Iga Ueno Castle, also known as Hakuho or White Phoenix Castle, is considered one of the more beautiful examples of an architectural style popular in Japan during its early modern period. Located in Mie Prefecture, Iga Ueno Castle was built to project political legitimacy during great civil unrest. The castle provides a visually striking reminder of a time in human history when stability was just a couple of bad harvests from breaking down, and a healthy country required tall, thick stone walls to have a chance of surviving. Without those great defensive bulwarks, feudal Japan’s fledgling government might not have lasted to evolve into the form that it holds today.

Perhaps it is fitting, then, that a child of Iga should be among the world’s foremost experts on biological defense—specifically, conceptualizing how the human body defends itself from illness. Yale’s Akiko Iwasaki, PhD, the Waldemar Von Zedtwitz Professor of Immunobiology and of molecular, cellular, and developmental biology, and a Howard Hughes Medical Institute investigator, has dedicated her professional career to researching how the body perceives and responds to certain infections.

As someone who helped develop the field of antiviral immunology, Iwasaki often focused her inquiries on the microbiome. One recent example involved medical trials with mice raised in laboratories.

“We found a few years ago that when you treat mice with antibiotics, and you get rid of most of the microbiome, these mice become susceptible to influenza,” says Iwasaki. She explained that the microbiome and the mouse’s “natural” immune system work together to keep each other healthy and prepared for infection, and that when one is compromised the entire system falls apart. “It seems that the microbiome is important for the well-being of the immune system in general,” Iwasaki says.

Scientists have known for some time that animals with germ-free guts are at higher risk of disease and defect. Iwasaki notes that these early observations from decades ago relied on culturing bacteria from stool samples with crude equipment, but that the technological advances of the last three decades have spurred a kind of categorical revolution in the field. “With sequencing technology, we can actually tell what type of bacteria live in a particular gut, even the ones one can’t culture in a lab. We have the whole picture of what kinds of bacterial species are present in a healthy or unhealthy animal or, increasingly, person,” says Iwasaki.

One portion of this equation that isn’t understood yet is the mechanical relationships between body and microbe; which causes produce which effects. In part this difficulty is due to the sophistication of the microbiome. Another difficulty, according to Iwasaki, arises because the microbiome itself is far more complicated than is easily imaginable.

“Going past the microbiome, and the human genome, you have the metagenome, which includes all the phages or viruses that live within the bacteria, and other viruses that live inside our cells. So, we must consider the virome, too.”

Another recent discovery is that the 90 percent of human DNA previously considered “useless junk” seems to have purpose, and may not be human DNA at all. “Retroelements occupy almost half of our genome,” says Iwasaki, noting that this is “huge real estate compared to our coding sequence. And we have very little idea what they’re doing, though they seem much more vital than originally envisioned.”

Iwasaki finds the question of infection fascinating—why under some circumstances bacteria and viruses are able to coexist with the body in healthy numbers and may even be critical to its healthy function; while under different circumstances an imbalance can create conditions for discomfort or even death. Many recent scientific advances have been accompanied by an exponential expansion in the number and complexity of questions for laboratories.

After the period of civil unrest ended in Japan, White Phoenix Castle deteriorated and was allowed to fall into ruin. Later, though, it was rebuilt for its architectural beauty and historical significance. One might debate its utility as a defensive structure necessary to the survival of Japan’s government, but it and castles like it are significant in ways their builders may not have imagined. As it turns out, the health or illness of a system can be immensely complicated, not just on a microscopic level but on a national level as well.