April 2006 Archives

Humans are sometimes challenged by the tiniest things. We continue to fail to control the spread of malaria carried by Plasmodium falciparum, the parasite responsible for the most deadly malaria disease in humans. Although malaria morbidity and mortality is difficult to establish, there are up to 515 million cases yearly, and one to two millions deaths. Disease, death, and significant economic repercussions because mosquitoes that weigh a measly 2.5 mg carry the protist in its sporozoite form until it reaches blood via a bite from the female insect. The parasite completes its lifecycle, invading the hepatocytes of the liver and the red blood cells and causing disease and/or death in its human host.

Acronym Required previously wrote about the challenge of malaria prevention and treatment in Malaria Prevention, Progress in Fits and Spurts. As that 2005 article discussed, Novartis had just revealed that it was again unable to produce the quantities of the drug that it had agreed to in its "private-public partnership" with the World Health Organization. Novartis is the sole manufacturer of the drug Coartem, an artemisin based combination therapy which has proven to be one of the most effective treatments for malaria. In 2004 the company had also fallen short of its production goals, but it had *promised* that 2005 would be different; that it was capable of meeting demand. Both years the company blamed their production failure on few initial orders and shortages of the plant quingtao, indigenous to China, from which arteminsin is derived.

Recently a group of scientists at University of California, Berkeley bioengineered yeast, Saccharomyces cerevisiae, to produce a precursor to arteminisin. The process involves the enzyme amorphadiene synthase that catalyzes the production of amorphadiene from farnesyl diphosphate (FPP). Cytochrome P450 then facilitates the next step of producing artemisinic acid. From artemisinic acid; the final step to the arteminisin compound is arguably cheaper than full synthesis of arteminisin would be. The research team says that this represents significant progress towards producing a more affordable treatment for malaria, although subsequent optimization of the process in order to produce a drug is likely 5 or 10 years away.

The researchers previously engineered E.coli to produce amorphadiene, an isoprenoid precursor to artemisinic acid, in research that was published in 2003 in the journal Nature Biotechnology; "Engineering a mevalonate pathway in Escherichia coli for production of terpenoids" (published online June 1, 2003), described here on the Berkeley press release site. At the time, the principal investigator Jay Keasling noted: "By inserting these genes into bacteria, we've given them the ability to make artemisinin quickly, efficiently and cheaply, and in an environmentally friendly way. Although E.coli replicates faster than yeast and can churn out more of the desired compounds, this next step, transformation of amorphadiene to artemisinic acid, turned out to be accomplished by cytochrome P450, a cellular membrane enzyme that functions in yeast but not E.coli. Keasling commented on the fortuitous research environment that led to the latest research:

"We reached our goal early, thanks to a number of miracles: The first gene Dae-Kyun isolated was the right one, the gene was functional in yeast, the gene's enzyme did in one step what we thought took three enzymes, and the artemisinic acid it produced didn't interfere much with the cell".

The research advances progress towards lower cost arteminisin production, which would potentially lower the cost of arteminisin combination therapy. Hopefully, this method, and/or vaccine development, or the judicious use of existing technologies, will eventually help abate malaria. As much as the spread of malaria is a scientific challenge, it is also a political and economic challenge, although arguably a more sure-fire scientific solution would ease the politics.The research is supported by multiple organizations, and UC Berkeley has issued a royalty-free license to both OneWorld Health and Amyris to develop the technology to treat malaria. Africa Malaria Day is April 25, 2006

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In addition to the article on malaria treatment progress listed above, Acronym Required also wrote about malaria vaccination development via private-public funding schemes for malaria vaccine development in Vaccine Development for Infectious Diseases. One World Health and Jay Keasling were also mentioned in a short post on Codon Devices.

About sixty years ago the first atomic test brought to fruition Roosevelt's nuclear program. Posthaste, a group of Manhattan Project scientists urged policies of non-proliferation. The scientists must have been jubilant about their technological success, so the turnaround to hand-waving caution, was remarkable. It was almost as thought they had thought ahead of time about the dangers of the science but were driven to do the experiments anyway. Needless to say, once unleashed, the nuclear technology thrived. Weapons and civilian applications of nuclear energy proliferated despite the scientists' caution.

Then came Three Mile Island and Chernobyl.

Twenty years ago an explosion and fire at the Chernobyl power plant in the Soviet Union unnerved a world that had grown accustomed to relying on nuclear energy. Through the Cold War, people got used to living with the alarms of air raids, but the ultimate containment of nuclear weapons. The accident at Three Mile Island in Pennsylvania had given ample warning of the type of accident that could happen, but Chernobyl truly frightened the world. In May 19, 1986, Time magazine reported on the wide repercussions of the accident:

• In Italy livestock that arrived from Eastern Europe were returned because radiation levels in the animals tested too high.
• In Japan milk and water were found to be contaminated.
• In Ottawa rain was found to have six time the amount of radiation than is safe for drinking water

In the US traces of radiation were found in ther Pacific Northwest and New York. People were concerned about drinking water. Donald Macdonald, Acting Assistant Secretary of health said, in what appears to be a more candid era: "I would drink it, and that's what the guidelines say, but I would prefer not to drink it."

A Financial Times reporter last week took a "holiday" in Chernobyl, where the tour business now apparently thrives. The author choice of vacation was paradoxical, perhaps a flurry of "publish and perish". He sallied forth:

"I paid $280 for a day with one personal guide and a second, official guide in the exclusion zone, which gave us freedom to roam pretty much where we wanted..." [and] "another $20 on what is locally known as "honey" - bottles of spirits and boxes of chocolates to ease the way through the several checkpoints on the way to the site."

The scene he describes is hardly inviting (and I am an adventurous traveler): "radioactive scrap yards where hundreds of vehicles [trucks, helicopters] that were used in the clean-up were parked in neat rows then abandoned". "Rust and corrosion [seeps]", from the hulking Reactor Four's "cracked and unstable" sarcophagus. Hundreds of workers still worker there for "two hours at a time", although the hundreds of so-called "bio-robots" who were hired to clean up after the initial disaster, have come and gone. Tour guides carry Geiger counters.

Nuclear energy has a wide array of supporters from business and science sectors. It's promoted as clean, cheap energy. The public is growing less wary of nuclear alternatives; with today's oil shortages, yesterday's nuclear catastrophes are easily forgotten.

In the decades since the last nuclear incident, the public has forgotten the terror of the accident. People are increasingly swayed by businesses that see opportunity in softening public opinion. To aid the perceptions of safety, some papers are reporting an abundance of wildlife inhabiting areas close to Chernobyl, as if the arrival of stray dogs and flower's in a radiation zone should stay our concerns about the renewed enthusiasm for all things nuclear.

The International Atomic Energy Agency (IAEA) issued a report last autumn, which said that deaths from Chernobyl would number about 4,000. However, Greenpeace writes in a recent report that that number is highly underestimated. The Greenpeace data places the actual numbers at 270,000 cancers and 93,000 fatal cancer cases directly caused by Chernobyl. On April 18, 2006: Greenpeace published "Chernobyl Catastrophe Consequences on Human Health". The report refutes the IAEA, and accuses it of "whitewashing" the data to promote nuclear energy. Among other things, Greenpeace faults the IAEA with deriving data from limited subsets of effected populations. One criticism is that IAEA notes that 212 of 72,000 clean-up personel died, but Greenpeace says that the more accurate number of "liquidators" or "bio-robots", was 600,000. Accurate data sets are essential for making public policy and if Greenpeace' contention is true, such data manipulation is unconscionable.

Nuclear technology continues to be propagated for political aims. The U.S. recently agreed with India to supply that country with enriched uranium for their domestic energy program. Congess has yet to debat the deal, but commentators expect it to go through. As nuclear energy is considered, so is nuclear war. Alarmingly, the U.S. is rumored to be eying Iran as a potential nuclear target, a report that the administration fervidly denies.Iran announced with fanfare yesterday that they produced enriched uranium which worries members or the U.S. Congress because India and Iran are embarking joint naval exercises in India.

Nuclear technology has the potential to be useful as well as lethal. Although scientists like those on the Manhattan Project, as well as politicians are rarely chastised when they only remember to criticize the repercussions of their experiments after the fact, we should remember the lessons we all learned - us and them. We understand very clearly dangers inherent with this technology and we have time now, before the clean-up, to consider the best ways to employ our power.