Jules Hoffmann showing a fruit fly slide at Lindau Credit: Christian Flemming/Lindau Nobel Laureate Meetings


Jules Hoffmann asked himself that question nearly fifty years ago and in the process of trying to figure out the answer, he eventually won a share of the 2011 Nobel Prize in Physiology or Medicine. His research also helped to determine what makes the base layer of the immune system—commonly called innate immunity—work so well.

(The other part of the immune system, in vertebrates at least, is known as adaptive immunity; that's the part that is responsible for creating antibodies.)

Speaking to a packed audience at the 64th Lindau Nobel Meeting in Lindau, Germany, Hoffmann chose to take the long view--the very long view--with the young scientists and fellow Nobelists in the conference hall.

The same genetic building blocks that give rise to the immune system found in the insects he has studied over the years are also found in sea urchins and sea anemones, Hoffmann said—species whose common ancestors date so far back in time that they are among the first animals ever to have lived on the planet.

Indeed, Hoffmann concluded from the evidence found in his and other labs that innate immunity must have evolved with the rise of multi-cellular organisms 1 billion years ago.

It started with grasshoppers

A quick peek at Hoffmann's biography shows that he started studying grasshoppers when he joined the laboratory of Pierre Joly at the French National Research Agency (CNRS) in the 1960s. Joly performed lots of transplants between grasshoppers in the course of his studies and marveled that they never succumbed to bacterial infections as a result.

Naturally, the experiments were performed under sterile conditions, but even so, you would have expected at least some grasshoppers to develop surgical infections as a result.

Hoffmann dedicated his PhD to studying this unexplained mystery in greater detail and found that he could destroy the grasshoppers' ability to stave off infection by irradiating some tissue around their hearts.

Now assuming you have read this far in the story, you may be asking yourself, why would anybody care so much about grasshoppers? Perhaps you have never heard about the grasshopper swarms that ate everything in their path in the American Midwest in the 1930s or that sometimes rain havoc on the farmlands of Chad, Mali, Nigeria and other parts of western Africa?

Figuring out what makes grasshoppers so resistant to infection could well have a practical benefit for agriculture, Hoffmann took care to point out in his Lindau lecture. But, I certainly got the sense, listening to him, that he was also riveted by the intellectual challenge.

In 1978, Hoffmann became head of his own laboratory and by the 1990s, he had changed the focus of his lab's research from studying grasshoppers to studying fruit flies (Drosophila melanogaster). The move, he said, came in large measure because the genes of fruit flies are easier to study. (One species of grasshopper, for example, has a genome that is 100 times larger in size than that of Drosophila melanogaster and six times greater than that of humans.) Fruit flies, like grasshoppers and other insects are also highly resistant to infection with bacteria (both gram-positive and gram-negative bacteria) and fungi.

In 1996, Hoffmann and his colleagues published their work showing that a previously discovered protein named Toll, which plays a role in development, also plays a fundamental role in maintaining the fruit fly's nearly impregnable defenses against infection. His lab later determined that another protein, known as IMD, was at the center of a second immune system pathway found in insects.

Later work by Bruce Beutler (who shared the Nobel Prize with Hoffmann and Ralph Steinman in 2011) showed a similar protein, dubbed a Toll-like receptor plays a key role in the innate immune systems of mice and people.

(And in case you were wondering about viruses, fruit flies defend against viral infections with a process called RNA interference, which Hoffmann, mentioned, but said he really didn't have time to explain.)

It turns out that insects really only need the innate immune system to survive and thrive—perhaps because they live for such a short period of time. If they lived any longer, they probably would have needed to evolve something else to layer on top of it.

Which is exactly what, in fact, a shark-like ancestor of ours did about 460 million years ago (give or take a few million). Most of the time, humans and other vertebrates do just fine with their innate immunity. But sometimes our innate immunity gets overwhelmed by the onslaught of infection or of toxins. And that's when adaptive immunity comes into play. Well, it's not actually so cut-and-dried as that makes it sound – but that's definitely a story for another time.