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Wednesday, December 21, 2011

This just in... again...

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So, this week, media reports once again discovered the influenza virus research by the Erasmus Medical Centre in Rotterdam that I commented on here.  Note that this research was originally reported at a scientific meeting in September of this year, so it isn't really  urgent, breaking news.  What is news is that the U.S. Government is asking the journal Nature to censor the research report.  

Once again I have been asked a number of questions about the ethics and the practicalities of the work.  The language of those condemning the research and public release of the information usually protrays the scientists as "educated idiots" and "dolts" to meddle in something as dangerous as influenza.  

Such vitriol does a great disservice to the scientists, hence my vigorous defense of the field.

So, here is a brief mailbag entry from Nate:  


S2LA,

Not saying the research should not have been done, just have issues with the apparent handling of it.

Do these universities have the needed controls and security to protect against accidental release? I know that here in the States the physical security varies incredibly.

What level of sophistication would be needed to do this type of forced mutations? Is it something that can be fired up in a community college level laboratory or a midsized state U or would it take a specialized research lab?

Is it something like nuclear weapons and most other technology? If you know it is possible to do it is much easier to reproduce?

What are the steps from where they are at to get to a useful vaccine?

Thanks, Nate
Very good questions, Nate, so let's look at them step by step:

Likelihood of release: 

If this is a viral research lab, it really doesn't matter which country the lab is in, they have to take precautions to not infect themselves, so there really is no difference between the lab in Rotterdam and one at say, Emory or Stanford.  It's probably a level 3 biocontainment lab.  There *is* a difference between that and a CDC Level 4 or 5 lab but still, the chances of release are low.

So, what if it *is* released – one to 5 people in a typical lab would be exposed to the virus – however, what form is it in?  To infect a human, H5N1 has to enter the lungs in aerosolized form.  What that means is that the virus needs to be in small fluid droplets with a certain amount of live or newly dead animal tissue in the droplets to keep the virus alive.  Sanitary precautions such as alcohol sanitizer and wipes, disinfectant containing bleach or iodine would kill it.  Then there is the fact that one virus particle alone is not enough to infect a healthy human, nor is one human enough to start an epidemic or pandemic.  Accidental release is unlikely to start a pandemic (although deliberate release might – so we'll discuss that later) it *may* result in a few people getting sick.

How bad is this flu?



From The Independent's story"The fear is that if you create something this deadly and it goes into a global pandemic, the mortality and cost to the world could be massive," a senior scientific adviser to the US Government told The Independent, speaking on condition of anonymity.
"The worst-case scenario here is worse than anything you can imagine."
This is fear-mongering, pure and simple.  No one talked to a physician about how the flu is spread, no one talked to a scientist.  They sat around and said "OH WOW, We think this is BAD" and published it.  I am so absolutely livid about this sort of thing that it is hard to type the response.



It is true that the H5N1 influenza has had a mortaility rate of about 60%, but there have been about 500 cases worldwide – EVER!  Only 500.  All of those cases were transmitted from chickens to humans, so the humans did *not* contract a human influenza, they contracted the actual avian version of the virus.  This virus infects the lower respiratory tract – the lungs – and causes pneumonia.  The persons who died, did so from pneumonia, not the flu itself.




But what about human transmission?  To answer this, I have to lecture a bit on how virus transmission works.  First, a human has to come in contact with the virus contained in a medium in which the virus will grow.  Viruses are not alive, they can't be grown in petri dishes or a test tube – at least not without living cells.  Viruses enter living cells, than take over the normal cell growth and replication mechanism by inserting their DNA/RNA in place of the cells' own.  The cell is forced to make new copies of the viruses, which then rupture the cell and spread.  Without cell material, a virus is inert.  When the environment dries out, many viruses become incapable of infecting cells.  Treatment with heat, soap, iodine, bleach, ammonia, etc.  will break down the protein coat of a virus making it "dead."
 
SO a virus has to be *in* a cell in order to make copies to infect more cells.  Note that mutations in the virus are likely to occur with each new type of cell entered – but more on that later.

Spreading the influenza virus:


Following the fate of one "golden virus" particle in Patient Zero (P0):  P0 handles poultry in Thailand, he beheads, cleans and plucks hundreds of chickens a day.  One chicken is infected with H5N1.  On beheading, the blood sprays everywhere forming a spatter and mist, some of which lands on P0's face, and some is breathed into his lungs.  Unlike H1N1, the virus landing in nose and mouth does not cause infection, however the mist is breathed deep into the lungs.  The ciliated cells of the nasal (nose) and pharyngeal (throat) mucosa do a pretty good job of catching and filtering out the aerosol droplets.    So do the ciliated cells of the trachea (airway) – unless P0 is a smoker, since nicotine paralyzes cilia.  

Nevertheless, 99.99% of the droplets are caught before entering the lower lungs.  H5N1 enters cells in the alveoli (air sacs) of the lungs.  One virus entering a weaker cell can produce between 100 and 1000 copies of itself.  Once the cell fills with virus particles, it dies, ruptures, and releases the virus.  However, not all cells are susceptible to entry by the virus.  Macrophages (immune cells) in the blood, lymph and lung tissue consume dead and dying cells, and the virus may not get a chance to spread.  


With repeated low exposure, P0 develops antibodies to the virus and it never gets a chance to spread, but let's suppose P0 gets a large virus exposure and has low resistance to viral infection.  More lung cells are infected, rupture, and the lungs start to inflame and fill with fluid.  This takes about 5-7 days.  Once there is fluid build-up, P0 starts to cough.  Now he is infectious to others, because when he coughs, he sprays a mist of fluid, dead and dying cells and virus into his environment.  Note that with a "dry cough" (smoker's cough, asthma or emphysema) there is little to no moisture to support the virus.  With a "wet cough" (bronchitis, allergy and pneumonia) the fluid in the airway sprays out with each cough.


A person breathing in the aerosol from P0's cough (5-7 days after his infection) can catch H5N1, right?  Um, no.  Not so far.  Once again, viruses tend to mutate when they enter new types of cells.  The avian influenza virus mostly has its effect by causing pneumonia – swelling and fluid accumulation in the extremely nutrient, oxygen and fluid-rich environment of the lungs.  It has mutated, and the version sprayed out in each cough does *not* have the ability to survive in dry air or infect other humans.
Yes, P0 has a 60% chance of dying of pneumonia, as of one year ago, there were 510 reported H5N1 infections and 303 deaths, but no proven, ubiquitous human-to-human transmission.
Again, from The Independent:  "For the first time the researchers have been able to mutate the H5N1 strain of avian influenza so that it can be transmitted easily through the air in coughs and sneezes. Until now, it was thought that H5N1 bird flu could only be transmitted between humans via very close physical contact."
Researchers in Rotterdam made five point mutations to the H5N1 virus that *PRESUMABLY* make it susceptible to human-to-human transmission.  They don't know it for fact, it wasn't tested on humans, so it is not completely proven.s, P0 has a 60% chance of dying of pneumonia, as of one year ago, there were 510 reported H5N1 infections and 303 deaths, but no proven, ubiquitous human-to-human transmission.
The Independent:  Dutch scientists carried out the controversial research to discover how easy it was to genetically mutate H5N1 into a highly infectious "airborne" strain of human flu. They believe that the knowledge gained will be vital for the development of new vaccines and drugs.


The discovery has prompted fears within the US Government that the knowledge will fall into the hands of terrorists wanting to use it as a bio-weapon of mass destruction. Some scientists are questioning whether the research should ever have been undertaken in a university laboratory, instead of at a military facility.

What does it take to perform the forced mutations?

OK, now we get back to Nathan's question about what it takes to do this sort of mutation and virology, can it be done at community college level?  Or does it take a specialized lab.  Offhand I would say that this sort of work requires a dedicated virology lab.  First, you need knowledge of culturing viruses, it's not easy, but can be readily learned.  Performing the actual mutations, though, requires gene sequencing equipment and a means to ensure that the appropriate sequences are maintained in the virus.


Is this like making nukes?  Once you know it is possible, it's easy to reproduce?

No, Johnny Jihadi is *NOT* going to be doing this in his bathtub.  The truth is that any lab *capable* of doing the mutations probably already has the knowledge and ability to do so.  Has anyone noticed how many med school and grad school students are foreign nationals?  At one point, my department was 1/4 Chinese, Indian and Middle Eastern students.  Many departments are even higher.  Does anyone *seriously* think that terrorist organizations and adversarial nations don't recruit highly educated people and supply them with what they need? 

The mutations are likely very easy to introduce.  Why?  Because viruses mutate naturally.

Let me say this again: Viruses mutate naturally.

OK, now I'm going to shout it:  VIRUSES MUTATE NATURALLY!  

The Influenza A virus which is the root of the "H" strain viruses is highly susceptible to mutation.  I mentioned this before and promised a discussion later – every time a virus enters a new host or new type of cell, it mutates.  Every year we need a new seasonal flu vaccine due to the mutations from the previous year.  One natural consequence is that most influenza epidemics burn themselves out because the second, third and fourth generation of the same virus has mutated to a *less* virulent form. 

In fact, Tom Kratman and I had to work quite a bit to come up with a scenario for a Smallpox virus that would become *more* not *less* virulent for Caliphate.  Frankly, being (presumably) human transmissible, the virus cooked up in Rotterdam isn't exactly H5N1 anymore, and we don't really know how it will react in the human population. 

Influenza is also contagious at the same time that the patient shows symptoms.  The very coughs and sneezes that are symptoms of the flu are the transmission vector, so the flu virus that the first generation patients could possibly catch from P0 is already mutated.
One blogger* wrote the following "Some dopes in a Dutch lab have made the threat a lot more real.  By mutating H5N1 into a more human threat, these scientists have given would-be bio terrorists something to salivate over. They say they did it because it could help them develop more effective vaccines in the future, but to me this falls into the category of things you just shouldn't mess with, no matter how pure your intentions."  [*Please note, the blogger is an IT security type, not a biologist, although I am not at all certain that should excuse his language.]
OK, so which "Dopes" would the blogger rather have – ones who performed the mutations to determine how easily it could happen naturally (which it really can!) and then be able to quickly produce vaccines – or ones who ignored the issue until Nature, or someone with less benign intentions, does it for them. 

IGNORANCE *IS* THE PROBLEM. 

The real issue in all of this research is that the mutations could very well happen naturally, and virologists have been expecting it since 2003. 

The unasked question...

Now, should it be classified?  HELL NO!

Yes, once it is known that there are only 5 mutations required, it may become easier for others to do so.  On the flip side, once the knowledge is disseminated and the articles published, it becomes common knowledge, and much harder to hide illicit virus or biological weapon production.  We can also have ready-made stocks of vaccines on hand to shut down a pandemic before it starts.  The true scare is *not* what if a terror lab produces the virus – but what if it occurs naturally?

But does this mean it should be done in a military lab instead of a college/university?  Not necessarily.  First, military labs and military funding are for research with military priorities.  It is na├»ve to think that research into weaponization of H5N1 isn't being done, but developing vaccines for civilian populations would not necessarily have as high a priority.  Research into influenza mechanisms for the sake of pure medical research is also probably not a high priority for a military lab. 

I'm not going to speak about the pros and cons of "entrusting" H5N1 to military labs, but rather look a bit more objectively at the issues with restricting such knowledge to closed intellectual compartments.  Classified and restricted information requires clearances and special treatment.  If an H5N1 outbreak occurs due to natural or belligerent causes, do we *really* want the knowledge of how to deal with it tied up waiting for bureaucratic clearances? 

It really boils down to the concept that folks who might have the will to use H5N1 as a bioterror weapon either don't have the technology to do so, or if they have the skills and technology, they probably have the knowledge of what and how to do through other sources – as I said, influenza viruses mutate, it's what they do, and anyone who studies them knows it. 

What are the steps to get a useful vaccine?

As far as making a useful vaccine – until we know a hell of a lot more about making human cells resistant to viruses – the first thing you need is the actual virus... in the form which infects humans. 

In other words, you need the virus produced in the Dutch labs.  

Again, thanks to Nate for his insightful questions and the opportunity to answer them here.   I am sorry that posting has been so irregular this fall, I will do my best to get back on a more regular schedule with the new year, and remember, you can always ask questions and I see what I can do to give reasonable, science-based answers that y'all can understand!


-Speaker

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