Reconstructing the ancestral microbiome: the American Gut approach

hadza-615I came across the human food project website today. This site is run by the American Gut project folks. You may have heard of their work before: you send them $99 and they send you a home sampling kit. You swab yourself, and they give you a list of the microbes living in your gut. Neat, right? And besides yielding fun information for you, it provides a rich data source for them to analyze (with the goal being to learn more about what Americans are carrying around in their intestines).

I’m waiting for my results to come back from uBiome, a similar service.

Anyway, on the website, I noticed a section entitled Ancestral Microbiome. Exciting! I’ve actually been thinking about how one could go about reconstructing the ancestral microbiome a lot myself lately. Recently, I published a paper entitled Genomics, the origins of agriculture, and our changing microbe-scape in the Yearbook of Physical Anthropology with George Armelagos. One thing we looked at is attempts to learn more about the pre-agricultural microbiome. This is a really tough problem, for several reasons.

One approach would be to use aDNA to characterize microbiomes from ancient remains. The aDNA approach has worked out for some ancient post-agricultural remains (check out Insights from characterizing extinct human gut microbiomes by Tito et al.), but so far nobody has gotten it to work on remains dating prior to the advent of agriculture. Bummer.

Another approach is to study contemporary hunter gatherer groups. This is pretty problematic too, though. First, the very few hunter gatherer groups that are still around have been able to protect their way of life primarily by fending off agriculturalist intruders. This means that they are probably not amenable to being studied by swab-bearing scientists. Second, learning about the hunter gatherer groups around today isn’t necessarily going to tell you all that much about the typical hunter gatherer group living tens of thousands of years ago. The very fact that a hunter gatherer society is still around in a very agriculturalist world suggests that it may be unique in some way. Third, even though some hunter gatherer groups have been able to maintain their traditional subsistence strategies, more or less, it’s possible that they have still been exposed to agriculturalist microbes, which might have altered their microflora.

So how are the Human Food project researchers going about reconstructing the ancestral microbiome? They are studying the Hadza of Tanzania. About 1,000 Hadza live around Lake Eyasi in the northern part of the country, and roughly one-quarter of them live as hunter-gatherers (no crops, no livestock). Not surprisingly, the Hadza are not completely cut off from the world outside their homeland. Contact with agriculturalists stretches back for at least a century. Most Hadza now speak Swahili fluently. Alcohol has become a problem for some, and microbes like TB have been introduced. In the mid 1990s, anthropologist Frank Marlowe found that about 10% of calories that came into Hadza camps was from non-foraged food delivered by missionaries or obtained through trade with agriculturalist neighbors. It’s possible that an increasing stream of money from tourism may result in more calories being obtained from purchased crops nowadays.

It will definitely be interesting to see how the microbiomes of the Hadza differ from those found in other groups in the area. I think this is a project worth doing. But my guess is that there has been a lot of “microbe-creep” between the Hadza and these neighboring groups (and perhaps even foreign tourists). This, along with the other problems I pointed out, would compromise our ability to draw conclusions about the “ancestral” genome. I’m eager to see how this will play out–and curious to hear what other people think.

Does the polio vaccine cause polio?

imgres-2One claim that I’ve heard a lot from vaccine opponents is that the polio vaccine is actually causing polio epidemics instead of preventing them. Scary, right? On websites like “GreenMedInfo” you see headlines like Polio vaccines now the #1 cause of polio paralysis. And Joseph Mercola maintains that because of problems like this, “the polio vaccine is not the ultimate solution to prevent” polio.

Is any of this true? As it turns out, there IS a grain of truth to this claim. But the truth is way more complicated than vaccine skeptics seem to understand, and, as it happens, the solution is more vaccination, not less.

Here’s the deal. There are two types of polio vaccine, one that involves the injection of dead virus and another that involves oral drops filled with live (but non-disease causing) virus. Here in the U.S., we use the first type of vaccine. But there are many benefits associated with the second type of vaccine: it’s easier to administer (drops vs shots), it provides stronger protection, and here’s the biggie: because it can spread after being administered, it effectively inoculates other people in the community. This is called passive immunization, and it’s definitely a good thing! It means the protection of the vaccine extends beyond just the people who get vaccinated. The virus can remain in a child’s feces for up to six weeks, during which time she has the potential to inoculate the people around her.

There is a dark side to this passive immunization, though. Give the vaccine-derived virus enough time to spread, and it can begin to mutate. Tick tick tick. Enough mutations, and it may regain its ability to paralyze. When does this happen? When the proportion of vaccinated kids is low. Surrounded by plenty of susceptible kids, the likelihood that a vaccine-derived virus can circulate for long enough to gain these mutations goes way up.

Unfortunately, this situation sometimes occurs. There have been a number of vaccine-derived outbreaks of polio. In total, scientists think that, since the year 2000, there have been 20 outbreaks of vaccine-derived polio in 20 countries, resulting in 655 vaccine-derived polio cases. The biggest outbreak, involving hundreds of kids, happened in Nigeria. This isn’t surprising, because vaccination stopped in some regions of the country for over a year in the early 2000s.

The counterintuitive solution to fighting vaccine-derived outbreaks is to increase vaccination rates. That way, children are inoculated with the harmless version of the virus and can’t be infected with any “bad” versions floating around. Vaccine-derived strains are nipped in the bud before they have time to accumulate dangerous mutations.

One thing to ask people critical of the polio vaccine because of vaccine-derived outbreaks is what they recommend as a substitute. Joseph Mercola’s big idea is to cut down on sugar, apparently. Sadly, sugar consumption isn’t a big problem in most of the places where polio is still a problem. So I think we can rule that solution out. Sayer Ji, founder of GreenMedInfo, recommends improved sanitation. While improved sanitation certainly cuts down on opportunities for infection (polio is spread through the fecal/oral route), it can paradoxically create more opportunities for paralysis. Why? The older you are when you become infected with polio (and the age of infection goes up when opportunities for infection go down), the greater the odds of paralysis. So I think we can rule that solution out too (although improved sanitation has many other benefits, and it is definitely a worthwhile goal).

So while vaccine-derived polio outbreaks are a real thing, they are not a reason to abandon the polio eradication campaign, which has reduced the number of new polio cases by 99% since it began in the late 1980s.

On reproducibility: the risks of the replication drive

ReplicationAn article called Reproducibility: the risks of the replication drive just came out in Nature. In it, Mina Bissell makes some great points.

The main idea: replicating studies is hard. It’s easy to tweak something (without even knowing that you did it) and end up with different results. Because of this, it’s important not to cast doubt on the results of someone else’s experiment too quickly. Communicating with the lab who did the original study is important if you find yourself running into problems. Failure to replicate can have serious consequences: good scientists can lose credibility, promising lines of research may not be pursued, etc. Thus, attempts at replication should be taken seriously, and everyone should try to remain civil during the process.

OK. I think everyone probably agrees with that!

But there were parts of the article that made me a little uncomfortable. Bissell gives compelling examples of how tiny changes–using the same cell line, but from different laboratories, for ex.–can torpedo replication attempts. I too believe that this happens frequently, so no arguments there. But unlike Bissell, I see this as a major problem. If you can’t replicate a study using virtually (but not totally) identical conditions, how generalizable are the original results likely to be? How useful is an experiment that yields such shaky findings? If we can’t replicate findings in the lab, what are the odds that they will describe what’s happening out in the messy real world?

Bissell describes a comforting example in which exploring a failure to replicate under slightly different conditions yielded valuable scientific data. I’m sure there are serendipitous situations like that one, but I also suspect that they are few and far between. My suspicion is that, in most cases, when other labs fail to replicate an experiment after credible attempts to do so, there is probably a real problem with the original study. Either (1) because the original results were faulty in some way or (2) because the original results, though valid, are not at all robust. Either way, the science community needs to know. So in my eyes, the drive for replication remains vital and the risks are well worth it.

A List of Things that Patients Should Question

I just learned about the Choosing Wisely campaign. It’s pretty amazing. The goal is to get each major medical specialty society in the US to make a list of 5 commonly done things that doctors and patients should question.

Being a patient is hard. People tell you that you are in large part responsible for your own care–but you are not a medical expert. When do you trust your doctor’s opinion? When do you need to do your own research? How many people are actually capable of doing this kind of research? The whole thing can be nerve-racking, especially if you are dealing with a serious health condition.

imgres-1The Lists for Choosing Wisely are still being written, but many are up on the website already. I wish they were being publicized more. I’d never heard of them until I happened on an article about the campaign in JAMA, and I doubt many other non-MDs are familiar with them either. I even asked a couple of MD acquaintances, and they hadn’t heard of these lists.

If you want to see them, you can check them out here. Unfortunately, they are not especially easy for patients to sort through. They may be helpful, though, especially if you know what you’re after. Take the American Academy of Pediatrics recommendations. Some are pretty well-known (no cough/cold meds for small children, no antibiotics for viral respiratory infections) but others might be less widely known (they all deal with common situations in which CT scans are not necessary–it was stuff I didn’t know).

Here’s a more user-friendly facet of the website: If you have questions about a particular condition/procedure, you may be able to find a fact sheet on it (look at the column on the left). Do you need a PAP smear? Maybe not! But you may have to convince your gynecologist of that. Are you thinking about scheduling an early delivery for your baby? Maybe not a great idea. But again, you might end up arguing with your OB about it. Need help controlling your migraines? Might want to avoid certain drugs. These fact sheets are being developed by Consumer Reports, so hopefully they will get disseminated widely. It’s a really nice idea!

One thing I like about this campaign is that it might give patients stronger footing when they decide to question a medical recommendation. Lots of times physicians recommend treatments that aren’t backed up by evidence, but patients are hesitant to speak up. Maybe this will give them (us) a little more confidence. It also may help people sort through the credible research and all the crazy stuff you find when you do a health-related internet search.

Can mice inherit learned fears from their fathers?

imgresVirginia Hughes wrote today about some exciting results presented on Tuesday at the Society for Neuroscience meeting in San Diego.

Here’s the setup: postdoc Brian Dias and colleagues used mild shocks to make male mice fear a certain scent. Then, they allowed the mice to mate. Their offspring, which had never been through the whole scent/shock thing, showed an increased startle response when they encountered the feared smell for the first time. And this was only true of the specific smell their fathers had been made to fear. Not only did the researchers report finding this inherited fear in the offspring of the shocked mice–they also found it in the grand-offspring! Neat, right? But also, really puzzling. How could information in the fathers’ brains be transmitted to their gonads and then to their offspring? The researchers admitted they have no idea what the mechanism is at this point, although I’m sure they have lots of plans to investigate just this.

With no mechanism in mind a priori, it kind of made me wonder how the team dreamed up this experiment in the first place. And with no biologically plausible mechanism to invoke, it is a little hard to believe that the results aren’t just some sort of fluke. There’s a great blog post by Kevin Mitchell, The trouble with epigenetics, that highlights some of the problems with similar existing epigenetic research (ie learned experience being passed on to offspring, with the mechanism being shaky/nonexistent).

Lots of things presented at meetings don’t make it past the hurdle of peer review. Or they are published in greatly changed form. There is nothing wrong with that–this is one of the most important functions of scientific meetings. Putting your stuff out there with your best interpretation of what it means, and hearing from other knowledgable people about their take on your data. I guess the fate of this fascinating dataset remains to be seen.

In the meantime, responses to the announcement of these findings are blowing up the twittersphere. Hughes set up a storify so you can check them out.

Using male circumcision to prevent HIV infection in Africa

01-circumcision paksA piece called AIDS prevention: Africa’s circumcision challenge just appeared in Nature. I thought it was a great update on where we stand as far as using circumcision to prevent HIV infections in Africa. At this point, four randomized controlled trials have shown that it reduces the odds of transmission for men. So big circumcision campaigns are now being rolled out. One of the big worries is that circumcision will change people’s sexual practices, lulling them into a false security so that they forgo condoms. Based on this article, it seems as though many of the men getting circumcised and their partners aren’t sure what protection is actually being offered. That’s not a good sign. Critics have also pointed out that if men were planning on using condoms, they probably wouldn’t sign up to be circumcised. If there is core population of guys who just aren’t going to use condoms no matter what, though, it seems like circumcision would be a good (though far from perfect) mitigation strategy.

Time will tell, but maybe this will be one more piece in the puzzle.

One thing I’ve heard a lot in debates about male circumcision in the US that kind of surprises me is that people don’t think the trials in Africa are relevant to men in the United States. That is, they don’t believe that circumcision will protect against HIV transmission here. I’m still not sure what the reasoning is. Yes, HIV is less prevalent here (well, depending on who your partners are). But for a given risky heterosexual interaction, is there a good reason to believe that the African RCT results wouldn’t transfer? I’d be curious to hear from someone who takes this position! The decision to circumcise obviously depends on lots of different factors, and I don’t think that protection from HIV is at the forefront of most new parents’ minds. That makes sense. But it does seem probable that circumcision would offer a little protection against HIV transmission.

The bogus HPV vaccine article that just won’t die

vaccinationI came across this article on Facebook today: Lead Developer of HPV Vaccines Comes Clean, Warns Parents & Young Girls It’s All A Giant Scam. It was published on some entertainment website called feelguide.com back in July, but it just won’t die. It’s got 198,000 Facebook likes, and it’s been tweeted 631 times. It claims that Diane Harper, a scientist involved in the clinical trials for Gardasil, one of the HPV vaccines, did a 180 and decided that the vaccine is no good. According to the article, she announced this abrupt change of face at the 4th International “Converence” on Vaccination in Reston, Virginia. She came clean to the audience so she “could sleep at night.”

The article conveniently makes it very difficult to distinguish between the (supposed) paraphrasing of what Harper actually said at that meeting and the interpolations of other people. It says scary things like “44 girls are officially known to have died from [HPV] vaccines.” Uh, really? Wouldn’t that death toll be all over the newspapers? Well, maybe not, since it’s not at all true.

You might wonder how this website can get away with printing things that are demonstrably false. Yesterday somebody pointed out to me the feelguide.com website’s disclaimer: “Feelguide.com contains published articles, speculation, assumptions, opinions as well as factual information. Information on this site may or may not be true and is not meant to be taken as fact.” And the author? Is he a vaccine expert? Nope, his name is Brent Lambert. As it happens, he is also Editor-In-Chief of this fabulous website, and you can reach him at his gmail address. Super professional.

Where did this article come from, you ask? Almost word for word, it was taken from an article that appeared on the website LifeWise in June. This article, in turn, seems to have drawn on a 2009 article in the Sunday Express by Lucy Johnston. (Note: The Sunday Express may sound respectable, but it’s actually a British tabloid.)  Their claims that Diane Harper said all this stuff were debunked back in 2009, the very week that they came out. Ben Goldacre of the Guardian talked to Diane Harper himself. In Harper’s words:

“I did not say that Cervarix was as deadly as cervical cancer. I did not say that Cervarix could be riskier or more deadly than cervical cancer. I did not say that Cervarix was controversial, I stated that Cervarix is not a ‘controversial drug’. I did not ‘hit out’ – I was contacted by the press for facts. And this was not an exclusive interview.”

The original article was promptly taken off the Sunday Express website, and Harper complained to the Press Complaints Commission.

How did this whole brouhaha start? For whatever reason, Harper decided to speak at the 4th International Public Conference on Vaccination, held by the National Vaccine Information Center in Reston Virginia. Sounds bland enough, right? But as it happens, the NVIC is one of the largest, most vocal anti-vaccine groups out there. Why would she attend such an event? I guess it’s possible that she was tricked, that she didn’t realize what she was getting into. Working in the vaccine field, it seems she would have to be familiar with the NVIC, though. Maybe she was trying to engage vaccine critics, hoping that a little education would bring them around. Perhaps we’ll never know. But not surprisingly, it appears that attendees twisted her words in the press.

So how did all the same 2009 tabloid junk get recycled in a 2013 article? And why do people take it at face value? Lord only knows.

I frequently see people post articles like this in places like Facebook after adding something like, “C’mon, people. Do your research. Vaccines are dangerous.” I am all for people doing research about vaccines. There is so much great vaccine research available that if most vaccine skeptics really delved into it, I think they would rapidly change their minds. But does anyone really consider reading an article like this research? Even if the lack of any citations didn’t clue you in, and you didn’t know about the backstory for this chunk of lies, wouldn’t the misspelled words, the disclaimer that says the website contains  information that “may or may not be true,” and the Editor-in-Chief’s gmail address give you reason to pause? Is this really where you want to get the information you use to make medical decisions? Feelguide.com? C’mon people. Do your research. For real.

If you’re interested, more information about this particular zombie anti-vaccine meme can be found on the Respectful Insolence and Skeptical Raptor blogs.