Moises Velasquez-Manoff was on the road to Tijuana, where he'd meet a man who would infect him with hookworms.
So begins An Epidemic of Absence, Velasquez-Manoff's new book about a tantalizing hypothesis for a modern medical mystery: Why autoimmune diseases, in which a person's immune system attacks their own body, are becoming more common, even as infectious and parasitic diseases are beaten back. (Read an excerpt from the book)
According to Velasquez-Manoff and the scientists he writes about, it's no coincidence. A fast-growing body of research suggests that immune systems, produced by millions of years of evolution in a microbe-rich world, rely on certain exposures to calibrate themselves. Disrupt those exposures, as we have through modern medicine, food and lifestyle, and things go haywire.
Velasquez-Manoff, who has several immune-related disorders, including food allergies and alopecia, had heard about the "hookworm underground" – people who infect themselves with parasites in the hopes of restoring immune balance. Though it's something he now recommends against doing, it marked the beginning of a reportorial journey into a frontier of science and health.
Wired talked to Velasquez-Manoff about his experiences.
Wired: What would parasites have to do with food allergies or alopecia?
Velasquez-Manoff: Parasites modulate your immune response. When you have them, the number of cells involved in tamping down inflammation increases. These cells have a bystander effect. They end up tamping down on all sorts of inflammation, not just that induced by parasites – and food allergy is an inflammation that's inappropriate. You shouldn't be throwing this huge response at what are essentially harmless pieces of plant. Your immune system has made a mistake. When you have parasites, the theory goes, your immune system is less prone to making these mistakes.
Wired: You also write that parasites and other microbes don't just keep the immune system from overreacting, but also help it know what to react to.
Velasquez-Manoff: That's how it ended up. These things are so intertwined. One way to look at it is this: Let's say you need 15 percent of all your T-cells to be regulatory T-cells. Your effector T-cells determine what to attack, and your regulatory t-cells help you stop attacking. If you're dropped into the world with those 15 percent already pre-programmed, and parasites induce another 10 percent, you end up with an immune system that doesn't work. You’ll get overwhelmed by invaders. You’re too soft. So as an adaptation, only 5 percent of your T-regs are pre-programmed. You get the parasite exposures, you get your extra 10 percent induced, and you're at the golden level. Now if you take away the parasites, you’re left with inadequate T-regs. That’s kind of the story. We're not born with enough immune regulation; we rely on other organisms to get us to the right level, because they were always around.
Instead, you're only genetically 5 percent pre-programmed. You get the parasite exposures, you get your extra 10 percent, and you're at the golden level. We're not born with enough immune regulation; we rely on other organisms to get us to the right level, because they were always around.
Wired: So without the proper exposures, our immune systems won't be calibrated correctly?
Velasquez-Manoff: Yes. We basically overreact to things, including our own tissues: the pancreas in diabetes, myelin in multiple sclerosis. Of course there's a certain amount of redundancy in this. If it was just parasite X that did the job, that would be horrible evolutionary design, because there's bound to be a time or place where parasite X isn't around.
Wired: Yet we're now living in a world where, despite those redundancies, we're not getting the exposures we need.
Velasquez-Manoff: Off the top of my head, there are at least 20 types of exposures I go over in the book. What's remarkable about modernity is that we've nearly removed them all. And when you look back at the history of the emergence of immune-mediated disease, and you dig through the earlier records before we started doing rigorous retrospective studies, it sort of begins late in the 19th century.
Wired: You write that tuberculosis might have been the first evidence of something amiss.
Velasquez-Manoff: We know tuberculosis, Mycobacterium tuberculosis, came out of Africa with us. It's been in the human body for at least 60,000 years, and probably longer. But beginning in the late 18th century, there was a wave of TB in Europe, and nobody has ever really been able to explain it. Some people argue that a more virulent strain emerged, and there is some evidence for that when they look at the genetics of it. But there's another hypothesis.
According to this, we had to acquire immunity to tuberculosis because of constant exposure to non-parasitic versions of mycobacteria that basically live in soil. But Europe begins to urbanize in the 18th century. The potato is imported from the Americas, causes a population boom, and people start migrating to cities. They lose the mycobacteria in the natural setting. And without that exposure, immune systems didn't know how to react to it.
Wired: Why is our exposure to parasites and microbes so different now than it was 100 years ago, or 500 years ago?
Velasquez-Manoff: Let's imagine people living in a rural environment, with lots of animals around. That's the first thing that's different. We were constantly exposed to each others' fecal microbes: Feces was on our hands, and we fertilized our crops with it. People were fermenting food or drying it.
Today's processed food is designed not to carry microbes. It's full of salt and sugar and grease. You've seen those photos of McDonald's hamburgers kept for a year or two that don't rot: Microbes can't get a foothold in them.
There's a story about the food question. Bengt Björkstén compared allergies in Sweden and Estonia, a neighboring Baltic country, right after the Iron Curtain started drawing back in 1989. In Estonia, they were lower by two-thirds. He thought the protection came from their food. They had been getting microbes from food that was grown locally and fermented, essentially because it was a poor country. Modern food has to have a shelf life. It has to travel long distances. That happens by various mechanisms, but essentially you're taking the microbiota off food.
Wired: There's another country, Sardinia, that has an instructive history.
Velasquez-Manoff: Sardinia was a cesspool of malaria for a long time. Part of it has to do with the hydrology of the island: Basins form in basalt rocks, and water just sits and collects in a lot of places.
The Sardinians have been invaded by wave after wave of people. They basically fled to the center of the island while various empires set up shop on the coast, and the next wave would come a few hundred years later: Carthaginians, Romans, Vandals, all the way through to Spaniards. There wasn't much genetic admixture. When they do those phylogenetic trees of the European family, Sardinians are less related to mainland Europeans than Iranians are.
Why does that matter? They developed adaptations to malaria over time. Then, after World War II, malaria is eradicated in Sardinia – and all of a sudden autoimmune diseases go crazy there. It's like the number-two place for Type I diabetes. It's near the top for multiple sclerosis. And the guy I visited there, Stefano Sotgiu, his hypothesis is that without malaria present their immune systems started going crazy.
Wired: We've talked a lot about exposure to parasites and microbes in the wild, so to speak. What about the microbes we get from our mothers?
Velasquez-Manoff: We get two things. First, in the womb, you're not exposed to any microbes yet, but you get the signal of a microbial community through your mother's immune system, which is turning out to be critical. If your mother is tolerating all these microbes, then your immune system knows not to overreact.
Where it really gets interesting is the resident microbes that live in your mother. We know these clearly set the tenor of the immune function. There are certain infections that cause problems: Some studies show that if a mother has vaginitis, an imbalance in vaginal flora, the child's risk of asthma goes up. It's the inflammatory signal that's skewing the fetal immune system toward asthma.
If you look at this in the context of what's been happening in the last 150 years, there's some evidence that the internal community is more inflammatory than it used to be.
Wired: You make a case in the book that inflammation is linked to autism.
Velasquez-Manoff: There is, at this point, reams of evidence indicating two things about autism. First, that in many autistic children, the immune system is completely off-kilter. There's lots of evidence of low-grade activation in the absence of any kind of infection. You can see it in their brains, too.
One of the seminal studies in this was published in 2005 by researchers at Johns Hopkins, who got brain tissue from autistic individuals who had died, and looked at it under a microscope. They found that astrocytes, these brain cells that are part of immune function in the brain and nervous system, were enlarged and huge in autistic brains, as if they were subject to this constant signal to be active.
When you think of classical autoimmune diseases, like multiple sclerosis, you actually see degeneration in the myelin, like it's stripped off. This wasn't the same thing. It was low-grade inflammation. And if you have low-grade inflammation, nothing else works. Your immune system needs to quiet down when it's not fighting something off, but in these kids it wasn't shutting off.
The second thing is that there are some very good animal models now where they induce autism. It starts in the womb, and it's related to some sort of inflammation in the mother. There's a natural phenomenon showing this: the children of mothers who were infected with rubella virus in the 1960s were far more vulnerable to autism. The infection doesn't even need to touch the fetus. It’s the inflammatory response.
But in the last half-century, when autism has gotten out of hand, maternal infections have actually gone down. Infection is not the problem per se. It's inflammation. It turns out some of the diseases I talk about in my book – asthma, allergies, autoimmune disorders – are closely linked to autism in the sense that if the mother has them, the chance of a child having autism goes up. When there's a problem with the mother's immune system, it may cause a problem with the developing fetus.
Wired: The New York Times essay you wrote about this drew some criticism. Emily Willingham, a science writer and autism expert, said the scientific evidence for this was limited, overstated and cherry-picked. What is your response to that?
Velasquez-Manoff: My response is this: Check it out with the scientists, like this Yahoo reporter did. Call them up. See what they say about the piece. The New York Times Sunday Review fact-checks, by the way. See my source list, which, yes, was posted regrettably late after the article went up. Did I cherry pick? I think I got a whole cherry tree. A valid question, however, is whether it’s the only tree around. Did I fail to qualify and caveat? Yes. It was an op-ed. But I’m making an argument scientists are making, one that’s very well supported by the literature. (The scientist Paul Patterson apparently penned a very similar piece, but couldn’t get it published.)
One issue Emily Willingham raises that’s important: How do we know what’s cause and effect here – the immune dysfunction or the autism? That question is partly addressed by the animal models. Scientists can reproduce some of the observations in humans – brain “overgrowth,” behavioral problems, a pro-inflammatory skew, similar gene expression profiles – with prenatal inflammation. Does that mean case closed? No. But it’s a remarkable body of evidence. Don’t take my word for it. Ask the scientists.
Wired: So do we know enough about all these effects to manipulate our bacteria and parasite exposures in a way that's good for our health?
Velasquez-Manoff: The easiest recommendation is to eat well. We've known for a long time what’s good, but we didn't know how it works. We know that a high-fiber diet is better than a junk food diet, that eating a lot of fruits and veggies and whole grains is better than junk food. But now we know why: In part, it's probably because it modulates your microbiota.
But other stuff needs to be learned. Take the whole fatty acid thing. There are people who eat flax seed meal, which is rich in omega-3 fatty acids, but nothing happens. Their omega-3 levels don't go up. Some studies in mice show they only go up if the mice are also taking probiotics. You need to have the right bacteria to help absorb the fatty acids that are good for you.
Wired: And some people are going so far as to expose themselves to parasites. How did your own experience with hookworm turn out?
Velasquez-Manoff: There were definitely some changes for the good, and definitely some side effects. I had a pretty severe reaction for a few weeks. I took it in November, and then by hay fever season my nose was completely clear. My fingernails were less pitted. Hair started growing here and there – very fine, like peach fuzz, which was pretty cool, but there was nothing near remission of anything.
As I point out in the book, there was a lot of variability. That's probably what happens with living organisms you buy on the black market. The thing about the underground is that you don't know the quality of the larvae, or even if you're getting what you think you're getting. I had my parasites genetically confirmed, so I have that confidence. But I have to say, the more I got involved with it, the less I thought it was a good idea.
I think the theory has great merit. The animal models are pretty much unequivocal. But when you start thinking about yourself, or your own children, you say, 'How certain am I?' And the uncertainty undercuts the idea. No one should do what I did. Let the science provide something safe, which it will.
