labor to get a sense for how much variation could be expected. And perhaps, it could be worthwhile to produce recombinant versions using reference sequences from those ethnic subgroups to minimize the appearance of such effects. At this time, most human reference sequences are overwhelmingly northern European. But the human family tree is large, and unfortunately those doing field work in the developing world are the most likely to have larger genetic distance.
Avatar of: Maien


Posts: 1

October 31, 2007

As a layperson, the information forms some troubling questions. \n\n"Enter the military." being the first. Images of production for military purposes, allowing destructive forces even more freedom to act with impunity does not invoke feelings of confidence.\n\nAs the militarys' requirements are satisfied, will a retail version, or a medical version be produced? Where in the process do genetic differences, incur further manufacturing changes and therefore costs.\n\nThere will be directives from the corporate world as to ownership and/or consumerism. Will it be used to support a two (or more) tiered society where 'access' determines the health and quality of life. \n\nWhere is there a herd of "transgenic goats"? Or are appropriate organs /tissue being manufactured to provide a source for this substance? Images of frankenstien factories flood, my sensibilities.\n\nDoes the budget include funds to create the manufacturing and of course further research on other uses for the goat herd. No opportunity should be left unturned for the possibility of a product!! Right? \n\nOf course there should not be any further costs to the environment, in order to 'harvest' from the goat herd. \n\nThis research is being done to solve a real problem. Poisoning from pesticide use. What about using the funds to direct a return to organic farming and green attitudes towards resource use. Benifets begin with the individuals, farming....and hugely impacts greenhouse gas emissions. I am not being simplistic! This is after all, only a comment.\n\nSolving problems lower down, in the 'chain' of production usually creates permanent and more effective results. Ever consider not using the pesticides? I bet all of the genius in the scientific community IS more than capable of finding simpler solutions. The advances of science should benefit first..all of life.... not a corporate elite who are enriched first then decide who, what and how anyone else may be enriched.\n\nI agree that the research must continue. The more we understand, the better positioned we are to create intelligent choices. However, when will science and acaedemia begin to work for 'life' and simpler solutions rather than maintaining the addictive stance it currently employs. The stance of continually, like a fixated ego-centric corporate child, ignoring the 98% of other available possibilities for the applications of their research and understanding.\n\nI am always amazed how a group who purports itself to be more mentally advanced than the majority, continues to function/behave with the attitudes of a recalcitrant 8-12 year old, finally obeying a clearly destructive corporate parent. Can science, rid itself of its addictive and blinkered parent, and grow up? A grown-up science community would be empowered to work freely....rather than focusing on making new 'products' with planned obsolescence. The current 'products' themselves of course always creating even more serious issues, for example ...using pesticides to help a very badly run system rather than fixing the system. \n\nI look forward to a scientific community which finds the courage to grow-up. I suspect that this community will amaze us as it benefits all of humanity. So much more interesting than the current technicians who are focused on production, maintaining a corporate elite. \n\n\n
Avatar of: Dr.Raam, shanthi

Dr.Raam, shanthi

Posts: 43

November 1, 2007

Threat of developing autoimmunity to any recombinant protein either injected or orally consumed is real and the long term effects of such effects should not be minimized. However, it looks like we do have a really potent antidote for OP poisoning and Alzhimers, produced in large quantities, that too with the help of government funds. It is high time we recognize this antidote's potential and conduct studies using animal models; with animals closest to humans in the structural resemblance of the enzyme in question. Most of the crucial questions related to expected and un-expected side effects (short term and long term, generational)could be answered prior to introducing testing of the recombinant enzyme in human clinical trials. Surely, our defence department would be open to that. Remember, the US.Army funding breast cancer research in the 90's?

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