Global Risk: A Quantitative Analysis

The scope and possible impact of global, long-term risks presents a unique challenge to humankind. The analysis and mitigation of such risks is extremely important, as such risks have the potential to affect billions of people worldwide; however, little systematic analysis has been done to determine the best strategies for overall mitigation. Direct, case-by-case analysis can be combined with standard probability theory, particularly Laplace’s rule of succession, to calculate the probability of any given risk, the scope of the risk, and the effectiveness of potential mitigation efforts. This methodology can be applied both to well-known risks, such as global warming, nuclear war, and bio-terrorism, and lesser-known or unknown risks. Although well-known risks are shown to be a significant threat, analysis strongly suggests that avoiding the risks of technologies which have not yet been developed may pose an even greater challenge. Eventually, some type of further quantitative analysis will be necessary for effective apportionment of government resources, as traditional indicators of risk level- such as press coverage and human intuition- can be shown to be inaccurate, often by many orders of magnitude.

More details are available online at the Society for Risk Analysis’s website. James Blodgett will be presenting on the precautionary principle two days earlier (Monday, Dec. 8th).

For both ethical and practical reasons, monoclonals are usually made in mice. And that’s a problem, because the human immune system recognizes the mouse proteins as foreign and sometimes attacks them instead. The result can be an allergic reaction, and sometimes even death.

To get around that problem, researchers now “humanize” the antibodies, replacing some or all of mouse-derived pieces with human ones.

Wilson and Ahmed were interested in the immune response to vaccination. Conventional wisdom held that the B-cell response would be dominated by “memory” B cells. But as the study authors monitored individuals vaccinated against influenza, they found that a different population of B cells peaked about one week after vaccination, and then disappeared, before the memory cells kicked in. This population of cells, called antibody-secreting plasma cells (ASCs), is highly enriched for cells that target the vaccine, with vaccine-specific cells accounting for nearly 70 percent of all ASCs.

“That’s the trick,” said Wilson. “So instead of one cell in 1,000 binding to the vaccines, now it is seven in 10 cells.”

All of a sudden, the researchers had access to a highly enriched pool of antibody-secreting cells, something that is relatively easy to produce in mice, but hard to come by for human B cells.

To ramp up the production and cloning of these antibodies, the researchers added a second twist. Mouse monoclonal antibodies are traditionally produced in the lab from hybridomas, which are cell lines made by fusing the antibody-producing cell with a cancer cell. But human cells don’t respond well to this treatment. So Wilson and his colleagues isolated the ASC antibody genes and transferred them into an “immortalized” cell line. The result was the generation of more than 100 different monoclonals in less than a year, with each taking just a few weeks to produce.

In the event of an emerging flu pandemic, for instance, this approach could lead to faster production of human monoclonals to both diagnose and protect against the disease.

Journal Nature article: Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

Nature 453, 667–671 (29 May 2008) | doi:10.1038/nature06890; Received 16 October 2007; Accepted 4 March 2008; Published online 30 April 2008

Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14–21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine1. However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination.

With the receptor identified, a therapy can be developed that will bind to the receptor, preventing the deadly immune response. Also, by targeting a receptor in humans rather than a particular strain of flu, therapies developed to exploit this discovery would work regardless of the rapid mutations that beguile flu vaccine producers every year.

The flu kills 250,000 to 500,000 people in an average year with epidemics reaching 1 to 2 million deaths (other than the spanish flu which was more severe

This discovery could lead to treatments which turn off the inflammation in the lungs caused by influenza and other infections, according to a study published today in the journal Nature Immunology. The virus is often cleared from the body by the time symptoms appear and yet symptoms can last for many days, because the immune system continues to fight the damaged lung. The immune system is essential for clearing the virus, but it can damage the body when it overreacts if it is not quickly contained.

The immune overreaction accounts for the high percentage of young, healthy people who died in the vicious 1918 flu pandemic. While the flu usually kills the very young or the sickly and old, the pandemic flu provoked healthy people’s stronger immune systems to react even more profoundly than usual, exacerbating the symptoms and ultimately causing between 50 and 100 million deaths world wide. These figures from the past make the new discovery that much more important, as new therapies based on this research could prevent a future H5N1 bird flu pandemic from turning into a repeat of the 1918 Spanish flu.

In the new study, the researchers gave mice infected with influenza a mimic of CD200, or an antibody to stimulate CD200R, to see if these would enable CD200R to bring the immune system under control and reduce inflammation.

The mice that received treatment had less weight loss than control mice and less inflammation in their airways and lung tissue. The influenza virus was still cleared from the lungs within seven days and so this strategy did not appear to affect the immune system’s ability to fight the virus itself.

The researchers hope that in the event of a flu pandemic, such as a pandemic of H5N1 avian flu that had mutated to be transmissible between humans, the new treatment would add to the current arsenal of anti-viral medications and vaccines. One key advantage of this type of therapy is that it would be effective even if the flu virus mutated, because it targets the body’s overreaction to the virus rather than the virus itself.

In addition to the possible applications for treating influenza, the researchers also hope their findings could lead to new treatments for other conditions where excessive immunity can be a problem, including other infectious diseases, autoimmune diseases and allergy.

The B612 Foundation is working towardcs the goal of of significantly altering the orbit of an asteroid in a controlled manner by 2015.

the B612 Foundation made estimates of Apophis path if a 2036 Earth impact were to occur.

The impact result is a narrow corridor called the ‘risk corrider’ which would be a few miles wide. Countries estimated to be in the direct path:

- southern Russia,
- across the north Pacific Ocean (relatively close to the coastlines of the California and Mexico), then
- right between Nicaragua and Costa Rica,
- crossing northern Colombia and
- Venezuela and over the Caribbean islands of Trinidad and Tobago,
- over the Atlantic Ocean to the west coast of Africa.

Earth’s Path of Risk for the 99942 Apophis Asteroid that is suspected to be on track for a collision course with earth in the year 2036. This image is self-made from data estimated by the B612 Foundation, this is why it is just an approximation. Credit: Mario Roberto Duran Ortiz Mariordo and the re-use of this image is based on ‘Fair use’ of public domain info by the B612 Foundation work on Apophis.

The hypothetical impact of Apophis along the path of risk could have more than 10 million casualties, however the threatened zones would be evacuated [as per B612 foundation comment. The threat of casualties would be for a similar sized object, if it was not detected.].

Spaceworks Engineering had an award winning plan to send a spacecraft to shadow the Apophis asteroid

A video Foresight: A Radio Beacon Mission to Asteroid Apophis is on Youtube.

The Foresight final report is here

As of October 19, 2006 [and also April 16, 2008′, the impact probability for April 13, 2036, was calculated as 1 in 45,000. An additional impact date in 2037 was also identified; the impact probability for that encounter was calculated as 1 in 12.3 million.

Genes are similar to the plans for a house; they show what it looks like, but not what people are getting up to inside. One way of getting a snapshot of their lives would be to rummage through their rubbish, and that is pretty much what metabolomics does. […]

Metabolomics studies metabolites, the by-products of the hundreds of thousands of chemical reactions that continuously go on in every cell of the human body. Because blood and urine are packed with these compounds, it should be possible to detect and analyse them. If, say, a tumour was growing somewhere then, long before any existing methods can detect it, the combination of metabolites from the dividing cancer cells will produce a new pattern, different from that seen in healthy tissue. Such metabolic changes could be picked up by computer programs, adapted from those credit-card companies use to detect crime by spotting sudden and unusual spending patterns amid millions of ordinary transactions. 

This could be used for traditional medicine, both to prevent pathologies and to detect those that are already present so they can be treated. But another use would be as part of an early-detection system to defend against pandemics and biological attacks. As mentioned previously, network-theory can help us better use vaccines. But once you have a cure or antidote, you also need to identify people that are already infected but haven’t died yet, and the earlier you can do that after the infection, the more chances they have to live.

Once the techniques of metabolomics are sufficiently advanced and inexpensive to use, they might provide better data than simply relying on reported symptoms (might be too late by then), and might scale better than traditional detection methods (not sure yet — something else might make more economic sense). It’s a bit too early to tell, but it’s a very promising field.

For more information, see Douglas Kell’s site or Wikipedia: Metabolomics.

Source: The Economist. See also Lifeboat’s BioShield program.

Researchers are now proposing a new strategy for targeting shots that could, at least in theory, stop a pandemic from spreading along the network of social interactions. Vaccinating selected people is essentially equivalent to cutting out nodes of the social network. As far as the pandemic is concerned, it’s as if those people no longer exist. The team’s idea is to single out people so that immunizing them breaks up the network into smaller parts of roughly equal sizes. Computer simulations show that this strategy could block a pandemic using 5 to 50 percent fewer doses than existing strategies, the researchers write in an upcoming Physical Review Letters.

So you break up the general social network into sub-networks, and then you target the most important nodes of these sub-networks and so on until you run out of vaccines. The challenge will be to get good information about social networks, something not quite as easy as mapping computer networks, but there is progress on that front.

In one of the most dramatic illustrations of their technique, the researchers simulated the spread of a pandemic using data from a Swedish study of social connections, in which more than 310,000 people are represented and connected based on whether they live in the same household or they work in the same place. With the new method, the epidemic spread to about 4 percent of the population, compared to nearly 40 percent for more standard strategies, the team reports.

Source: ScienceNews. See also Lifeboat’s BioShield program.