The power of our immune systems

JAX immunologist Adam Williams, Ph.D. says the immune system is like a playground for a scientist – a nearly perfect system that provides different cell types with specialized functions that all work together.

“I have come to appreciate how amazingly complex and powerful the immune system is,” said the assistant professor during the latest  speaker series event. 

“From an experimental side we can isolate pure populations of different cell types and they can be cultured in the lab. From the clinical perspective, the immune system in intimately involved with most human diseases. So I developed a passion for understanding the programs that orchestrate this complex system.”

As part of a virtual conversation moderated by JAX Genomic Medicine Scientific Director Charles Lee, Ph.D., FACMG,  Williams shared that it was the Human Genome Project that initially shaped his scientific interests. “We initially thought that if we knew the sequence of our genome, we would be able to learn what makes us human,” said Williams. “We would also be able to understand what causes disease.”

But the results of the Human Genome Project proved somewhat surprising: the sequences of DNA that were believed to be important, because they contained genes, made up only approximately 2% of the genome. There were also many fewer genes than originally thought, and they were essentially the same (i.e. well conserved) as in other species. This raised even more questions for Williams than it answered. For example, if all of our genes are virtually identical to other species then why are we so different? What makes us human?

LncRNAs: the instruction manual for cells

It turns out that the other 98% of the genome is also important. These extra sequences were for a long time considered “junk DNA” and thought to be left-over mistakes from evolution. But we now know that this “junk” actually contains the instructions that determine when genes should be tuned on or off.

“Something else hiding in this dark matter is a different type of gene called long non-coding RNAs, or lncRNAs,” said Williams. Although these genes were initially deemed genomic oddities, work from Williams’ lab has contributed to the growing understanding that IncRNAs are intimately associated with different human diseases.

“Normally when we think of a gene we often think of region of DNA that ultimately encodes for a protein, through an RNA intermediate,” explained Williams. “However, lncRNAs never make any protein, rather it is the RNA itself that carries out a function. And although we still don’t know how many lncRNAs genes there are, upper estimates suggesting there may be four times the number of lncRNAs compared to protein-coding genes.”

LncRNAs often serve as coordinators within cells, says Williams, helping to shape their development and identities, as well as their responses. He compared the system to a set of LEGO blocks: the protein-coding genes are the blocks themselves, while lncRNAs as part of the instruction manual that directs assembly. 

'Lung in a dish:' A unique intersection of research areas

The Williams lab is one of only a handful of labs world-wide studying the role of IncRNAs in human lung biology and disease. Williams conducts his research by using a cutting-edge “lung in a dish” culture system that allow direct experimentation on the cells in the lung. 

“The lung is a complex tissue composed of different cell types, and our ‘lung in a dish’ system contains many features of the lung, including beating cilia and mucus creation,” said Williams. “This allows us to perform lots of different types of experiments that would not otherwise be possible, and to use technologies such as Cas9 to start making genetic changes to these cells to see how this alters their function.”

The ultimate goal of this work is to understand how IncRNAs control the identify and function of cells in the lung and how they may contribute to lung diseases such as asthma – so that in the future, researchers can harness IncRNAs to provide new diagnostic and therapeutic approaches. 

An important discovery related to allergies

Food allergies are on the rise, and the worst response is anaphylaxis, a severe allergic reaction which can be fatal. In 2019, the Williams lab discovered a new type of cell called Tfh13 which could someday help in reprogramming the immune system to prevent or reverse allergic responses like anaphylaxis. 

“It has been known for some time that for anaphylaxis to occur you need a special type of antibody called high affinity IgE,” said Williams. “However, it was not known what directed the B cells, which are the antibody-making cells in the immune cells to produce these high affinity IgE anitbodies.”

Using mouse models and human samples, Williams and his colleagues identified a population of T cells that they named Tfh13 cells. Interestingly, these Tfh13 cells communicate with the B cells to direct high affinity IgE production, and people with food allergies or allergic asthma have elevated numbers of these cells circulating in their blood.

Next, Williams hope to define the molecular programs that control these Tfh13 cells. “If we can figure out how these cells are programmed, we can eventually learn how to change the programming of the cells and be able to prevent anaphylaxis,” he said.

Collaboration in the era of COVID-19

Williams has been using the “lung in a dish” culture system to study respiratory infections for the last few years, and has now started to use it to try to better understand COVID-19.

Working with collaborators at Mount Sinai and Yale, Williams and his research team are infecting these cultures with SARS-CoV-2, the virus that causes COVID-19. “This allows us to understand exactly which cells get infected, and how they respond to the virus,” said Williams. “We can also perform genetic editing in these cells to understand what genes are important in the viral life cycle and in the host response to infection.”

Lee noted that the collaboration across the research community has been unprecedented: “There are thousands of scientists all over the world that are combining their expertise so that we can rapidly understand more and more about the biology of the SARS-CoV-2 virus,” he said.

“I’ve been thrilled about the fact that scientists are not only collaborating to really study the virus, but they are sharing their data in an unprecedented way, so that other scientists can build on it rapidly and we can come up with treatments, cures, and vaccines faster than we’ve ever done before."