What if New York City was dirty bombed? We'll pop some pills and see the "walking dead." New Scientist.
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Nuclear nightmare in Manhattan
18 March 2006 • Bruce Goldman

A TRUCK pulls up in front of New York City's Grand Central Station, one of the most densely crowded spots in the world. It is a typical weekday afternoon, with over half a million people in the immediate area, working, shopping or just passing through. A few moments later the driver makes his delivery: a 10-kiloton atomic explosion.

Almost instantly, an electromagnetic pulse knocks out all electronics within a radius of 4 kilometres. The shock wave levels every building within a half-kilometre, killing everyone inside, and severely damages virtually all buildings for a kilometre in every direction. Detonation temperatures of millions of degrees ignite a firestorm that rapidly engulfs the area, generating winds of 600 kilometres an hour.

Within seconds, the blast, heat and direct exposure to radiation have killed several hundred thousand people. Perhaps they are the lucky ones. What follows is, if anything, even worse.

The explosion scoops out a crater 20 metres across and 10 metres deep, sending thousands of tonnes of highly radioactive debris into the air as a cloud of dust. What goes up must come down, and radioactive detritus starts piling up.

Within the first hour, enough fallout settles to fatally irradiate tens of thousands of people in the immediate area. Even 20 kilometres downwind, the majority of people caught in the path of the plume are exposed to life-threatening levels of radioactivity. Anyone less than 30 kilometres downwind will need to get out or find shelter, fast. For 150 kilometres or more downwind of the blast, dangerous amounts of fallout continue to drizzle down.

This nightmare scenario is one the US government is taking seriously. In the past two years alone, it has committed hundreds of millions of dollars to dealing with the aftermath of an act of urban nuclear terrorism, or a 9/11-style attack on a nuclear plant.

Making a bomb is not as difficult as you might imagine. The "gun-type" atomic weapon akin to the one dropped on Hiroshima is essentially a matter of shooting one piece of highly enriched uranium into another. Princeton University physicist Frank von Hippel, in a New York Times interview not long after 9/11, estimated that simply dropping a 45-kilogram lump of weapons-grade uranium onto a second piece of a similar size from a height of about 1.8 metres could produce a blast of 5 to 10 kilotons - that is, the explosive force of 5000 to 10,000 tons of TNT. With enough highly enriched uranium in the world to make hundreds of thousands of such weapons, and frequent reports of nuclear material being stolen from the former Soviet Union, it is far from unthinkable that terrorists could get their hands on enough to make a bomb.

In 2004, a US government-funded working group published an estimate of the number of radiation casualties that would follow a 10-kiloton detonation in a mid-sized city of 2 million, the size of Washington DC (Annals of Internal Medicine, vol 140, p 1037). The numbers make for sobering reading: 13,000 killed immediately; 45,000 facing certain death regardless of treatment; 255,000 at risk of dying without hospital treatment; and a further 140,000 in need of observation. Even a 1-kiloton explosion, from a smaller device or an imperfectly executed detonation, would produce perhaps a third to a half that number of radiation casualties, according to group member Jamie Waselenko of the Sarah Cannon Research Institute in Nashville, Tennessee.

It is the quarter of a million lives that could be saved that are exercising the minds of US policymakers. All of those casualties will be suffering from acute radiation syndrome, otherwise known as radiation sickness. All are potential survivors, but at present there would be little that doctors could do for them.

Most of what is known about radiation sickness comes from animal studies and accidents, and from medical records from Hiroshima and Nagasaki. The syndrome is a collection of symptoms that get progressively worse with increasing exposures. The simplest measure of exposure is a unit called a gray - the number of joules of radiation energy absorbed per kilogram of tissue.

Walking dead

Any exposure above 2 grays or so is deadly serious. People irradiated to this level or higher quickly get sick, then get better again. However, this "latent phase" is only temporary. Some time later, from a few days to a month, they fall ill again, and often die. Not surprisingly, the more radiation you absorb, the more organs are involved, the quicker the immediate symptoms come on and the shorter the latent phase.

The body's most susceptible vital tissue is the bone marrow, specifically the stem cells within it that give rise to new blood cells. These are impaired at doses as low as half a gray and are usually wiped out completely and permanently above 5 grays. When the stem cells die, blood-cell counts - most critically those of neutrophils and platelets - start to drop, eventually plunging to zero after days or weeks. Without neutrophils, the first-responders of the immune system, radiation victims are at high risk of opportunistic infections. Losing platelets is also seriously bad news: without them blood cannot clot, leading to potentially fatal bleeding from even the smallest wound.

Upwards of 5 grays, the gastrointestinal tract is also affected. Radiation kills any rapidly dividing cells, such as the ones lining the intestinal tract. The resulting damage can cause gut bacteria to leak into the bloodstream, where they overwhelm the already compromised immune system and cause septic shock. At exposures above 10 grays, the central nervous system is damaged too, and death is certain, with or without treatment.

The standard treatment for radiation syndrome is "supportive care": blood and platelet transfusions, antimicrobials, fluids, anti-emetics and other "comfort measures". These treatments are better than nothing but are often not enough, and would be extremely difficult to deliver on a mass scale in the aftermath of a nuclear attack. Which means that despite receiving technically survivable doses of radiation, a large proportion of those 255,000 people will die.

The US government is determined to shift the odds in their favour. "What we're aiming to do is to be able to treat every casualty," says Norm Coleman of the National Cancer Institute in Bethesda, Maryland, who has been helping the Department of Health and Human Services plan its response to a nuclear attack.

The government is putting its money where its mouth is. In 2005 it awarded a total of $47 million to several groups of radiation researchers, including $29 million to the newly formed Centers for Medical Countermeasures against Radiation (CMCR). Their mission is to gain a better understanding of the biology of radiation damage, find faster ways of diagnosing radiation exposure levels, and discover better drugs. In July 2004 President Bush signed the Bioshield Act into law, committing $5.6 billion to counter nuclear, biological and chemical threats. And late last year, the government put out a call for companies to develop drugs that preserve and restore neutrophil counts in radiation syndrome, with secondary emphasis on platelets. So far no such drugs have been approved in the US, but there are candidates.

One obvious option is G-CSF (granulocyte colony-stimulating factor), a cytokine that stimulates the bone marrow to pump out new blood cells. Sold by Amgen of Thousand Oaks, California, to treat neutrophil loss caused by cancer therapy, G-CSF works by preventing the death of the bone-marrow precursor cells destined to become neutrophils, and by boosting their rate of proliferation.

G-CSF is not yet licensed for radiation sickness, but it has been used in 28 cases of accidental radiation exposure and boosted neutrophil counts in 25 of them (although many of the patients died anyway). The animal results also look good. In November, Tom MacVittie of the University of Maryland in Baltimore reported that G-CSF, in combination with supportive care, improved survival rates in irradiated dogs. The US government already has large amounts of G-CSF stored in a strategic national stockpile.

Even so, there are serious doubts over G-CSF's suitability for mass administration in the event of a nuclear terror attack. The drug is expensive, up to $400 per dose, and a patient would typically need daily doses for at least two weeks. It can't be left unrefrigerated for more than 24 hours. Worse still, although it has been given to thousands of cancer patients, side effects are common and can be severe, says Waselenko. Another Amgen cytokine, thrombopoietin (TPO), has shown promise in platelet deficiency, but has been ruled out as a radiation countermeasure because it sometimes causes life-threatening side effects.

Doctor's dilemma

Cytokines' adverse effects present doctors treating radiation syndrome with a dilemma. To save lives you need to treat everyone who might have been exposed, but diagnosing exposures with any real precision takes days, and you don't want to give a drug with potentially serious side effects to people who don't actually need it. One quick-and-dirty sign of serious exposure is nausea and vomiting. The trouble is that almost half of those with dangerous radiation exposure won't vomit, while large numbers of people who are merely traumatised will.

Compounding the problem is the fact that after a detonation, many people will probably be instructed to hunker down in a sheltered spot such as a large building until the fallout has diminished enough to make a dash for it. "These people are going to be several days from even being evaluated," says Waselenko. But you don't have days. G-CSF only works if started within a day or two of irradiation.

So the search is on for better drugs. An ideal radiation countermeasure would be effective, cheap, and easy to make and administer. It would have a long shelf life, minimal side effects if given to someone who turned out not to need it, and would still work even if administered days after exposure. One drug, a steroid called 5-androstenediol or 5-AED, seems to hit most of those targets.

5-AED is cheap, chemically stable and apparently very safe. Developed by Hollis-Eden Pharmaceuticals of La Jolla, California, as an adjunct to chemotherapy, 5-AED was identified as a radioprotectant by Mark Whitnall of the Armed Forces Radiobiology Research Institute (AFRRI) in Bethesda, Maryland, in 1996. It is now being jointly developed as a radiation sickness drug by AFRRI and Hollis-Eden.

Last October, Hollis-Eden announced that in their clinical trial 5-AED significantly increased platelets and neutrophils, without adverse effects, in a group of non-irradiated human volunteers. And in a study led by haematologist Gerard Wagemaker of Erasmus University in Rotterdam, the Netherlands, reported at the annual meeting of the American Society for Hematology in Atlanta, Georgia, in December 2005, 5-AED significantly reduced symptoms in irradiated rhesus monkeys and accelerated the recovery of their neutrophils, platelets, red blood cells and all-important stem cells.

"This steroid exactly mimics the actions of [the platelet-stimulating cytokine] TPO and G-CSF combined - so far, the most effective combination of cytokines for radiation damage to the bone marrow," says Wagemaker.

Although 5-AED is AFRRI's most advanced and, to date, star performer, it's not perfect. Like G-CSF, you need to get it to people quickly: it has yet to be shown effective if used more than a couple of hours after exposure.

Whitnall's team is also looking at other compounds. They have identified some analogues of vitamin E that have mild radioprotective effects in rodents when given prior to irradiation. "At this point we don't really know how they work, though," admits Whitnall. A soybean isoflavone called genistein also appears to provide modest levels of radioprotection, with virtually no side effects. Another very early-stage option is based on stem cells (see "Saved by a cell").

Some other drugs are also racking up good results in mice. One agent, a protein isolated from a parasitic microbe, temporarily switches off cells' programmed suicide apparatus, according to Andre Gudkov, chief scientific officer of the agent's developer, Cleveland Biolabs of Cleveland, Ohio. Fewer self-destructing cells seems to translate into higher survival rates for irradiated mice. Another molecule, developed by Proteome Systems of Sydney, Australia, mimics the ability of two closely paired mitochondrial enzymes, superoxide dismutase and catalase, to scavenge for free radicals, and can also keep irradiated mice alive.

The drive to develop radiation countermeasures could have some everyday pay-offs. For one thing, drugs such as 5-AED might allow us to go back to nuclear power with more confidence. And as Wagemaker points out, ageing populations will become increasingly vulnerable to blood disorders, just as the supply of donors will be dropping. "It is expected that the number of platelet infusions that are needed will at least double in 10 years' time," he warns.

No one knows the real odds of a nuclear attack on a big city. Hopefully, the nightmare will never come true, but if it does, at least there may be a stash of lifesaving drugs waiting in the wings.