by XMRV Global Advocacy on Thursday, June 30, 2011:
The following is from the talk W. Ian Lipkin gave at the WPI on the 24 June 2011.
May be reposted if a credit is given to XMRV Global Advocacy.
WHITTEMORE: Good afternoon and welcome. I'm Annette Whittemore, President of the Whittemore Peterson Institute, and I'm happy to welcome all of you to Dr. Ian Lipkin's presentation on Microbe Hunting. Dr. Lipkin is the Director of the Center for Infection and Immunity and John Snow Professor of Immunology and professor of Immunology and Pathology at the Mailman School of Public Health at the College of Physicians and Surgeons at Columbia University. A physician scientist, Lipkin is internationally recognized for his work with West Nile Virus and other viruses such as SARS and the discovery of the molecular methods strategy, techniques pioneered in his lab. Many of you who are patients who have Chronic Fatigue Syndrome are also aware that he is coordinating a multi-center study of the relationship between XMRV and Chronic Fatigue Syndrome. Welcome Dr. Lipkin.
LIPKIN: Thanks, Annette, for that generous introduction. I don't know how many people in this audience are scientifically sophisticated and less sophisticated, but my talk is really directed to an audience that really does know a fair amount about medicine in some sense. So, if you have questions at the end, anything specific that I have not touched upon, just let me know and I'll try to address that.
I never quite know... I have so many mics hooked up here, I know that at least one of them is working. Is the one that's hooked to the film working as well? Good. So I'll get started.
This is Pandora. Many of you will remember from Greek mythology that she was told not to open this box. She did so anyway, and there were all these diseases that flew out to plague mankind. She was closing it, and just as she was about to close it, she heard one little plaintive voice, and that plaintive voice was hope. And so this is a very nice way of thinking about hope in terms of infectious diseases, including Chronic Fatigue Syndrome. And the attribution is Waterhouse. And as Frank Ruscetti has said, I've selected one of the more "dressed" versions of this particular depiction. There are others that are more scantily clad. This is not meant to be an X-rated presentation.
Now, we find a lot of infectious agents using molecular methods, and finding an agent doesn't necessarily mean that it can be implicated in a disease. And there are a number of ways in which people try to approach this problem. The classic descriptions of these were done by Loeffler and Koch in the late 1800's in looking at tuberculosis, and they really don't fit but just to review them briefly. What Koch said is that you have to be able to find a microbe in every case of disease... and that it had to be specific for that disease. So, for example, let's say you find a herpes virus, which is present in five people and only one of them has disease. It would be very difficult to evoke Koch's postulates, so there are clearly problems with that, and I'll come back to that in a moment. You have to be able to isolate the microbe, grow it in a laboratory, and put it back into the individual animal or human and demonstrate that it causes the disease. So by these sorts of criteria, we haven't proven that HIV causes AIDS, because nobody has deliberately put HIV into humans, to our knowledge. But clearly, I think most people here would agree, that that's a pretty strong link.
So using that as a paradigm and thinking about the kinds of issues that we need to address in chronic fatigue and other chronic illnesses, we have to consider the fact that there are instances where we can't grow a microbe in the laboratory. We may not have an animal model system with which to test it, particularly if there are subtle signs of disease.
Thomas Rivers, in 1937, at the Rockefeller University, began to talk about ... at that point it was called the Rockefeller Institute--forgive me--adaptive immunity. You look for neutralizing antibodies as a way of proving relation to the disease. The idea is, if you mount a specific response to a bacterium or to a virus in association with a disease, that's very strong circumstantial evidence for that association. And in the mid-90's Dave Fredricks and Dave Rummand(?) at Stanford, both of them began looking at host environmental factors. Excuse me, looking at molecular markers as a sort of introduction to the PCR, and they said, you know, we have to demonstrate that the agent is present using molecular markers. Maybe we can't grow it but that is sufficient. But even here, there are a number of problems and I think the disease that we're talking about is a classic example of that because not everyone who is exposed will necessarily manifest the disease. There can be a whole series of environmental factors--nutritional, there are genetic factors, and so forth. And there are instances where you may become infected with an agent and not appreciate disease for decades.
Now when I typically give talks like this and I have more time, I give a number of examples. But let's just take a couple.
So, botulism. You can have clustered botulinum growing in your intestinal tract or in your skin, but have paralysis. How do you make the link between those two things--something in the GI tract or something in the skin and paralysis? But we have made those links, and as a result, we've been able to find ways in which we can address those problems. Tetanus is a similar sort of an example.
So what we have tried to do is to use a sort of very practical approach. In the instances where we can take something all the way through Koch's postulates: grow the virus, grow the bacterium, put it into an animal, replicate disease, that's the ideal. But there could be situations where we can't achieve that. So we have different levels of certainty in linking the presence of a microbe, or a factor--like cigarette smoking to lung cancer, for example--to the outcome. And the level of certainty will fluctuate at various points in the time that you are finding it.
So, let's say, as a for instance, you find an agent that you determine is associated with Chronic Fatigue Syndrome. Maybe it's XMRV, maybe it's MLV. It starts at the level of being a canidate. Then you need to slowly address, using all these other tools, is there an immunological response to it, can I develop an animal model, can I get some sort of a drug that's specific for that agent and prevent disease? And you slowly build the case until you can convict that particular bug. And that's really what you need to do ultimately, is to convict the bug.
Now this is ... I don't have time to go through all of this, but this paper lays down all of my thoughts on how you go through this process, and it's available on the web.
One of the questions that people frequently ask is how many viruses are yet to be discovered, and the answer is, it's an enormous number. So if you just consider that we've got 50 thousand vertebrate species--talk about fish all the way up to birds and the higher mammals and primates and stuff, and if each one has only 20 endemic viruses, that means there are a million viruses yet to be discovered. That doesn't mean these will all be associated with disease, but it means that there is an enormous amount of work yet to be done. If you actually consider the biomass of the globe, viruses comprise the majority. Because if you look in the oceans, they infect plankton and all sorts of other organisms. It's a massive...massive...amount of viruses. There is a lot of work to be done in virology.
Now, this is just an effort to try to understand the number of viruses that have been discovered, and what factors might lead to their discovery. So the viral sequence database, this is at the National Center for Biotechnical information, has been growing exponentially. The most important factors appear to be improvements in the technology. And there are another couple of things which also come up. The West Nile, people have been looking for West Nile variants or SARS or influenza or endemic influenza and so forth. But really the key is the technology. We started looking at the genome, it was a dollars per genome, now it's down to fifty thousand. I can do it for ten thousand. The numbers are going to drop further. And as these databases become more and more complex, the opportunities to find agents and to look for further association with disease is going to also increase. But again, finding something is not tantamount to proving that it causes disease.
Now this is a New Yorker's view of the world. It's just to sort of vulnerability that we all have. You could do the same experiment in LAX or SFO or wherever else you want to look. From JFK, so this doesn't even include Newark, we have 72 countries direct flights, 190 thousand international flights, 21 million passengers. You can see all of the destinations you can reach via nonstop flight, just from JFK. So, in a one-hour timespan, the green flights are coming into JFK and the red are leaving JFK. See, there is a staggering amount of new material that's coming in all the time.
So there are new viruses and new bacteria being introduced. Everybody's talking now about e.coli but this is just the tip of the iceberg.
The other issue for us is that we are beginning to have industrialized food production on a level we have never before experienced, and pork and beef and poultry are moving all over the world more and more and more rapidly. This is one of the reasons that I've become a vegetarian.
AUDIENCE MEMBER: I thought you liked fish.
LIPKIN: Yeah, well, I don't get them out of farms.
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