Let us start by understanding the human immune system with its two major divisions – the innate and the acquired immune systems. The innate immune system is a baseline system that cannot adapt to changing needs. Its components are skin, enzymes in saliva, tears, and cells such as macrophages. The acquired immune system is an adaptable entity that can change according to needs. It comprises primarily of T-lymphocytes and B-lymphocytes; the latter is responsible for making antibodies. Acquired immunity has evolved over millions of years into being able to recognize what is “self” and what is “non-self” (ie, foreign). The “self vs non-self” education of the acquired immune system takes place in the thymus of the developing fetus. By the time a child is born, the immune system already knows what “self” molecules are, and what is not recognized as “self” by the immune system is treated as foreign. And attacked. The most usual targets of attack are, naturally, bacteria and viruses.

The T-cells cannot recognize the foreign substance themselves. Specialized cells called antigen-presenting cells (APC), components of the innate immune system perform that job. The APC ingest the bacteria or virus and destroy it by digesting it. Then the APCs present parts of the destroyed bacteria or virus (now called an antigen) on their surface using specialized molecules called major histocompatibility complex Type II molecules (MHC). The MHC is really the key to the process. If the antigen presentation is improper or inadequate, the T-cells do not get activated and infections run amuck. On the other hand, if the MHC presents a “self” antigen, under the proper circumstances, it can lead to autoimmune diseases such as diabetes, rheumatoid arthritis, etc. Therefore, it should not be a surprise that a strong relationship exists between certain diseases and MHC subtypes. In other words, these MHC subtypes tend to present certain auto-antigens and if one happens to have these MHC subtypes, one is at a greater risk of developing an autoimmune disease compared to someone who does not. An example is the MHC HLA B27 and the disease ankylosing spondylitis.

MHC molecules differ among different races. For example, the MHC that leads to the propensity for ankylosing spondylitis tends to be higher in Caucasians compared to Orientals. The reasons for MHC differences are not known. However, it is speculated that migration from Africa early in the evolutionary process lead Caucasians to loose MHC that are important for combating bacteria and viruses since infections are less prevalent in temperate zones (Jeffery KJ, Bangham CR in Microbes Infect 2000 Sep; 2(11): 1335-41). At present, MHC differences are not very well characterized, though the human genome project will help solve part of that problem.

Even if humans have not characterized MHC differences, microorganisms have. Bacteria and viruses have evolved along with the human immune system and have exploited the variations in MHC and associated molecules to their advantage. For example, alleles in MHC class II loci and interleukin 10 promoter have been demonstrated to influence the outcome of viral hepatitis (Antiviral Res 2001 Nov; 52(2): 113-6). Similarly, variations in class I MHC can affect susceptibility to HIV (Immunol Letters 2001 Nov 1; 79 (1-2): 151-7), and allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region affect susceptibility to malaria (Nitric Oxide 2000 Aug; 4(4): 379-83). As a final example, MHC DQ3 may affect hydrocephalus due to toxoplasmosis (Int J Parasitol 1999 Sep; 29(9): 1351-8). Some racial differences have been noticed but not characterized such as the susceptibility of blacks to tuberculosis (N Y State J Med 1991 Jun; 91(6): 239-42).

How do bacteria and viruses take advantage of racial differences? Some microorganism use components of the MHC as receptors for binding and invading cells. Gene terrorists can take a page out of the microorganisms’ book and create super bugs that target certain genetic profiles. They can alter the tropism of bacteria and viruses, changing parts of bugs that bind cellular receptors by a technique called site directed mutagenesis. In other words, it would enable a bug to attack cells bearing certain MHCs more avidly. And since certain ethnic groups preferentially express those MHC molecules, it would lead to ethnic or racial targeting. That is one way ethnic targeting by bio-weapons can take place (there are others, but due to space constraints, those interested can read my book, Germs of War).

How does this affect India? First, who are India’s principal adversaries? Pakistan and China.

Pakistanis are, genetically, not different from Indians. An interesting study published in Nature News 2009 (Published online 23 September 2009| Nature|doi:10.1038/news. 2009.935) showed that in India, there is tremendous homogeneity despite caste, religion, and regional divisions. Other studies have extended this observation to Pakistan. The implications are, that, if either country were to develop and launch a targeted biological weapon against the other, its own populace would suffer equally (unless it had undertaken mass vaccination or other similar preventative measures prior to the launch). I want to emphasize this and hope the Jihadis understand this critical point before they embark on a Bio-Mumbai type attack. Not to dwell on this too much but as an aside, Israel would be a plumb target for Jihadis in Pakistan.

China is a different story. A study published in Dec 2009 by HUGO (human genome organization) showed that South Asia was the hub of human propagation in Asia, (http://www.genomeweb.com/arrays/hugo-pan-asian-snp-consortium-maps-genetic-diversity-asia) and South Asians have the greatest genetic diversity in Asia. Chinese, to put it simply, are derived from Indians, and have much less genetic diversity. This puts the Chinese at a comparative disadvantage when it comes to biological weapons (BWs). Anything China develops against Indians will also affect its own people. But the reverse is not true. India can develop BWs that can affect almost all Chinese (especially Han Chinese) with limited impact on its own people. Not that I would advocate it but it is also a point I hope the mandarins in Beijing (sorry for the pun) understand. Considering that the Chinese communists had no qualms about killing more than 30 million of its own people during the cultural revolution, I don’t think empathy for Indians would dissuade them from launching a BW against India. But the thought of losing their whole country just might.

The post Bioweapons : Ethnic Targeting by Bioweapons appeared first on IMR.

Dr. Ketan Desai

By now, everyone now knows what weapons of mass destruction are. They fall into three categories – nuclear, chemical, and biological weapons. Of the three, I consider biological weapons to be the most dangerous. To get a better perspective, consider plague and smallpox. The former, inadvertently launched by the Tartars in 1348, decimated 30 per cent of European population within 3 years. Smallpox was even more deadly, causing the deaths of 90% of Mayans and Aztecs, enabling the Spanish to conquer the ‘new world”.

The potential of biological weapons has not been ignored by armies of the world. Between World War I and ratification of the Biological and Toxins Weapons Convention, it is estimated that at least 20 countries had biological weapons program. The reasons are not hard to understand. Biological agents are easy to make, merely requiring a laboratory on par with what is found in most universities today, and can be created by any graduate student. They are not resource intensive, and most ingredients are easily available. This is in marked contrast to nuclear weapons which are very expensive to make, require radioactive precursors that are under the tight supervision of international agencies, and require technology that are not easy to come by. This is why, despite intense efforts, only a few countries in the world possess nuclear weapons.

Biological weapons have additional attractiveness, in that they can be tailor made, based on the requirements of the “manufacturer”. In order to understand this point, it is important to differentiate between bio-terrorism and biological warfare. The former includes agents designed to spread terror but with limited number of deaths. A perfect example of this is the ‘anthrax scare’ in the US in 2001, where the amount of fear far exceeded the number of those affected. In contrast, biological warfare uses agents that have the potential to cause large number of deaths, numbering in the hundreds of thousands or millions.

Thus, a perpetrator of bio-terrorism would chose diseases such as anthrax and botulism, with agents that are not self-replicating (so as to limit spread) but which have a high lethality (to increase fear). Think of it as a “biological Unabomber”. While dangerous to those exposed, this is a limited threat.

In contrast, biological weapons tend to be self-propagating agents (to increase spread) that are inhaled (to increase dispersal) and one which are made resistant to antibiotics).

“In light of the September 11 tragedy, we can no longer afford to be complacent about the possibility of biological terrorism,” warns a commentary in Nature Genetics. “The revolution in biology could be misused in offensive biological weapons programs, directed against human beings and their staple crops and livestock.”

Thus, the next generation of biological weapons may exploit knowledge about genomes, with calamitous effect. A couple of years from now, there may be as many as 70 pathogens whose genetic code has been cracked. The genome of cholera, leprosy, the plague and tuberculosis are already in the public domain, as is Staphylococcus aureus that is becoming resistant to antibiotics. There is fear that a bioterrorist with lots of money and a good laboratory could use this readily available data, inserting or swapping genes in bacteria and viruses to create new, horrifyingly virulent agents.

There are at least two documented cases in which biologists have created doomsday bugs. One was a strain of the common intestinal bug Escherichia coli that was 32,000 times more resistant to the antibiotic cefotaxime than conventional strains. The superbug’s creator was Willem Stemmer, chief scientist with Maxygen, a California pharmaceutical research firm, who was exploring the function of resistance genes in bacteria. The technique used, DNA shuffling, involves shattering multiple copies of a gene and then reassembling them. The process produces a range of daughter genes with the fragments stitched together in subtle but new ways. The enzymes involved in the re-assembly are prone to errors, leading to mutations and, therefore, greater diversity. The daughter genes can then be re-introduced into the bacteria and the resultant bacteria with the desired strains (such as those good as biological agents) selected. Fragments from different bacteria can be mixed and matched by this technique. Needless to say, the potential of this in the wrong hands is enormous. In response to an appeal by the American Society for Microbiology, the E.coli created by Stemmer was destroyed.

In another example, Australian scientists Ron Jackson and Ian Ramshaw unwittingly created a vicious strain of mousepox, a cousin of smallpox. They were attempting to control the population of mice by altering the genes of mousepox to make it more lethal. To create their mouse contraceptive, they took a relatively benign strain of mousepox and added genes for proteins carried on the surface of mouse eggs. The idea was that cells infected by the viruses would churn out egg proteins, causing female mice to produce antibodies against their own eggs. To maximize the vaccine’s effectiveness, Jackson and Ramshaw also engineered the virus so that it contained the gene for interleukin 4, a cytokine that boosts anti-body production. The IL-4 gene also shut down the mice cellular immune response so they were unable to fight off the virus. The effect was lethal, with mice that were previously immunized against mousepox dying within days. The implications are obvious and profound.

Two kinds of people would use such weapons. The first could be nihilists and anarchists, who find all aspects of modern society despicable and feel they need to start all over again. Such persons could create a recombinant agent (such as a virus) that could literally destroy society as we know it. Unfortunately, such an agent would not be hard to create. For example, HIV-1 could easily be inserted into Adenovirus (after removing the dispensable E3 gene of the latter) creating inhaled AIDS. Needless to say, such a creation would be devastating.

The other perpetrators of biological warfare could be terrorists groups such as Al Qaeda. Groups such as this could gamble that even though biological warfare would hurt them as much in the end, it would level the playing field, where they have the long term advantage (in their view, thanks to their fanaticism). A tactic they could use is to select agents to which they are relatively immune while the Western world is relatively naïve. This can be created by insertion of antibiotic resistant genes or genes that selectively attack certain racial groups (in another article, I will show how such agents can be created). Given the jihadi mentality, such groups will consider their own mortality as martyrdom, while those of the enemy as the ultimate goal.

============

Diseases/Agents Listed as Potential Bioterror Threats by the US Centre for Disease Control and Prevention (CDC)

CATEGORY A:  Easily disseminated; high mortality rates.

Bacteria (single-celledorganisms):
Anthrax (Bacillus anthracis)
Plague (Yersinia pestis)
Tularemia (Francisella tularensis)

Viruses:
Smallpox (Variola major virus)
Viral Hemorrhagic Fevers: Ebola, Marburg,
Lassa, Machupo (various families of viruses)
Biotoxins (poisonous substances produced by living or ganisms):
Botulism (Clostridium botulinum toxin)

CATEGORY B: Moderately easy to disseminate; low mortality.

Bacteria:
Brucellosis (Brucella species)
Glanders (Burkholderia mallei)
Melioidosis (Burkholderia pseudomallei)
Psittacosis (Chlamydia psittaci)
Food safety threats (e.g., Salmonella species, Escherichia coli O157:H7, Shigella)
Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum)

Viruses:
Viral encephalitis (Alphaviruses)
Rickettsia (micro-organisms that live in cells)
Qfever (Coxiella burnetii)
Typhus fever (Rickettsia prowazekii)

Biotoxins:
Epsilon toxin of Clostridium perfringens
Ricin toxin from castor beans
Staphylococcal enterotoxin B

CATEGORY C:  Emerging infectious diseases.

Viruses:
Examples are Nipah virus and Hantavirus
Coronaviruses

The post BIOWEAPONS : Do Not Underestimate The Potential Of Biological Weapons appeared first on IMR.