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  • Swine Flu News: What is the significance of D225G?
    Swine Flu News: What is the significance of D225G?

    By Ilene

    Dr. Henry L. Niman

    With the current rush of news about the swine flu virus morphing into more aggressive lung-shredding and tamiflu-resistant mutants, there is some confusion as to why these changes are being seen in people in “hotspots” around the world, with no clear connection to each other. Officials at the WHO and CDC suggest that the same mutations are arising spontaneously in multiple locations but this doesn’t quite make sense. To better understand how changes in the swine flu virus may be occurring, I contacted Dr. Henry L. Niman, founder and president of Recombinomics. Dr. Niman has been an active researcher in the evolution of flu virus. His latest thoughts on the ongoing progression of the flu pandemic may be found at his website, Recombinomics.   

    For a little background, the D222G mutation or D225G mutation (same mutation, different numbering system) was found in three cases in Norway (“Norway” mutation), and in other countries, including Brazil, China, Japan, Mexico, Ukraine, the United States, and more recently Hong Kong. The change in a single nucleotide results in an amino acid change in the virus’s receptor binding protein. This has the effect of allowing the virus to bind receptors in the lung tissue, rather than the more usual binding to cells in the upper airways. Theoretically, this may confer greater virulence to the virus, potentially leading to more severe disease as the infection invades deeper in the respiratory tract. This change was also seen in the 1918 flu pandemic, in some (but not all) cases.  (See also my previous article, H1N1 Flu Perspective.)

    Recombinomics

    The name of Dr. Niman’s company “Recombinomics” is taken from the word “recombine” or “recombination” the driver of rapid molecular evolution and the emergence of infectious agents. Recombination* is a mechanism whereby small bits of genetic information pass between viruses so that a virus may quickly acquire a genetic change that evolved previously over the years in other viruses. Recombination is similar to reassortment, but with less genetic material being exchanged.

    Sporadic mutations do not usually lead to successful adaptive changes – often they have no effect or prove to be non-adaptive, with the mutation failing to be further replicated. In contrast, recombination allows viruses to quickly alter their characteristics by acquiring genetic material that already exists in the viral reservoir (i.e., the pool of viruses circulating in a population). This genetic material has already survived the trial and error period of natural selection. The viral reservoir consists of wild-type viruses (the predominant viruses) and a low levels of variants carrying a variety of different sequences (genetic “polymorphisms”).  

    Dr. Niman explained that recombination is not the favored theory regarding how the flu viruses evolve. Nevertheless, Dr. Niman’s theory has led to accurate predictions about the swine flu’s course during this pandemic. CDC and WHO officials may be slow to understand the changes we are seeing in the swine flu virus, but as this disease progresses, the consensus view on how viruses evolve may also change.

    My questions to Dr. Niman about recombination may have prompted him to write the following article explaining how the D225G marker, which is a genetic change that enables the virus to invade and replicate in the lungs, may begin to appear in many geographical locations at once. The process of recombination explains this phenomenon better than the competing theory of sporadic mutation, which assumes that these genetic changes are occurring independently as copy errors in multiple places at the same time. 

    Spontaneous Mutation Media Myth
    Recombinomics Commentary
    November 24, 2009

    The mutations appear to occur sporadically and spontaneously. To date, no links between the small number of patients infected with the mutated virus have been found and the mutation does not appear to spread. [WHO briefing]

    The above comment from the WHO briefing on D225G (aka D222G) in Norway describes how the “mutations appear”.  However, this appearance is based on an outdated view of influenza evolution, which maintains that all newly acquired drift “mutations” are based on copy errors.  For D225G, this would require the same copy error to occur again and again on multiple [genetic] backgrounds, which simply is not reality based.

    Although the “random mutation” explanation is one of the basic tenets of the WHO and CDC view of influenza evolution, this explanation is only viable in the absence of data.  Extensive influenza sequence data moved this hypothesis into the indefensible category years ago, but it remains at the core of WHO explanations of drift variants, such as the comments above.

    The “random mutation” and failure to spread would require each detection to be an independent event. Thus, in Norway, the same copy error would have been made in each of the three patients with D225G.  Similarly, the same error would be required for each of the four fatal cases in Ukraine.  Moreover, the same error would be made in the vaccine target, A/California/7/2009, because one of the [candidate clones for the flu mist vaccine had D225G].  As the number of sequences with D225G increases, the likelihood that the same error happens again and again, among a very small number of differences… becomes untenable…

    For D225G, the change was present in one of the earliest isolates [viral material isolated from a sick patient] in the United States. It could jump from one [genetic] background [virus] to another via recombination between sequences that are closely related.  As a result, the new acquisitions lead to a new single nucleotide polymorphism, which looked like a point mutation, but was really recombination between closely related sequences.

    [D225G] moves from one genetic background [virus] to another via recombination. A new spontaneous mutation is not required for each isolate [viruses isolated from a patient] and the same sequence in a given area is just due to clonal expansion [growth] of an isolate….

    Thus, the movement of the same polymorphism via recombination is common. It explains the sudden appearance of the same marker on multiple genetic backgrounds, and forms a basis for predicting changes.

    However, the reliance on a “random mutation” produces “surprise after surprise” among influenza “experts” and creates “appearances” such as spontaneous mutations and lack of transmission which are not based on reality.

     
    *****
    The D225G Marker

    According to Dr. Niman, the most likely explanation for the concurrent emergence of the D225G variant in multiple regions is that the “strain” of swine flu virus circulating is not a homogeneous strain but consists of a predominant (wild-type) strain with a variety of less common variants, including viruses with the D225G genetic marker and viruses that have the genetic sequences conferring tamiflu resistance. Dr. Niman believes viruses with the D225G marker are not adequately represented in the flu database because this variant is not easily detected in nasopharyngeal swabs.  However, there is enough of the D225G variant in the viral reservoir to act as “donor sequences” so the D225G change can jump from one virus to another, leading to its detection in many locations around the same time. The reason detection increases is that the viral reservoir, along with numbers of D225G variants, expands as flu season progresses. As the viral reservoir grows (more viruses, greater numbers of people infected), greater numbers of D225G viruses begin to show up in more and more flu cases.

    The background presence of the D225G mutation in the H1N1 virus strain explains why cases with the mutation are found throughout the world and why these mutations have been found in mild as well as severe cases. The presence of virus with the D225G marker should not be seen as an all-or-nothing phenomenon. Theoretically, if a D225G subclone takes hold in the lungs and expands, it can cause a more severe flu. While the D225G marker may increase the virulence of the virus, the receptor binding profile is only one of a number of factors influencing the severity and outcome of an infection. Other factors include the viral load (how much virus a patient is exposed to), the patient’s immune system (does the patient have antibodies against the virus?), and other characteristics of the infecting viruses (e.g., how transmissible is the virus?).

    Supporting the suggestion that viruses with the D225G marker are more virulent than the wild-type virus is the finding of D225G sequences in isolates from the 1918 Spanish flu pandemic. There is also evidence that this marker may have become more common in the Ukraine, where the swine flu seems to be particularly severe. Nevertheless, further evidence is needed to draw conclusions. Research is needed to answer questions such as what proportion of flu isolates contain the D225G marker? Is the D225G variant more prevalent in countries such as Ukraine where the flu seems to be more aggressive–is the increased severity of the flu in fact due to the presence of the D225G genetic change? Is the ratio of wild-type virus to D225G virus different in different geographical regions? Does this ratio differ in mild vs. severe cases? Are viruses with the D225 marker found in lung tissue of patients with mild flues? Is the ratio of D225G variant to the wild-type variant changing?

    Answers to these questions will greatly add to our understanding of the mechanisms by which flu viruses change their genetics to become more (or less) virulent and develop resistance to anti-viral agents. Solving the mystery of how the flu virus so quickly evolves may help us stay one step ahead with our yearly flu vaccines, anticipating changes, rather than chasing them. Hopefully, Dr. Niman will continue to make predictions and present evidence for his theory that the flu virus is able to change so quickly because it recombines with other flu viruses, exchanging small bits of genetic information with its viral neighbors. In time, perhaps the WHO and CDC will pay attention. 

    For more detailed discussions, see: 

    Identification of hemagglutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor

    A silent change appearing at the same time on multiple backgrounds:
     
    A paper on tamiflu resistance (H274Y):
     
    Detailed description of D225G, made 9 days BEFORE the Ukraine sequences were released: http://www.recombinomics.com/News/11090902/Ukraine_1918.html   
     
    More on D225G, before the sequences were released http://www.recombinomics.com/News/11180901/Ukraine_D225G.html  
     
    Here is the Oct 22, 2005 prediction on S227N http://www.recombinomics.com/News/10220501/H5N1_H9N2_Recombination.html 
     
    *Note on definitions of recombination and reassortment: Flu Trackers blog.  As Dr. Niman uses the term “recombination,” the genetic material does not undergo a reciprocal exchange, but rather, a double infection in the same cell results in the potential for a sequence in one virus to be replaced during copying with a sequence from another virus. – Ilene

    ********

    Dr. Henry Niman earned a PhD in biochemistry at the University of Southern California in 1978. His dissertation focused on feline retroviral expression in tumors in domestic cats.  Working on his post-doctorate at the Scripps Clinic and Research Foundation, Dr. Niman developed monoclonal antibody technology.  He later accepted a staff position at Scripps, and subsequently had a joint appointment as an Instructor in Surgery at Harvard/Massachusetts General Hospital and as a Research Associate at the Shriner’s Burn Center across the street from Mass General. (These were research positions – he did not teach or do surgery.)

    In 1982, Dr. Niman developed the flu monoclonal antibody, which is widely used throughout the pharmaceutical, biotech, and research industries.  He also produced a broad panel of monoclonal antibodies against synthetic peptides of oncogenes and growth factors.  The technology developed by Dr. Niman was used to form ProgenX, a cancer diagnostic company that became Ligand Pharmaceuticals. More recently, he became interested in infectious diseases.  He founded Recombinomics and has been studying viral evolution.

    As a coincidence, I also discovered that Dr. Niman and I worked in the same pathology/biochemistry lab at the University of Southern California in Los Angeles, separated only by about ten years.

     

    Nov 25 10:45 PM | Link | Comment!
  • Swine Flu News

    Swine Flu News

    By Ilene

    flu virusThe good news is that the number of new cases appears to be dropping off in most of the United States. More good news is that the swine flu vaccine appears to be reasonably safe, with no increases in serious events, including death, above the expected baseline rate. The not-so-good news is that a currently noted "peak," in flu language, is temporary. Additional waves of increasing illness are expected.  The other bad news is that pediatric deaths from the swine flu are already considerably higher than in past seasonal flues, and the numbers are expected to continue rising.

    Estimated Statistics:

    Update from the CDC, Weekly 2009 H1N1 Flu Media Briefing, Anne Schuchat, director of vaccination and respiratory disease at the C.D.C

    these estimates will give a single number and then a range, a lower and upper estimate around each number….  So for April through October 17th, we estimate the 22 million people have become ill from pandemic influenza.  We estimate 98,000 people have been hospitalized so far through October 17th.  And the upper and lower estimates on hospitalizations are from 63,000 to 153,000. We estimate that 3,900 people have died so far in the first six months of the pandemic from this virus.  And the estimates there are from 2,500 up through 6,100 people having died so far.  We’ve been talking a lot about this pandemic being a younger person’s disease, that it’s disproportionately affecting children and young adults and relatively sparing the elderly, very different from seasonal flu… [In] children under 18, we estimate 8 million children have been ill with influenza, 36,000 hospitalized, and 540 children have died…

    I do believe that the pediatric death toll from this pandemic will be extensive and much greater than what we see with seasonal flu…The numbers I’m giving are through the first six months through October. We have had a lot of disease since then and we’ll probably have a lot of disease going forward…

    What does this look like compared to previous pandemics.  The estimates I’m giving you are the first six months.  This is April through the middle of October.  We have a long flu season ahead of us.  In typical seasonal flu we see disease from December to May, it’s only November.  So exactly what we will see as a full toll of illness from this pandemic is very difficult to say.  I can say, though, that what we’re seeing with this h1n1 virus is nowhere near the severity of the 1918 pandemic.  That caused much larger numbers six months in…

    Number of cases declining in U.S.

    The New York Times reports that according to the American College Health Association, "new cases of flu among college students have started to drop, hinting that this wave of the swine flu pandemic has peaked… The association does weekly surveys of more than 250 colleges and universities with a total of three million students, and new cases of flu in the week that ended on Friday dropped by 27 percent from the previous week. About 80,000 of the students have had flu symptoms, about 150 have been hospitalized and last week there were two deaths." According to the LA Times only 3% of college students have been vaccinated.

    The current wave of swine flu seems to have peaked in the U.S. However, Dr. Schuchat warns that "peaking" does not mean the flu is going away. Further waves of infection are typical of flu viruses. The spread of disease is also increasing in some regions, such as Hawaii, Maine, Canada, Norway, and Eastern Europe, and Central Asia. Signs That Swine Flu Wave Has Peaked in U.S., Centers for Disease Control and Prevention

    Moreover, even if new infections decline, that will not instantly be reflected in hospitalization and deaths. (But see H1N1 deaths, hospitalizations slow in California.)  Dr. Lone Simonsen, a former C.D.C. epidemiologist, expects a third wave of infections in December or January. And according to Anne Schuchat, more H1N1 flu is circulating now compared to the height of usual flu seasons. "It is so early in the year to have this much disease. We don’t know if these declines will persist, what the slope will be, whether we’ll have a long decline or it will start to go up again." Swine Flu Seen as Cresting (WSJ).

    D222G Mutation

    A mutation, called the D222G mutation has been found in three people in Norway.  The D222G mutation is on the receptor binding domain, and it allows the virus to penetrate further into the lungs. According to Geir Stene-Larsen, director of the Norwegian Institute of Public Health, only three of Norway’s 70 tested samples had the mutation and it did not appear to be circulating. Rather, this mutation appears to arise in cases spontaneously.  NY Times, Signs That Swine Flu Has Peaked:

    Asked about that, Dr. Schuchat said the same mutation had also been found in mild cases in several countries, and it did not make the virus resistant to vaccine or to treatment with drugs like Tamiflu. She said she did not want to “underplay” it, adding that “it’s too soon to say what this will mean long term.”

    The D222G mutation allows the virus to bind to receptors on cells lining the lungs, which are slightly different from those in the nose and throat. Henry L. Niman, a flu tracker in Pittsburgh, has been warning for a week that D225G — the same mutation under a different numbering system — has been repeatedly found in Ukraine, which is in the grips of a severe outbreak and where surprising numbers of people have died with lung hemorrhages — the kind of pneumonia that can be caused by an immune system’s “cytokine storm” attacking a new virus.

    According to the Washington Post, Norwegian scientists detect mutated form of swine flu,

    “the Norwegian Institute of Public Health said the mutation “could possibly make the virus more prone to infect deeper in the airways and thus cause more severe disease,” and that ”there was no indication that the mutation would hinder the ability of the vaccine to protect people from becoming infected”…

    The World Health Organization said viruses with a similar mutation had been detected in several other countries, including Brazil, China, Japan, Mexico, Ukraine and the United States. “No links between the small number of patients infected with the mutated virus have been found and the mutation does not appear to spread,”…

    Several flu experts said that the mutation should not cause widespread alarm. “Influenza is a mutable virus, and changes are to be expected,” said Arnold S. Monto of the University of Michigan in an e-mail. “This is typical early in the spread of a pandemic virus.”

    The Norway mutation may cause more severe disease by infecting deeper into the respiratory track.  However, viruses from numerous fatal cases have not shown this mutation and the significance of the Norway mutation needs to be further investigated. (Washington Post, WHO says swine flu samples from Ukraine showed no significant mutation, WHO investigating Norway swine flu mutations.)

    Other mutations have also been found.  Bloomberg reported that "five patients at a hospital in Wales contracted swine flu that resisted treatment with Roche Holding AG’s Tamiflu, and three more infections are being analyzed… Four patients had resistance in a North Carolina hospital."  This mutation may have spread to other patients.  "The infections in Wales may have passed from a person using Tamiflu to patients who haven’t taken the drug, raising the possibility that a hard-to-treat form of the disease may spread,…" Mutated Swine Flu Strains Block Drugs, Worsen Illness.

    Vaccine – evidence of safety

    The World Health Organization reported that among the 65 million adults and children who received a swine flu vaccine since September, less than 30 died and less than 10 developed Guillain-Barre Syndrome. None of the deaths appeared to be associated with the vaccine. The findings so far indicate that the swine flu vaccine has a negligible risk for causing serious side effects, such as Guillain-Barre syndrome, and death.  See Safety of pandemic vaccines, Pandemic (H1N1) 2009 briefing note 16:

    19 NOVEMBER 2009 | GENEVA — To date, WHO has received vaccination information from 16 of around 40 countries conducting national H1N1 pandemic vaccine campaigns. Based on information in these 16 countries, WHO estimates that around 80 million doses of pandemic vaccine have been distributed and around 65 million people have been vaccinated. National immunization campaigns began in Australia and the People’s Republic of China in late September.

    Vaccination campaigns currently under way to protect populations from pandemic influenza are among the largest in the history of several countries, and numbers are growing daily. Given this scale of vaccine administration, at least some rare adverse reactions, not detectable during even large clinical trials, could occur, underscoring the need for rigorous monitoring of safety. Results to date are encouraging…

    To date, fewer than ten suspected cases of Guillain-Barre syndrome have been reported in people who have received vaccine. These numbers are in line with normal background rates of this illness, as reported in a recent study…

    A small number of deaths have occurred in people who have been vaccinated. All such deaths, reported to WHO, have been promptly investigated. Although some investigations are ongoing, results of completed investigations reported to WHO have ruled out a direct link to pandemic vaccine as the cause of death…

    Previously, I suggested that the seasonal flu vaccine confers some protection against the swine flu.  There have been studies showing a protective effect, studies showing no effect and one study suggesting an increase in risk.  Weekly 2009 H1N1 Flu Media Briefing, Anne Schuchat.

    Ukraine Update

    H1N1 Update: Ukraine Swine Flu deaths are not a mutated version of H1N1

    Great panic ensued after 16 swine flu deaths occurred in a single day in Ukraine. This caused many scientists to wonder if the virus had mutated from its original form or was more similar to the Spanish Flu than Swine Flu.

    However, after analyzing 34 samples, it is clear that the Ukraine swine flu deaths were just that: deaths due to H1N1, not a mutated version of the virus.

    Flu deaths rise to 354, but Ukraine Health Officials plan to lift quarantine

    The Ukraine virus, which is similar to the swine flu, according to the World Health Organization, has now claimed the lives of 354 people since the beginning of October. According to recent reports, the Ukraine government intends to lift the quarantines and other protective measures put in place to protect against the spread of the Ukraine flu… Government officials have stated that the situation has stabilized, and quarantines are no longer necessary. In addition, there may be some concern of quarantines interfering with the upcoming presidential elections.

    In summary, the swine flu vaccine appears to be safe, the infection rates in most of the U.S. appear to be dropping off (though expected to resume), and the significance of the Norway mutation is unknown.  Investigations of the Norway mutation, as well as mutations leading to Tamiflu resistance, are ongoing.


    Nov 21 1:22 PM | Link | Comment!
  • Correspondence with Phil Davis regarding how oil speculation affects oil prices.

    Correspondence with Phil Davis regarding how oil speculation affects oil prices.

    Phil to me:

    this is a complicated issue as it's not just the act of creating a contract. 

    Let's say there are 100,000 barrels of oil in the world and 10 are sold each day and they are shipped from various places in various amounts but generally there are, at any given time, 30 days of oil at sea (300 barrels).  If I am taking straight delivery, I would contract with the producers to deliver me 1 barrel of oil per day for a year or 5 years or whatever for $50 a barrel.  My interest is to have a steady supply and the producers interest is to have a steady demand.  He wants to charge as much as possible, I want to pay as little as possible. 

    Enter the speculators.  Rather than me (the actual user) haggling with the producer directly (as is done in most business transactions), the speculator steps in and offers to buy as much oil as the guy can produce for $40.  I can't do that because I only need one barrel a day but if the guy can make 1.3 or 1.6 barrels a day or he can add a new pump and make 2 barrels a day, knowing he has a buyer at $40, he will be thrilled (assuming the profits work selling 2Bpd at $80 vs 1Bpd at $50). 

    In a perfect world, the speculator is simply taking on some risk and will make the difference between the $40 they are paying and the $50 I am willing to pay and they will sell the excess for $40-50 and make a nice overall profit. 

    But then the speculators get greedy.  They know I NEED 1 barrel per day and perhaps there was some seasonality to pricing or natural fluctuation but all the speculator has to do is wait for the price to rise and then hold it there.  If supply is uneven, they can divert some to storage.  They are still buying it, creating demand but they are not delivering it so there is suddenly a "shortage" where none existed before.   As they accumulate more barrels in storage (say 100) they realize that getting the price up to $60 makes them not only $10 a day more per barrel they sell me, but it increases their "wealth" by 20% as the 100 barrels they have in storage are now valued at $60 - even though they are actually unwanted barrels that have been manipulated out of circulation. 

    Given this situation, it is always in the interest of the speculator to encourage demand, even when supply will fall behind.  They can encourage highways to be built, block public transportation, fund the use of plastics for everything, get government to stockpile oil, discourage clean air laws and block alternative energy legislation and encourage auto companies to make gas guzzling cars and extend credit to anyone who wants to buy a cargo truck to take the kids to the grocery store. 

    It is also in the interest of the speculators to curtail supply, which also boosts the value of what they have.  They can do this by teaching the producers to form a cartel to control prices, they can downgrade refiners and get clean air legislation passed so none can be built, they can refuse to lend money for oil exploration or give money to groups who are against drilling or use their PR departments to vilify governments who are able to supply oil but are not under their thumb.  They may even start a war or two to destroy existing supplies and knock out competitors' competing operations. 

    Another fun thing speculators can do is to get other people to speculate.  Once you get more and more people speculating (and ETFs are great for this) then more and more product is pulled off the free market and into the hands of speculators, who end up hoarding something they actually have no use for, except as an investment.  You can goose speculation all kinds of ways - by making people think they can get rich, by making up stories of shortages, by manipulating price spikes - you name it. 

    On top of all that, you can manipulate the contracts on the "free" market.  All you have to do is get a friend (me) to agree to jack up the price with you.  You and I have 100 barrels of oil in storage and another 30 barrels in ships on the way and contracts for more years at $40 a barrel (say 750 barrels).  We have a few stories printed in the news about peak oil and demand and whatever nonsense and then I offer a barrel (1 of 10 sold that day) for $61 on the open market and you buy it.  Then you offer a barrel (10% of a normal day's trading) at $62 and I buy it.  Then I offer the barrel for $63 and you buy it and then you offer the barrel for $64 and I buy it.  What has happened?  You and I have spiked the volume of trading by 40% for the day and ramped the price up 6.5% by trading the same barrel back and forth 4 times. 

    You paid $61, I paid $62 (+1 to you), you pay $63 (+1 to you) and I pay $64 (+1 to you) so the whole scam costs me $1 but we have raised the "value" of our 800 barrels of oil by $4 ($3,200), not a bad ROI for a day's work. 

    So that's the short version of how it works.  It's kind of like the 4 blind men who feel an elephant and each guy thinks it's something else because the part he's feeling is so different from the others - unless you step back and get the whole picture, it's hard to make sense of it but once you do get the big picture, the parts become obvious....

    For a free 90-day subscription to PSW Report, click here.

    Nov 14 12:32 PM | Link | Comment!
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