Can Inoculating Newborns with Innocuous Strains of Bacteria Save Them from Deadly Ones?

  

A Wild Bet: Can Inoculating Newborns with Innocuous Strains of Bacteria Save Them from Deadly Ones?

A Wild Bet: Can Inoculating Newborns with Innocuous Strains of Bacteria Save Them from Deadly Ones? - Recently, one of Paul Cezanne's missing paintings was rediscovered. The painting shows Paulin Paulet, a gardener on Cezanne's family estate, looking at his poker cards. Cezanne painted Paulet as part of a series of paintings between 1890 and 1896. This particular painting is called A Card Player. It had not been seen since 1930; its whereabouts were unknown. When the owner of the painting came forward, the art world was agog. The painting was small but stunning. It sold for 19.1 million dollars at Sotheby's. Hidden for decades, it was now among the more valuable pieces of art in the world.

Image 1. Another painting from the same series as "A Card Player." This one, entitled "The Card Players" also shows Paulet, at right. 

I was thinking about this painting recently while reading through an old scientific paper. Like A Card Player, this paper seems to have a worth that is hard to calculate. It will not fetch millions of dollars (I got it for free from D.H. Hill Library) but it could improve millions of lives. It too features a gardener placing his bets.

The story begins in an undisclosed hospital in which newborns were getting skin lesions and other infections. A nurse in the hospital was inadvertently carrying a pathogenic strain of Staphylococcus bacteria (Staphylococcus aureus type 80/81, hereafter 80/81) from one newborn to the next. She had had contact with 28 newborns with the first 24 hours of their lives. Six of those newborns were colonized by the 80/81 strain. But the nurse also held and cared for 31 infants who were more than a day old. None of those infants was colonized by 80/81. Herein was a mystery in among the fates of newborns. It was a mystery to which Heinz Eichenwald, a professor at the University of Texas, Southwestern Medical Center, was drawn.

Eichenwald imagined two possible explanations for the mystery. The first and more ordinary explanation was that age conferred some sort of immunological maturity that better allowed the newborns to defend themselves. Alternatively, perhaps the older babies had had more of a chance to be colonized by other bacteria species and that those species conferred resistance to newly arriving pathogens such as 80/81. Just how the bacterial species might confer resistance was unknown, but it was speculated that they might outcompete the pathogens by taking up space or resources before the pathogens could gain a foothold. This second possibility seemed much more far fetched and yet it was, to Eichenwald, inescapably interesting.

Eichenwald devised an experiment. It was well known that in hospitals around the U.S. the incidence of colonization of newborns by 80/81 was very variable. In one nursery, just 11% of newborns were colonized by 80/81 whereas in another 50% were. What if, Eichenwald imagined, newborns who were initially placed in a nursery with a low incidence of 80/81 were moved to the nursery with a high incidence. Would they be protected by their early colonization by bacteria other than 80/81? The experiment was done and, yes, they were, even though they were just a day old, too young for their immune systems to have become any more developed with age.

This experiment was clever (though ethically dubious). It suggested a role for bacterial interference, maybe. Yet it left open a range of other possible explanations. Eichenwald could not convince himself something else wasn't going on and so he did the perfect experiment, a technically unassailable, but, again, ethically challenged, experiment; he decided to try to garden the bodies of hundreds of babies.

Eichenwald found hospitals around the country in which 80/81 was epidemic. He and his colleagues then inoculated the nasal cavities or umbilical stumps (belly button nubs) of half of a group of newborns with an innocuous strain of Staphylococcus (502). They then examined whether the inoculated individuals stood a reduced risk of 80/81. They were, in essence, gardening the bodies of newborns, or trying to anyway. They were planting one species, a crop, and hoping that it would ward off another, a weed. This was risky gardening, a poker game in which the bet was the fate of newborns and yet Heinz F. Eichenwald placed his bet. He placed it hundreds of times, one time for each newborn he inoculated with the good bacterium but also once for each of the control infants he did not inoculate. Then he waited.

The results to a study like this one were potentially important (if heeded) in the 1970s, they were important to each newborn infected with 80/81 or any other pathogen in each hospital around the world. They were probably of relevance to, at that point, hundreds of thousands if not millions of lives. With time, the potential value of this study, however, has increased. It has increased in direct proportion to the number of infections in hospitals but also the severity of those infections. Infections with 80/81 were often problematic (producing boils and lesions) and sometimes dangerous. Now, infections with bad Staphylococcus strains are often a matter of life and death. Times and bacteria have changed.

In the 1960s and 1970s when this study was done, even when strains of Staphylococcus aureus, in particular 80/81, were serious they could usually be treated with antibiotics. 80/81 was susceptible to Methicillin, for example. However, since that time antibiotic resistance has evolved in and spread among strains of Staphylococcus aureus. Many strains of Staphylococcus aureus are now categorized as MRSA, Methicillin resistant Staphylococcus aureus. These resistant strains include strains very closely related to 80/81, strains one might reasonably describe as 80/81's far more dangerous descendants. In this regard, one might wonder not only whether the infants in the hospital who were dosed with a good/innocuous Staphylococcus were spared 80/81 but also whether, in modern hospitals, dosing infants with good bacteria might reduce their risk of infection with MRSA or, by the same token, whether living a life that doses us with good bacteria might, more generally, decrease our risk of MRSA. These seem to be important questions.

Meanwhile, Heinz Eichenwald did not have to wait long for results. Of the 108 infants in which the good Staphylococcus established, 4.6% became colonized with 80/81. More than one might hope for. But in the 143 infants in which the good Staphylococcus was not established, 39.1%, nearly ten times as many, became infected with 80/81 or one of its close relatives. Gardening the body in self defense seemed to unambiguously work. But this was not enough. Eichenwald would try something else. He would inoculate all of the newborns in the hospitals he was studying with the good Staphylocccus. When he did, 80/81 entirely disappeared from those hospitals. The results could not have been more clear and so, on their basis, Heinz F. Eichenwald concluded, "during the presence of a severe epidemic of staphylococcal disease, the use of 502-A represents the most immediate, safest and effective method of terminating the epidemic. I feel that we now have enough data, involving several thousand babies to indicate that this is a completely safe procedure."

In the immediate aftermath of this work, excitement boiled. The other scientists who reviewed the paper clearly imagined instituting similar approaches in their own hospitals. It seemed like an approach that might spread ward to ward around the world and it might spread not only among nurseries but also among doctors treating adults. Could inoculation prevent us all from MRSA? Or reduce the risk? Recently, a great deal of attention has been given to the value of fecal transplants or transplants of microbes among ears for those with depauperate or severely infected microbial faunas. But it would be much simpler if we could actually just inoculate those individuals faced with depauperate microbiota with a few good lineages, lineages such as the good Staphylococcus (Recent work has shown that one of the factors that allows beneficial Staphylococcus to exclude pathogens is the production of enzymes that prevent the pathogens from forming biofilms). Eichenwald's idea really seems like a multi-million dollar one. But this value is unrealized as much as if it were, well, a forgotten painting by Cezanne. After its initial success, Eichenwald's idea enjoyed modest popularity and then floundered (Perhaps in part due to one fatality associated with the accidental introduction of the "good" Staphylococcus into the blood of a newborn; http://archpedi.jamanetwork.com/article.aspx?articleid=504327). Eichenwald himself moved on to other things.

Since 1990, Heinz Eichenwald's study has been mentioned in a scientific paper just once (at least according to Google Scholar) and even then only in passing, but a few new studies have begun to suggest his approach anew, often as though it were a new frontier rather than an old one being revisited. There seem to be complexities. Eichenwald might have gotten lucky in his choice of species to consider and yet his results are beyond reproach for those species. Could Eichenwald's approach save lives if it were implemented now? Maybe. Dosing young mice with beneficial Staphylococcus (S. epidermidis) seems to ward off pathogenic Staphylococcus, including deadly MRSA. In a way, I'm auctioning Eichenwald's idea off here. Why don't you see what you can get for it, how much traction or progress. You can join the small group of scientists now considering the idea. Meanwhile, I should mention a final irony. Cezanne's painting, the one that lay hidden all those years, was hidden, and I kid you not, with Eichenwald. The man who gardened life in human bodies and did so while taking risks, was the keeper of Cezanne's card playing gardener. Eichenwald's father appears to have bought the painting from a gallery in Berlin around 1930. The family then fled to New York to escape the Nazi's and brought the painting with them. It stayed with the family until, upon Heinz's death in September of 2011, his widow, Linda, decided to sell the work. When she did she found that in the time that the painting lay hidden it had appreciated many fold in value and relevance. Time will tell whether the same is true of Eichenwald's greatest work, his idea to garden bodies. It remains his tremendous but unplayed hand. ( Scientific American )