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The Diarrhea Pioneers

PALO ALTO – On top of the devastation caused in Haiti by the January earthquake, Hurricane Tomas this month, and the subsequent dislocations, exposure, and malnutrition, the country is now experiencing an accelerating cholera outbreak. At least 8,000 people are currently in hospital, and the death toll is near 600 from this waterborne bacterial disease. And, given the widespread unavailability of clean water, basic sanitation, and medical facilities, those numbers are sure to increase.

Even in the absence of natural disasters, diarrhea is the number-two infectious killer of children under the age of five in developing countries (surpassed only by respiratory diseases), accounting for roughly two million deaths a year. However, thanks to a simple but ingenious innovation by an emerging bioscience company, those numbers could become a relic of the past, like mortality from smallpox and bubonic plague.

Since the 1960’s, the standard of care for childhood diarrhea in the developing world has been the World Health Organization’s formulation of rehydration solution, a glucose-based, high-sodium liquid that is administered orally. This low-tech product was revolutionary. It saved countless lives and reduced the need for costly (and often unavailable) hospital stays and intravenous rehydration.

However, this product did nothing to lessen the severity or duration of the condition, which over time leads to malnutrition, anemia, and other chronic health risks. Other approaches to treatments and preventative measures – including changes in public-health policy, improvement of water treatment, and development of vaccines – have not yielded significant, cost-effective results.

The solution (literally and figuratively) may be an ingenious, affordable innovation from Ventria Bioscience that combines high- and low-tech components to deliver what could be a veritable Holy Grail: two proteins produced inexpensively in rice that radically improve the effectiveness of rehydration solutions.

It has been known for decades that breast-fed children get sick with diarrhea and other infections less often than those fed with formula. Research in Peru has shown that fortifying oral rehydration solution with two of the primary protective proteins in breast milk, lactoferrin and lysozyme, lessens the duration of diarrhea and reduces the rate of recurrence.  The availability of such an oral rehydration solution to people in the developing world would be a near-miraculous advance.

Ventria joined with researchers at the University of California, Davis, and at a leading children’s hospital and a nutrition institute in Lima, Peru, to test the effects of adding lactoferrin and lysozyme to a rice-based oral rehydration solution. The new brew provides more nutrition than glucose-based oral rehydration solution and tastes better to kids, so they are more likely to drink it.

The researchers found that when lactoferrin and lysozyme are added to solution, the children’s illness is cut from more than five days to 3.7. This improvement is thought to be caused by the antimicrobial effect of lactoferrin and lysozyme, long known to be the primary protective proteins in breast milk.

Moreover, over the twelve-month follow-up period, the children who had received the rice-based solution had less than half the recurrence rate of diarrhea (8% versus 18% in the control sample). This effect is probably caused by the lactoferrin, which promotes repair of the diarrhea-damaged cells of the intestinal mucosa.

What makes this approach to managing diarrhea feasible is Ventria’s invention of a genetic-engineering method that uses rice to produce lactoferrin and lysozyme. This process, dubbed “biopharming,” is an inexpensive and ingenious way to synthesize the large quantities of the proteins that will be necessary. In effect, the rice plants’ inputs are carbon dioxide, water, soil, and the sun’s energy, and its output is a rice kernel containing large amounts of the proteins. The kernel is processed to extract and purify the proteins, which are then used to formulate the improved rehydration solution.

Rice is self-pollinating, so out-crossing – interbreeding with other rice varieties – is virtually impossible. However, to ameliorate even such hypothetical concerns, Ventria has chosen to grow its rice in Kansas, where there are no other rice growers.

The proteins used to supplement the oral rehydration solution have the same structure and functional properties as those in natural breast milk, and the process is analogous to that used routinely for the production of proteins from other organisms, such as bacteria and yeast. The proteins were judged by a regulatory panel of experts to be “Generally Recognized As Safe” (GRAS) for inclusion in food products like oral rehydration solution.

The typical approach prior to commercialization would be a notification to the United States Food & Drug Administration (FDA) that the rice-produced proteins had been determined to be as safe as their natural counterparts. Then, the regulators’ review would take no more than six months.

But, while the first GRAS notification was submitted to FDA in 2004 and was followed by further notifications, the FDA took no action; eventually, Ventria withdrew the notifications in March of this year. Although the company could market the product without the FDA’s approval, the financial risks would be prohibitive.

Researchers at the University of California, Davis, have faced similar regulatory obstacles in attempting to produce lysozyme in the milk of genetically engineered goats. Their solution was to move the project to Brazil, where it is progressing.

Biopharming has brought us to the verge of a safe, affordable solution to one of the developing world’s most pressing health problems. But, thanks to bureaucratic obstructionism, it will come too late for the many who will be stricken with diarrheal diseases in Haiti and other poor countries in the coming weeks and months.

Regulators and public-health authorities should be beating down doors and demanding life-saving products like lactoferrin and lysozyme. Instead, all we hear from them is a deafening silence – and, in Haiti and elsewhere, the silence of the grave.

Henry I. Miller, a physician, molecular biologist, and fellow at Stanford University’s Hoover Institution, was the founding director of the Office of Biotechnology at the US Food & Drug Administration.

Copyright: Project Syndicate, 2010.

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