Martin J. Blaser, M.D.
Rutgers University
New Brunswick NJ, USA
1.For me, 1962 was a big year. That is when I entered Jamaica High School, a wonderful public school in New York City (which sadly has since closed!). [Had he gone to public school, Donald Trump would have attended Jamaica, about a year ahead of me]. Through very good luck and the intersession of my older sister I was placed in the XH Science Track, along with 39 other students for an intensive education in science. This was after Sputnik, and the sentiment in the USA was that more scientists were needed. In my biology course with an inspired teacher (Mr. Herman Gillary), I first learned about the Greenhouse Effect-how human activities were warming the planet through the burning of fossil fuels, yielding CO2, one of the major greenhouse gases. This was 1962, decades after the idea was first developed in publications dating at least from the 1930’s (1). As a high school student, I was introduced to the idea that human activities could affect our natural world on a large scale. Of note: this was at the level of high school science more than six decades ago, and sad that it continues to be denied by many today.
2.As part of the XH program, all of the 40 students were together in most of their classes, with some of the best teachers in the school. For English, we had Mrs. Dora Barmack, who was passionate about linking literature and science. Among other books, we read The Voyage of the Beagle, Charles Darwin’s account of his journey (1822-24) as a young man around the world as the naturalist on the HMS Beagle (2). It was on that voyage that he began to develop the ideas that led to the Theory of Natural Selection. That was my introduction to the idea that through exploration, and making observations, new ideas can be developed, leading to big discoveries. At the time, in the class we made of fun of Mrs. Barmack’s passion for literature, but I now know how important her teaching was.
3.My parents subscribed to The New Yorker, then and now a weekly periodical that highlighted the arts, science, current events, politics, film, theatre, and has great cartoons! I often looked through it, reading all of the cartoons, and then sometimes finding articles that seemed interesting. By chance, I happened to see the issue of September 27, 1962 which included the first part of the serial of a new book that was called Silent Spring (3). Rachel Carson, its author, was a zoologist who worked for the US Fish and Wildlife Service and was one of the pioneers of the environmentalist movement. Published during her ultimately fatal illness of breast cancer, Silent Spring focused on pesticides such as DDT which were used on a massive scale to control mosquito populations, in part to curtail malaria. Although that goal was quite worthwhile, through her beautifully written text Carson showed its unintended consequences, killing wildlife including birds and insects, and thus her metaphor of a ‘silent spring’. Like millions of others around the world, I could immediately see the veracity and importance of what Carson was writing. Her work as an author galvanized the world and led to important actions such as the banning of DDT.
4.Reading newspapers, I became aware of a medicine called thalidomide. Originally developed as a sedative to help people sleep better, doctors began prescribing it to pregnant women to help them with ‘morning sickness’, episodes of nausea in early pregnancy. Used by millions of women in the late 1950’s, especially in Europe, it never was approved for use in the USA, because studies of its safety had not been adequately conducted. After several years, it became clear that thalidomide led to birth defects, including a signal deformity called phocomelia which led to abnormal development of arms and legs. Once this was realized, thalidomide was banned, but untold damage had been done. From this, the world learned about the unintended consequences of medications given early in life (in utero) that only became visible many months after the exposure.
5.By 1971, my education had proceeded, and I was now a medical student. We were encouraged to subscribe to and read The New England Journal of Medicine, a leading weekly publication presenting advances in medicine. A paper was published on April 22, 1971 that made a deep impression on me. Dr. Arthur Herbst and colleagues reported about a series of cases of a cancer occurring in young women (4). Called adenocarcinoma of the vagina, this was an uncommon cancer in general, and very uncommon in young women until then. When considering possible causes, the investigators found that for seven of the eight affected young women, their mother had taken the drug DES (diethylstilbesterol) while they were pregnant. Fourteen to 22 years later, their daughters developed this rare cancer. None of the mothers of 32 young women who were matched controls had had a similar exposure. Herbst and colleagues had linked the exposure of the mothers to DES during their daughter’s pre-natal days to the unexpected consequence of that rare cancer. In fact, that was the tip of the iceberg since it now is known that DES exposure in utero has many other health consequences, sometimes affecting even the third generation, importantly developing decades or generations after the exposure.
6.My education had proceeded through medical school graduation, residency in Internal Medicine, and subspecialty training in Infectious Diseases. As a research project, I had been studying the human intestinal pathogen Campylobacter jejuni. In 1979, I was accepted by the Centers for Disease Control to become an EIS (Epidemic Intelligence Service) officer to investigate disease outbreaks, and I was assigned to the Enteric Disease Branch. Among many issues, they were concerned about antibiotic resistance in Salmonella, a bacterial pathogen that people usually acquire from eating foods of animal origin. At CDC, I learned that since the late 1940’s farmers had been giving their livestock antibiotics in low doses in their feed to promote their growth. Ever since, famers all over the world have been using it for their chickens, swine, cows, and other domesticated livestock, because it works (5). By adding small amounts of low-cost antibiotics, the animals became 5-10% heavier; for many farmers that was the profit margin. CDC was rightfully concerned about this practice because of how it spread antibiotic-resistance. I was assigned to work on a project and after it finished (6), that issue went off my radar screen. But I took that practice on the farms as a given, as I continued to study intestinal pathogens.
7.In 1983, at a medical conference, I learned about a new Campylobacter that lived in the human stomach; later, the bacteria’s name was changed to Helicobacter pylori. Over the next two decades, I studied many different aspects about H. pylori, its constituents, its interactions with humans, and its relationship to disease. I was especially intrigued about how the organism was able to persist in humans for decades if not for life; it was a great example of adaptation to a host. Although it seemed obvious to me that H. pylori was an ancient inhabitant of humans, its prevalence around the world was decreasing. As it was disappearing, classical stomach cancer and idiopathic peptic ulcer disease, conditions in which it played a causal role, were declining. This was definitely good news, but new diseases were rising, especially in the esophagus. We and others found that the presence of H. pylori was inversely related to the newly rising adenocarcinomas and with its precursor lesions (7,8). I wondered whether the same organism could be both harmful and beneficial to humans; our work indicated that those strains that were the most harmful also were the most beneficial (7-9). [Because as it turned out, those were ones that interacted the most vigorously with their hosts]. And then there was the paradox of peptic ulcer disease rising in the 19th century, just when H. pylori seemed to be starting to fall. Such observations already suggested that the adaptation of H. pylori to its human niche could not be explained linearly in terms of present knowledge; a more ecological view was needed (10).
8.But was H. pylori really an ancient organism of humans? And if it was indeed ancient, then its decline might not be so beneficial. We know that humans colonized the Americas by migrating across the Bering Straits. The last time that there was a land bridge between Asia and the Americas and the Straits were closed was during the Ice Ages ~12,000 years ago. The ancestors of the indigenous populations of the Americas essentially all arrived before the land bridge was lost. We sought to take advantage of that fact by studying indigenous peoples in South America, reasoning that they would have East Asian subtypes of H. pylori. Working together with Maria Gloria Dominguez Bello (later to become my wife), we studied strains from isolated Amerindians in the amazonian forests of Venezuela. They indeed had East Asian signatures, providing evidence that H. pylori had colonized those human stomachs for at least 12,000 years ago (11), and soon the clock went back 60,000 years (12). From there, I wondered why was an ancient well-adapted organism disappearing, and what were the consequences?
9. Now events started to converge. It was known that on average people who had H. pylori in their stomach were shorter than people without the organism, and we all know that people have been getting taller in recent years. But I knew from studies in the 1970’s that children who had a lot of infections when very young were shorter than their compatriots, and I remembered from CDC days that farmers feeding antibiotics to their livestock raised bigger animals. I decided to develop the hypothesis that microbes are part of the story of our increasing human height. I recruited an outstanding medical student, Albertine Beard, and asked her to look into the literature. She found great materials—the records of armies, showing changes in height over centuries, and studies of skeletons that showed that height had fluctuated greatly in the past, among other work. Together, we crafted a theory that the human body has plasticity in height, and that the nature of their microbial exposures affect how much of their genetic height potential a person will realize (13). We already were thinking about the ‘endogenous organisms’ (now microbiota) affecting the morphometry of the human body in 2001.
10. For me, the main idea took form in 2002. I had returned to my alma mater NYU to become the Chair of the Department of Medicine. A part of my responsibilities was the counseling of young doctors considering different directions for their medical training. One such young doctor, a Resident in Internal Medicine, was considering a career in Endocrinology and he was weighing in which institution to continue his training. He asked me to review with him their research programs, and in one there was a scientist who was studying obesity. The Resident said that obesity was not particularly interesting to him. Then I told him. “…you know, farmers use antibiotics to fatten up their livestock…” And just as I was saying it, I felt like a light bulb went off. I thought: “this is what we are doing to our kids!”
Although intending well, by treating their ear, throat, and chest infections with antibiotics, we also were affecting their microbiome at a critical time, when physiologic development was occurring. It took me some time to study the literature and flesh out the ideas. By 2005, I had a general view, which was published the next year (14). Learning from both the farm and from H. pylori, I developed a hypothesis about microbes and modern diseases. My idea was that changes in human ecology had changed the composition of the microbes living in the human body (like the loss of H. pylori), and that such changes affect physiology and ultimately disease risk. By 2009, the ideas took form in a Perspective, written with the late Stan Falkow (15). We defined some of the key ecological effectors, and developed the idea that our mcrobial diversity has been stepping down, generation by generation over the past century, and leading to health effects. This was modeled on H. pylori but I reasoned that if one organism was disappearing, there would be others. By then, the idea was mature, but during that time and since, I have sought to keep testing the ideas, to assess if they were true or not and to provide important details related to mechanisms.
11. In 2006, we began to conduct experiments to assess whether we could recapitulate in the lab what farmers everywhere were doing: would giving antibiotics in mice change their growth and development. It took us some years to establish the proper experimental conditions but the clear answer was a ‘yes’ Mice given antibiotics early in life grew faster and bigger, with changes in their fat distribution and metabolic characteristics (16), and it was the antibiotic-altered microbiome that was the active agent (17); importantly, we showed that even a transient perturbation of the early life microbiome, occurring during a critical window of development would have essentially life-long consequences (17). Perturbing the co-evolved early-life microbiome was changing hosts in ways that in children would lead to diseases.
Over the last decade, we have continued experiments in models that also teach us about allergy and asthma, juvenile diabetes, inflammatory bowel disease, and autism. Many of these studies are ongoing. At the same time, we have studied populations of children to ask whether early life exposure to antibiotics might be associated with increased rates of disease development. These studies (18, 19) and the work of many others, provides strong evidence in human children, consistent with the experimental evidence in mice, that antibiotics have costs that were never understood before.
I have called this “The theory of the disappearing microbiota” (20,21) and this brief essay, I show how some key ideas I was exposed to decades earlier played a role in how the idea developed. From Darwin, I learned how organisms evolve in response to changes in their environmental circumstances-that nothing is fixed in biology. As a doctor, I came to see that diseases rise and fall depending on the environmental context. From climate change, I learned that a single cause if sufficiently powerful, can have many consequences that do not appear to be related-like hurricanes and droughts, and melting of the ice caps -but actually are related to the underlying cause. So it is not overly simplistic to think that the massive change in the human microbiome that we have been experiencing over the past century could play a role in diseases as dissimilar as obesity, asthma, and autism?
From Rachel Carson, I learned that manipulating nature, even with good intensions (like the use of DDT) can lead to multiple unexpected consequences. From the tragedies of thalidomide and DES, I learned that exposures early in life have the greatest impact on disease development, and that there could be latencies from the exposure to the manifestation that last for years or longer. From the farmers, I learned that antibiotics change host development. The lesson from the farm was most profound, since from the early 1950’s one could deduce that the antibiotics were affecting a principle broadly conserved across evolution, that it was related to changing of bacterial populations (because anti-virals and antifungals did not work), and the earlier it was imposed the stronger the effect - pointing to the criticality of early life exposures. From H. pylori, I learned that even ancient organisms can disappear, and that that this could lead to health consequences, both good and bad. And from considering the changes in human height over history that the populations of microbes to which we are exposed and carry can change our very shape and thus our development.
These great teachers and this long process have provided a strong foundation for my current ideas. Like climate change, the hole we have dug will deepen unless we turn it around. A part of my life’s work now is to share these ideas broadly so that scientists, health providers, and the public can take the necessary actions. I am gratified that the ideas have been corroborated by studies by many scientists and labs, and although the outline is clear, many details still must be fleshed out. From the details and the mechanisms will come the preventives and the therapies.
