Monday, August 25, 2008

The rise and fall of human genetics and the common variant - common disease hypothesis.

There is an enormity of positive press coverage for the Human Genome Project and its successor, the HapMap Project, even though within the field the initial euphoric party when the first results came out has already done a full 180 to be replaced by the hangover that inevitably follows such excesses.

For those of you not familiar with the history of this field and the controversies about its prognosis which were present from the outset, I refer you to a review paper I and a colleague wrote back in 2000 at the height of the controversy - Nature Genetics 26, 151 - 157 . The basic gist of the argument put forward for the HapMap project was the so-called common variant/common disease hypothesis (CV/CD) which proposed that "most of the genetic risk for common, complex diseases is due to disease loci where there is one common variant (or a small number of them)" [Hum Molec Genet 11:2417-23]. Under those circumstances it was widely argued that using the technologies being developed for the HapMap project, that one would be able to identify these genes using "genome-wide association studies" (GWAS), basically by scoring the genotype for each individual in a cross sectional study for each of 500,000 to 1,000,000 individual marker loci - the argument being that if common variants explained a large fraction of the attributable risk for a given disease, that one could identify them by comparing allele frequencies at nearby common variants in affected vs unaffected individuals. This point was contested by researchers only with regard to how many markers you might have to study for this to work if that model of the true state of nature applied. Many overly optimistic scientists initially proposed 30,000 such loci would be sufficient, and when Kruglyak suggested it might take 500,000 such markers people attacked his models, yet today the current technological platforms use 1,000,000 and more markers, with products in the pipelines to increase this even more, because it quickly became clear that the earlier models of regular and predictable levels of linkage disequiblrium were not realistic, something that should have been clear from even the most basic understanding of population genetics, or even empirical data from lower organisms.

Today such studies are widespread, having been conducted for virtually every disease under the sun, and yet the number of common variants with appreciable attributable fractions that have been identified is miniscule. Scientists have trumpetted such results as have been found for Crohn's disease, in which 32 genes were detected using panels of thousands of individuals genotyped at hundreds of thousands of markers - this sounds great until you start looking at the fine print, in which it is pointed out that all of these loci put together explain less than 10% of the attributable risk of disease, and for various well-known statistical reasons, this is a gross overestimate of the actual percentage of the variance explained. Most of these loci individually explain far less than half a percent of the risk, meaning that while this may be biologically interesting, it has no impact at all on public health as most of the risk remains unexplained. This is completely opposite to the CV/CD theory proposed as defined above. In fact, this is about the best case for any complex trait studied, with virtually every example dataset I have personally looked at there is absolutely nothing discovered at all.

At the beginning of the euphoria for such association studies, the example "poster child" used to justify the proposal was the relationship between variation at the ApoE gene and risk of Alzheimer disease. In an impressively gutsy paper recently, a GWAS study was performed in Alzheimer disease and published as an important result, with a title that sent me rolling on the floor in tears laughing: "A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease" [ J Clin Psychiatry. 2007 Apr;68(4):613-8 ] - in an amazingly negative study they did not even have the expected number of false positive findings - just ApoE and absolutely nothing else... And the authors went on to describe how important this result was and claimed this means they need more money to do bigger studies to find the rest of the genes. Has anyone ever heard of stopping rules, that maybe there aren't any common variants of high attributable fraction??? This was a claim that Ken Weiss and I put forward many times over the past 15 years, and Ken has been making this point for a decade before that even, in his book, "Genetic variation and human disease", which anyone working in this field should read if they are not familiar with the basic evolutionary theory and empirical data which show why noone should ever have expected the CV/CD hypothesis to hold...

In many other fields, the studies that have been done at enormous expense have found absolutely nothing, and in what Ken Weiss calls a form of Western Zen (in which no means yes), the failure of one's research to find anything means they should get more money to do bigger studies, since obviously there are things to find but they did not have big enough studies with enough patients or enough markers - it could not possibly be that their hypotheses are wrong, and should be rejected... It is a truly bizarre world where failure is rewarded with more money - but when it comes to promising upper-middle-aged men (i.e. Congress) that they might not die if they fund our projects, they are happy to invest in things that have pretty much now been proven not to work...

While in a truly bizarre propaganda piece, Francis Collins, in a parting sycophantic commentary (J Clin Invest. 2008 May;118(5):1590-605) claimed that the controversy about the CV/CD hypothesis was "... ultimately resolved by the remarkable success of the genetic association studies enabled by the HapMap project." He went on to list a massive table of "successful" studies, including loci for such traits as bipolar, Parkinson disease and schizophrenia, and of course the laughable success of ApoE and Alzheimer disease. To be objective about these claims, let me quote from what researchers studying those diseases had to say.

Parkinson disease: "Taken together, studies appear to provide substantial evidence that none of the SNPs originally featured as PD loci (sic from GWAS studies) are convincingly replicated and that all may be false is worth examining the implications for GWAS in general." Am J Hum Genet 78:1081-82

Schizophrenia: " do not provide evidence for involvement of any genomic region with schizophrenia detectable with moderate [sic 1500 people!] sample size" Mol Psych 13:570-84

Bipolar AND Schizophrenia: "There has been great anticipation in the world of psychaitric research over the past year, with the community awaiting the results of a number of GWAS's... Similar pictures emerged for both disorders - no strong replications across studies, no candidates with strong effect on disease risk, and no clear replications of genes implicated by candidate gene studies." - Report of the World Congress of Psychiatric Genetics.

Ischaemic stroke: "We produced more than 200 million genotypes...Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke." Lancet Neurol. 2007 May;6(5):383-4.

And the list goes on and on of traits for which nothing was found, with the authors concluding they need more money for bigger studies with more markers. It is really scary that people are never willing to let go of hypotheses that did not pan out. Clearly CV/CD is not a reasonable model for complex traits. Even the diseases where they claim enormous success are not fitting with the model - they get very small p-values for associations that confer relative risks of 1.03 or so - not "the majority of the risk" as the CV/CD hypothesis proposed.

One must recall that in the intial paper proposing GWAS by Risch and Merikangas (Science 1996 Sep 13;273(5281):1516-7) - a paper which, incidentally, pointed out that one always has more power for such studies when collecting families rather than unrelated individuals - the authors stated that "despite the small magnitude of such (sic: common variants in)genes, the magnitude of their attributable risk (the proportion of people affected due to them) may be large because they are quite frequent in the population (sic: meaning >>10% in their models), making them of public health significance." The obvious corollary of this is that if they are not quite frequency, they are NOT having high attributable fraction and are therefore NOT of public health significance.

And yet, you still have scientists claiming that the results of these studies will lead to a scenario in which "we will say to you, 'suppose you have a 65% chance of getting prostate cancer when you're 65. If you start taking these pills when you're 45, that percent will change to 2". Amazing claims when the empirical evidence is clear that the majority of the risk of the majority of complex diseases is not explained by anything common across ethnicities, or common in populations... (Leroy Hood, quoted in the Seattle Post-Intelligencer). Francis Collins recently claimed that by 2020, "new gene-based designer drugs will be developed for ... ALzheimer disease, schizophrenia and many other conditions", and by 2010, "predictive genetic tests will be available for as many as a dozen common conditions". This does not jibe with the empirical evidence... In Breast Cancer for example, researchers claimed that knowledge of the BRCA1 and BRCA2 genes (which confer enormously high risk of breast cancer to carriers) was uninteresting as it had such a small attributable fraction in the population. Of course now they have performed GWAS studies and examined tens of thousands of individuals and have identified several additional loci which put together have a much smaller attributable fraction than BRCA1 and BRCA2, yet they claim this proves how important GWAS is. Interesting how the arguments change to fit the data, and everything is made to sound as if it were consistent with the theory.

I suggest that people go back and read "How many diseases does it take to map a gene with SNPs?" (2000) 26, 151 - 157. There are virtually no arguments we made in that controversial commentary 8 years ago which we could not make even stronger today, as the empirical data which has come up since then basically supports our theory almost perfectly, and refutes conclusively the CV/CD hypothesis, despite Francis Collins' rather odd claims to the contrary...

In the end, these projects will likely continue to be funded for another 5 or 10 years before people start realizing the boy has been crying wolf for a damned long time... This is a real problem for science in America, however, as NIH is spending big money on these rather non-scientific technologically-driven hypothesis-free projects at the expense of investigator-initiated hypothesis-driven science. Even more tragically training grants are enormously plentiful meaning that we are training an enormous number of students and postdocs in a field for which there will never be job opportunities for them, even if things are successful. Hypothesis-free science should never be allowed to result in Ph.D. degrees if one believes that science is about questioning what truth is and asking questions about nature, while engineering is about how to accomplish a definable task (like sequencing the genome quickly and cheaply). The mythological "financial crisis" at NIH is really more a function of the enormous amounts of money going into projects that are predetermined to be funded by political appointees and government bureaucrats rather than the marketplace of ideas through investigator-initiated proposals. Enormous amounts of government funding into small numbers of projects is a bad idea - one which began with Eric Lander's group at MIT proposing to build large factories for the sequencing of the genome rather than spreading it across sites, with the goal of getting it done faster (an engineering goal) instead of getting more sites involved so that perhaps better scientific research could have come along the way. This has led to a scenario years later in which the factories now want to do science and not just engineering, which is totally contrary to their raison d'etre, and leads to further concentrations of funding in small numbers of hands when science is better served, perhaps by a larger number of groups receiving a smaller amount of money so that more brains are working in different directions thinking of novel and innovative ideas not reliant on pure throughput. Human genetics has transformed from a field with low funding, driven by creative thinking into a field driven by big money and sheep following whatever shepherd du jour is telling them they should do (i.e. innovative means doing what they current trend is rather than something truly original and creative). This is bad for science, and also is bad science. GWAS has been successful technologically, and it has resoundingly rejected the CV/CD hypothesis through empirical data. If we accept this and move on, we can put the HapMap and HGP where it belongs, in the same scientific fate as the Supercollider, and let us get back to thinking instead of throwing money at problems that are fundamentally biological and not technological!

(most notably in terms of the big money NIH is sending into these non-scientific technologically-driven hypothesis-free studies, rather than investigator initiated hypothesis-driven science - one of the main causes of the "funding crisis" at NIH where a tiny portion of new grants are funded - get rid of the big science that is not working - like the supercollider! - and there is no funding crisis)

Friday, August 15, 2008

De facto States and Western Hypocrisy over the South Ossetian Crisis

For almost two decades, I have had a very obscure and obsessive interest in reading about and travelling to the various de facto countries that remain unrecognized by the international community despite having all the actual trappings of statehood. They remain unrecognized by the international community largely owing to provisions of the UN charter and the Helsinki Final Act of the Conference on Security and Cooperation in Europe of 1975, effectively guaranteeing territorial integrity of all signatory states from secessionist movements or external aggression with borders fixed in stone as of that time in perpetuity. Following the collapse of the Soviet Union and Yugoslavia, the "constituent republics" of those two unions were granted the rights of states under these provisions, with borders as defined by the earlier union countries, while denying the rights of territorial integrity to any smaller autonomous subunits (like the ASSRs vs the SSRs in the Soviet Union), even as the borders of those states were often determined to force people of different ethnicities into the same state to help the center maintain control over the periphery by reducing the correlations between ethnic boundaries and republican boundaries.

In Yugoslavia, the resulting "countries" were Slovenia, Croatia, Bosnia-Herzegovina, Montenegro, and Serbia. Autonomous regions without the rights of states included Kosovo. At the time of its dissolution, in the USSR there were the 15 now-recognized union republics (SSRs), several autonomous republics (ASSRs), autonomous oblasts (AOs) and further autonomous okrugs, each with gradually lower levels of autonomy within the republics. Abkhazia was an ASSR that had earlier been a union republic (SSR) prior to being unified with Georgia by Stalin in 1931, and accordingly reduced in status to an ASSR within Georgia, Stalin's native republic. Abkhaz, however, are an Islamic population unrelated to the Christian Georgians, and resisted incorporation in Georgia. South Ossetia was an AO within Georgia, while North Ossetia was an ASSR within Russia, the separation largely stemming from events during the Russian Revolution. Stalin's mother being Ossetian encouraged him to maintain their autonomy, which included use of the Ossetian language in schools and daily life among other rights which were rescinded by the Georgian SSR in the late 1980s, leading South Ossetia to apply for promotion to an ASSR but which was never fulfilled. Nagorno-Karabakh is another former AO within Azerbaijan that is populated largely by Armenians. This region was awarded to Azerbaijan also by Stalin in the 1920s in part to placate Turkey which is ethnically tied to the Azeris, and led Stalin to give both Naxchivan and Karabakh to Azerbaijan to try and seduce Turkey into their sphere of influence. Nevertheless the tensions there simmered as well, with NK petitioning to be moved to the Armenian SSR many times in the 80s and 90s without success. The other de facto state remaining in the former Soviet Union is the Prednestrovian Moldavian Republic (PMR), also known as Transnistria. the PMR was never an autonomous region within Moldova, but it was an area largely populated by Russians and the Soviet 14th Army was stationed there. When Moldova reinstituted Moldovan as the sole official language, the Transnistrians declared their territory to be a union republic separate from Moldova, but this was rejected by Gorbachev, though the Transnistrians retained control over their territory anyway, and retained Russian as an equal language with Moldovan and Ukrainian on their territory.

The PMR fought a war with Moldova for its independence from 1990 - 1992, and as of 7/21/1992, a cease fire was declared and the PMR began building its own state apparatus, which today is effectively independent of Moldova. I have visited the PMR on two separate occasions, first in 2000, and more recently in July 2008. The PMR has formal border crossing posts established with both Ukraine and Moldova proper, the latter with Moldovan authorities and Russian peacekeeping posts in the middle, each to be negotiated separately, but the machinery of statehood is effectively complete, except that no country in the world recognizes the reality of their independence, and the UN pushes them to negotiate with Moldova for some compromise with the PMR incorporated within Moldova in some manner, despite the de facto independence of the area, and use of their own currency, the Prednestrovian Ruble. Accusations are made by Moldova and the West about smuggling of arms, drugs, and humans through this region, but it is difficult to understand why or how this would happen in practice, when the PMR has no airport nor direct sea access, being a landlocked country. The border control posts are set up with full inspection as in any other country with inspections carried out by both PMR and Moldovan or Ukrainian authorities on their respective sides of the border, so it is unclear how this actually would be possible without the Ukrainian or Moldovan participation on an equal level.

Nagorno-Karabakh formally declared its union with Armenia in 1989, and later after the Soviet Union rejected this declaration, NK declared itself to be an independent nation on 12/10/91. Wars between the NK Armenians, supported by Armenia fought with Azerbaijan for control over the region between 1988 and 1994, with a cease fire being declared on 5/12/94, though battles have continued over areas of Azerbaijan proper that are occupied by NK forces, and so on. The international community still considers NK to be part of Azerbaijan because of these same principles of international law described above, even though the population of NK overwhelmingly desires to be either independent, or formally part of Armenia, which is the way it is de facto at the moment. I have visited NK in 2006 by car from Yerevan, Armenia, and while there is a formal border crossing post in a valley on the road, there was no barrier to our continuing unabated into NK without even slowing down. I had the paperwork for a visa to visit NK, but noone checked it, and my driver did not even slow the car near the border, so effectively while NK has printed some of its own money and has its own armed forces, police, and governmental machinery, it really is acting de facto more like a province of Armenia with only the symbolic trappings of an actual independent country. Nevertheless it has all the symbolic machinery of government and statehood in place. As an aside the leader of the Karabakh Armenians amd first president of NK, Robert Kocharian, was subsequently elected president of Armenia itself, as further evidence of the lack of clear borders between NK and Armenia proper.

Abkhazia formally declared its independence from Georgia in 1992, after which a war ensued over the next two years until the Abkhazians drove out the last Georgian forces with Sukhumi falling in late 1993. In April 1994, a cease fire agreement was signed, establishing a peacekeeping force of Russians along the cease fire line between Abkhazia and Georgia. Since then, Abkhazia has functioned as an independent state, which I had the chance to visit also in 2006, with only limited areas of the former Abkhazian ASSR still remaining under Georgian control as of July 2008. They have their own government, army, and all the trappings of statehood and have functioned as an independent country de facto since the early 1990s.

South Ossetia was an AO within Georgia as mentioned above, and after the Georgians declared that only the Georgian language should be used throughout Georgia, and they rescinded the autonomy of South Ossetia completely in 1990. Following a war in 1991-1992, a cease fire was declared with OSCE setting up peacekeeping posts manned by Russian forces along the cease fire line in late 1992. A referendum in 2006 received near unanimous support for continued independence of the RSO from Georgia, though possibilities for unification with North Ossetia within Russia have been considered and proposed at various times over the last two decades since the skirmishes began in 1988.

Kosovo was an autonomous region with Serbia in the former Yugoslavia. In 1989 Slobodon Milosevic's government moved to reduce the autonomy of Kosovo, leading to an intial declaration of independence in 1990, which was only recognized by Albania (directly parallel to NK being recognized only by its ethnic parent, Armenia). Armed conflict with Serbian forces by the Kosovo Liberation Army supported by Albania began in earnest in 1996, culminating with the involvement of US and NATO forces on the side of the KLA in 1999. During the Kosovo war, NATO forces bombed targets across Serbia and Montenegro, and entered the conflict on the ground in defense of the Kosovar Albanians from Serbian forces that legally controlled the territory by the same principles of international law that put South Ossetia and Abkhazia under Georgian adminstration formally in the eyes of the international community. The United Nations Mission in Kosovo (UNMIK) administered the territory and borders of Kosovo from 1999 through 2008, when Kosovo declared its independence, a move which has been recognized by 45 countries, including the vast majority of the EU nations and the USA, while Russia, China and the CIS countries consider this independence declaration illegal by the principles of international law referred to throughout this entry. I personally visited Prishtina and other parts of Kosovo in the summer of 2007, and can say that it has vastly less of the trappings of statehood in any condition to function than NK, RSO, Transnistria, or Abkhazia, but the West chose to recognize its statehood leading to enormous ramifications in the other de facto countries which are hoping this will serve as a model for their own recognition abroad, but the west has refused to extend the same treatment to those countries to date, and Russia is not even keen on the idea because of their own danger of separatist movements in Chechnya and Tatarstan among others.

Of course, China likewise is uninterested in any modifications of the principle of territorial integrity, as they have their own de facto state - Taiwan - also known as the "Republic of China". On Taiwan there is a movement towards formally declaring independence, but even they still claim to be the legitimate government of all of China, and only recently has Taiwan ameliorated this position to the dismay of the PRC. Of course the entire world realizes that Taiwan has been functionally independent for roughly 60 years, and for 22 of those years it held the permanent seat on the UN security council as "China". After 1971, however, it was expelled from the UN and has appealed ever since for international recognition and representation in the UN and has been continually rejected because the PRC refuses to have diplomatic relations with any country that fails to accept its "One China" policy by recognizing Taiwanese independence. I have been myself in both Taiwan and China, and the strange thing was the strength of public opinion in China. In the midst of rational discussions with scientists and other professors at a human genetics conference in Changsha (I speak fluent Chinese, so we were speaking in Mandarin), someone asked what I thought about Taiwan, and I replied with a rational statement that politics aside, Taiwan is de facto an independent country, controlling its own territory and foreign relations, whatever people wish the truth were on either side. This provoked rational people turning into irrational - with slogans replacing logic "There is only one china and can only be one china!" - when I pointed out that there were two Koreas and China recognizes both of them, the conversation degenerated into them yelling emotionally whenever I tried to discuss matters rationally... The only comic incident I had was in the PRC with a police officer who stopped me on the street near Tiananmen Square. He asked for my passport, as they were stopping all the foreigners that day in the late 1990s. His first question was "what is your religion?" - I was confused but explained that I had none, and then he asked "what do you think about Falun Gong?" - I responded that I don't think about them except to notice their rather odd behavior outside the Chinese consulate in NYC. Then he saw my Taiwanese visa and asked what I thought about Taiwan. All I could respond with was that "In Taiwan, the police never stopped me on the street to ask about my religion!" - he laughed and I walked away (only because I did it with a smile and in Chinese do I think I got this sort of reaction :)) ). Anyway, with both China and Russia having permanent seats in the security council, it is unlikely that Kosovo, Taiwan, or any of the de facto states on the territory of the former Soviet Union will be recognized any time soon, with the constant legalisms about "international law" being thrown around that basically stem from these frozen conflicts.

The European Union has its own separatist issue as well - Cyprus. When the EU expanded to include the Eastern European nations, Greece threatened a veto of their accession if Cyprus was not allowed to enter the EU as well, even though it has a frozen conflict on its territory. The Greek Cypriot government is now a full member of the European Union as a result of this, while the Turkish Republic of North Cyprus is not. Cyprus claims that the principle of territorial integrity mean that the TRNC should not and could not be recognized internationally, even though the TRNC declared its independence in 1983 and has been functionally independent (though supported by its ally, Turkey) for 25 years. In 2004, the border was opened to let people cross from North to SOuth and vice versa, through the UN manned demilitarized zone. I had the opportunity to cross from South to North through this passageway in the summer of 2007. The TRNC functions as a state, though it uses Turkish currency much as Nagorno-Karabakh uses Armenian currency. The Turkish Cypriots overwhelmingly accepted Kofi Annan's plan to reunite the island and let them have the benefits of EU accession as well through a power-sharing plan, but this was rejected by the Greek Cypriots in the south, as they have the power and the EU membership and the seat at the UN, while the North is excluded from all international organizations, and only has formal diplomatic relations with Turkey - completely parallel to the Karabakh situation. Because of this situation within the boundaries of the expanded EU, they are likewise reticent about recognizing any of the de facto states formally, though 20 of the EU nations do have relations with Kosovo - this may, however, be more parallel to Turkey recognizing the TRNC and Armenia recognizing Karabakh because the EU nations in NATO were active participants in the war on the side of the separatists. Nevertheless Kosovo's accession to the UN and the rest of the international community will not be likely to follow soon because of the other entrenched conflicts.

Issues around the Israeli occupied territories are a lot more fuzzy, but the only thing which is clear is that they are not legally part of Israel under these principles of international law. The West Bank, Golan Heights, Gaza Strip, and Sinai Peninsula were occupied by Israel as a result of this war, and only Sinai has been returned to Egypt in 1979. The UN and other international organizations do not recognize the Israeli occupation as legal, and the Golan Heights is legally as much a part of Syria as South Ossetia and Abkhazia are parts of Georgia, for example. Of course, any attempt by Syria to reclaim this territory, as in the Yom Kippur war, would be met by resistance from Israel and its allies, much as the Georgian attempts to reassert control over South Ossetia were met by resistance from South Ossetia and its allies. The status of the West Bank, Gaza, and Jerusalem in international law stem from the partitioning of the British Palestinian mandate after World War Two into a Jewish state, Israel, an Arab state in West Bank and Gaza, with Jerusalem to be an internationally administered enclave. This partition is the basis for the Palestinian claims to the right of statehood on these territories and is supported by the UN and the international community, making this the simples (??!!) of these de facto state problems to solve, in theory...

So what happened in South Ossetia in a nutshell? The Georgians launched an offensive to try and reassert their control over this de facto state by force of arms. The South Ossetians were easily overrun as their population is only about 70,000 people while Georgia has 4.4 million. The border between Georgia and South Ossetia is manned by peacekeeping forces from Russia, and according the cease-fire mandate, their job is to defend the borders against aggression from either side, so when Georgia pushed to retake Tskhinvali, the Russians were automatically involved, as their troops were stationed between Georgian and South Ossetian border positions. It is significant to note that most South Ossetians have both South Ossetian as well as Russian passports, since they cannot travel internationally with an RSO passport since no other country recognizes the existence of the RSO. But that further made the attack on South Ossetia an attack on Russian citizens. Russia responded by sending its armed forces over the border from North Ossetia in the Russian Federation (the only open border between Russia and Georgia, as the borders along the Georgian Military Highway between Vladikavkaz and Kazbegi have been sealed for a long time - I had the opportunity to drive up the Georgian Military Highway, a pothole filled path over the Caucasus that requires a 4WD moving about 5mph to navigate, to the border with North Ossetia and Chechnya from the Georgian side in 2006), to retake Tskhinvali and assert control over the territory of South Ossetia. In the process of retaking South Ossetia, targets inside Georgia were attacked including their naval stations in Poti, as well as military bases in Gori (Stalin's hometown) and Senaki. They further sealed the road leading into Gori and between Eastern and Western Georgia, a highway that goes within a mile or two of the South Ossetian border, ostensibly to prevent arms smuggling and military operations by the Georgians. The Abkhazians and Russians further asserted Abkhazian control over the entire territory of Abkhazia, eliminating the few Georgian military troops that were in the Kodori Gorge area, and asserting Abkhazian control over their territory as well as Ossetian control over theirs. Substantial humanitarian aid from Russia and the CIS has been sent to South Ossetia, and there are many refugee camps set up in North Ossetia in the Russian Federation to deal with the aftermath, and Russia has further committed to rebuilding the infrastructure in South Ossetia and guaranteeing its freedom from future Georgian military incursions. Russia agreed to the ceasefirs terms only with Georgian guarantees not to use force in the future against South Ossetia or Abkhazia, effectively guaranteeing that the frozen conflicts will remain frozen indefinitely given the political circumstances involving Taiwan, Cyprus, Kosovo, Chechnya, and the other frozen conflicts around the world.

Now, first to deal with the legality of Georgia's decision to attempt to assert its control over South Ossetia by force, in principle, although it violates the terms of the ceasefire agreement they signed with the Ossetians and the Russians, it was technically within their rights, as international law does not recognize the de facto independence of South Ossetia for the last two decades. By the same principle, Serbia had the right to assert its control over Kosovo as it did in 1999. And in theory, China would have the right to invade Taiwan anytime it wishes to; The Republic of Cyprus and the EU have the right to "reassert authority" over North Cyprus; Azerbaijan could theoretically attempt an invasion of Nagorno-Karabakh; Moldova could "put down the uprising" in the PMR, and Syria would have the right to "re-acquire" the Golan Heights.

US and EU government officials are talking about territorial integrity and principles of international law every day on the television, on the floor of the UN, and in the written media. China is conspicuosly silent, merely requesting both sides to stop fighting during the Olympics and return to the negotiating table. Of course they are not able to take sides with the Russians, because what Russia did is equivalent to the US defending Taiwan from a Chinese attack (which would inevitably happen should China take that approach). Similarly, they are not about to take sides with a country like Georgia that has named the main thoroughfare from Tbilisi airport to Tbilisi "George W Bush Street". So they say nothing. The European Union is forced to take sides against Russia because Georgia is a future NATO member whose forces are trained by NATO, and further the Baltic states and the Eastern European countries that were overrun by Russia after WWII are not keen to see Russia involved in military ventures on its periphery. Cold War scars are deep, and the media presentations in the West make this situation resemble Prague in 1968, or Hungary in 1956. And of course the US sees Georgia as its major ally in the region, and as a means to hold Russian power in check in the Caucasus, much as the Russians are seeing Cuba as their equivalent in the Americas - something which has been resurgent as well in recent months, not independent of the greatly increased US and NATO presence in Georgia on their Southern flank in a revival of Cold War political mentalities.

As to Russia's involvement on the side of the South Ossetians, one can question its technical legality, as it did violate the internationally accepted borders of Georgia. But the fact is that the US and NATO did exactly the same thing in Kosovo. In Kosovo it was argued that the Serbs were oppressingand even "ethnically cleansing" the Albanians in the area - driving them to refugee camps in Albania and Macedonia to escape oppression, and the Western powers were defending the Albanians' rights to self-determination and freedom from persecution. In the South Ossetian conflict, Ossetians were rushing across the border to refugee camps in North Ossetia, and thousands of Ossetians are acknowledged by both sides to have lost their lives in the conflict. Russia claims to have sent its troops in with the goal of protecting its citizens, and the Ossetian people from the violations of the cease fire by the Georgians, and also in response to Georgian attacks on the peacekeepers manning the DMZ between South Ossetia and Georgia, between Gori and Tskhinvali. The arguments could not be more parallel, and yet the West claims they were right and the Russians are wrong, largely because of geopolitical issues involving Georgia's planned accession to NATO, and residual Cold War mentalities. It makes no sense to say Russia is wrong because Georgia is our friend and ally, while simultanously claiming that we were right in Kosovo, when we attacked Serbia, who is Russia's friend and ally.

Additional complaints have been made that Russia attacked targets inside Georgia, and not solely within South Ossetia, but continued the battle beyond the borders of Ossetia. Do we not remember the CNN coverage of the bombing of Belgrade during the Kosovo war, and the demolishing of bridges in Nis and other areas of Serbia proper? That was done for military reasons, just as the attacks on the military bases in Gori, Poti, and Senaki were done for military reasons. Blockading the road between Gori and Tbilisi is not different in purpose or function than the West destroying bridges in Serbia, to blockade transport of military infrastructure. Again, both Russia and NATO used similar tactics and both extended their battles into the territory of the country proper they were battling. How can this not be equally right or wrong, then? NATO claims they were right and Russia is wrong, but on what basis other than that "we are the good guys, so we must prevail by any means necessary, while the bad guys must follow the letter of the law". Scary and hypocritical. The questions one should ask is whether the officials who are criticizing Russia would take a consistent position if the People's Republic of China moved to retake Taiwan by force, or should the Syrians try to reassert control over the Golan Heights. My hunch is they would be "somewhat" contradictory...

After the Kosovo war, Kosovo was governed by UNMIK, the United Nations Mission in Kosovo until 2008 when Kosovo declared independence, and 45 countries have recognized it (21 of them in NATO, and the rest are close allies of the NATO countries, or are themselves supporters of other separatist unrecognized states - like Turkey and Armenia). Russia insists the declaration of Kosovar independence is illegal, Georgia adamantly insists that negotiations with the Serbs must continue longer - though its prime minister said in 2008 that, hypocritically, Georgia would inevitably recognize Kosovo since most of its friends already have... China did not support the independence declaration, also for obvious reasons. It will be interesting to see how Russia handles this situation. Clearly it would like to recognize Abkhazia, RSO, and the PMR, as each has substantial majorities of Russians or Russian citizens, but it is wary of doing so because of its position on Kosovo (vis a vis the Serbs) and more importantly Chechnya and Tatarstan, the latter with which Russia came to a peaceful resolution granting enormous amounts of autonomy to Tatarstan within the Russian Federation, though Russia did sign an agreement acknowledging the "Declaration on State Sovereignty of the Republic of Tatarstan".

The entire issue of self-determination vs territorial integrity is at the core of all these disputes along with Cold War mentalities leading to the "we are always right and they are always wrong" mindset prevailing in the West, and probably in the East as well, since each side is equally dug-in in their defense of their respective geopolitical allies. Resolution of these conflicts is frighteningly far removed from the actual peoples involved, but is being played out on a global scale in what amounts to little more than a fight among the superpowers for domination over a small number of small regions of little consequence to anyone beyond their regions. Most Americans and Europeans alike never heard of Abkhazia or South Ossetia until August 2008, and many more still have never heard of Nagorno-Karabakh or Prednestrovie. During the Kosovo war a frightening portion of the populations of the NATO countries did not know where Kosovo was or why we were fighting there, much as they knew little about Bosnia. What percentage of people in the EU know of the existence of the Turkish Republic of North Cyprus, other than people who have visited South Cyprus on booze and beaches vacations? These problems are being played out by the major superpowers because these little countries are on their periphery, in areas where other competing superpowers are asserting themselves. China has to deal with the US in Taiwan, Russia has to deal with NATO in Georgia, Turkey has to deal with the EU over Cyprus, and the EU (as it warms up to Moldova) has to deal with Russia over the PMR. Of course, Armenia has to deal with the relatively enormous Turkey over the problem in Karabakh, and to this day has fully sealed borders on its entire Eastern and Western borders to those countries - its only open borders being with Iran (a more natural ally of the ethnically related Azeris) and Georgia (not exactly the friendliest of relations there either...).

Meanwhile the people living in these territories have no diplomatic relations, no representation in the international community, and furthermore the international community has no way to regulate their activities either, and thus it is only natural that undergroud economies and various illegal activities find their way to these places which are not subject to international law as they are not part of the international community. For these reasons it is imperative that we do something to resolve these matters and deal with the inconsistencies between the internationally recognized rights to self-determination and territorial integrity...