When Iron and Bacteria tragically collide: From the Middle Ages to the University of Chicago

Science brings us the bizarre, tragic but medically fascinating story of Malcolm Casadaban, a microbiologist working with plague bacteria at the University of Chicago, who died unexpectedly in 2009 of a then-unexplained cause. Obvious culprits were the plague bacteria he worked with. But the bacteria had been specially attenuated to be harmless in humans. So how could they kill?

It turned out that Casadaban had been the victim of an unfortunate double coincidence where two extremely rare causes combined to produce a lethal combination. It turns out that the plague bacteria he was working with had been rendered impotent by knocking out specific proteins which metabolize iron. More specifically they were engineered by knocking out a gene called pgm which codes for a protein allowing the bacterium to absorb iron from its surroundings. Iron is as essential to bacteria as it is to humans, and in the absence of iron-absorbing proteins the bacteria were useless as pathogens. Except that in this case they were not. Casadaban also suffered from hemochromatosis, a rare genetic disorder known for hundreds of years that causes the body to lock down stores of iron resulting in iron overload. From here it's not hard to put two and two together; when the iron-starved bacteria were suddenly introduced to Casadaban's body and its ample stores of the metal, they came to life like Frankenstein resurrected. The sudden windfall of virtually infinite stores of iron gave them the nutrient they lacked, transforming them into a fatal force that killed Casadaban.

Very unfortunate, but utterly fascinating from a medical standpoint. The reason I find it even more interesting is that it seems to at least superfically contradict an equally fascinating story from the Middle Ages, and in the process provides a plausible explanation for what happened. There is a remarkable and horribly tragic piece of history that possibly supports the evolutionary benefit of a debilitating condition like hemochromatosis. In the Middle Ages, when the Black Death struck Europe on a terrible scale, Jews were often accused of bringing this malady into people's homes through some kind of mystic powers. Thousands of Jews were killed for the sake of this superstitious belief. And the fact that Jews as a population seemed to be less affected by the plague only encouraged the paranoia and madness. One of the reasons that's traditionally offered for this relative immunity is the hygenic kosher conditions which Jews practised which made their homes less attractive to rats. But another hypothesized factor is the higher prevelance of the hemochromatosis gene among Jews, especially Ashkenazi Jews who are widespread among Jewish communities. It seems that just like other bacteria, the plague bacterium Yersinia pestis needs iron to survive. By locking up iron stores, the bodies of Jewish individuals denied this valuable nutrient to Yersinia, which made the germ less successful in colonizing its victims. Thus hemochromatosis, while causing harm by storing excessive iron, might have compensated for that harm by serving as a defense against the deadly plague. This theory is quite controversial and may indeed be wrong, but it underscores the basic point that diseases which may seem to be presently harmful could have served a useful purpose in the past by defending against infections. Since Yersinia is largely no longer a concern in the modern world because of medical advances, we see only its ugly side.

But this seems to contradict what we have just heard. If hemochromatosis could deny iron to iron-starved plague bacteria in the Middle Ages, how could the same condition have the opposite effect on even more iron-starved bacteria in Casadaban's body? I don't know the answer, but a plausible explanation is that the ultra iron-starved, genetically engineered bugs simply evolved to be much more efficient at scavenging iron from Casadaban's cells than normal plague bacteria. We have all seen how the phosphorus-starved bacteria in the arsenic fiasco are widely thought to have evolved an ability to mop up and zealously guard phosphorus stores even more efficiently. When the going gets tough, the tough gets going, especially in the bacterial world. It is well-documented how remarkably fast bacteria can evolve their biochemical machinery to tide over unfavorable circumstances and efficiently utilize low concentrations of essential nutrients down to the last atom. It won't be suprising at all if the impotent bacteria in Casadaban's unfortunate body simply retooled to forcefully rip out iron from his cells and proliferate. A small, routine step for bacteria with giant, terrible implications for a human being.

What an unfortunate story, but it's implications are utterly sobering. It tells us how much we still don't understand about the risks of modifying genomes of simple organisms. Genetically engineered organisms can combine with naturally engineered human bodies in bizarre, unexpected and tragic ways. We may have started to come to terms with the synthetic modification of life, but we still have a long way to go before we understand how the different parts of the natural and artificial worlds dynamically interact with each other in ways that we cannot anticipate. There's miles to go before we can sleep.

Help!

I am looking around for a specific indicator for ferric ions that's very specific for ferric over ferrous. It should be water soluble and stable at room temperature and neutral or basic pH. In addition, it should be very sensitive and should be able to detect slight increases in ferric concentration by a bright colour change. And of course, the colour change should be easily detectable by a spectrophotometer, or more preferably, by the human eye.

Help will be much appreciated!

AD, metals, and evolution

There always seems to be something new emerging in Alzheimer's disease research. In the last few years, at least one widely accepted hypothesis, the amyloid hypothesis, has come under scrutiny. In AD, it was thought that peptides aggregate into beta-amyloid fibrils (Aß) which causes toxicity to neurons.

However, many reports in the last two years are suggesting that it's not the aggregated beta-amyloid, but its soluble precursors that seem to be more toxic. There were some indications that this was true before too. For example, neuronal damage and memory impairment did not always correlate with Aß levels.

Another big hypothesis that has been widely prevelant in the AD community is that metals such as copper, aluminium, iron, and zinc, might correlate with Aß aggregation. New reports also suggest that these metals may in fact bind to the soluble and toxic forms of Aß, and help them to aggregate. One very interesting aspect of metabolism emerging from this research seems to be that it's not necessarily a larger amount of these metals from our environment or diet that's causing the problems, but an age-related breakdown in metal metabolism in the brain, which is an especially capacious reservoir of metals. Thus, perhaps we need not be especially worried about getting more copper or zinc from our diets.

One more thing that the metals might be doing is to help in free-radical generation, that might damage neurons. Again, there is still a correlation vs causation problem with this hypothesis, but free radicals are being increasingly found in vitro, when metals are added to Aß fibrils. While aluminium seems to have been largely a scare idea, zinc and copper are emerging as more plausible agents for free radical production and neuronal damage.

Based on evolutionary concepts, I cannot help but think that there may actually have been some protective function of amyloid in ancient human civilizations. Maybe it sequestered copper and provided a ready source when there was a lack of copper (or iron for that matter) in the diet. Or maybe it recruited copper to fight microorganisms and especially bacteria, at a time when there were no defenses against them except for natural ones. In this way, it could have dealt a double blow; denying essentials metals to the bacteria, and recruiting them to produce free radicals which would kill the little beasties.

In any case, AD research at the molecular level seems to be advancing rapidly, and we can expect some interesting discoveries in the years to follow.

References:
1. A nice review on AD and amyloid, free radicals, and oxidative damage
2. A recent Angewandte Chemie paper on the influence of copper concentrations on Aß geometry, morphology, and aggregation.