ScienceAdviser

Indeed, as a postdoctoral researcher in Paul Kubes’ lab at the University of Calgary, she worked alongside fellow postdoc and clinician scientist Moritz Peiseler to understand how livers that become rife with scar tissue—a condition known as fibrosis, which occurs in many liver diseases—are still able to battle blood-borne pathogens. In doing so, she earned co-first authorship on the recent Science paper reporting their findings: that when a liver becomes fibrotic, its huge, resident bacteria-eating immune cells—macrophages called Kupffer cells—get a kind of cellular amnesia and forget what they’re supposed to do. Luckily, macrophages from elsewhere in the body come to the rescue, forming ‘superclusters’ that take over the job of filtering bacteria from the blood.

ScienceAdviser recently talked with David about the work. Below is that conversation, edited for brevity.

How did you end up working on this particular project?
That was a project Moritz started. He wanted to better understand the fibrotic liver, because it’s something he sees a lot in the clinic. And the immune component of liver fibrosis, it’s overlooked. The basic biology of it—and I kind of hate the word basic here, because it gives the impression that it’s not important—but the basic, or perhaps foundational biology, was not well explored. And he ended up finding these giant macrophage clusters that no one had ever seen before, and that’s when the project took shape and we began to investigate the origin of them, which is a huge part of the paper.

In addition to the big cells, we found these huge morphological changes in the liver, which was something we were not expecting. Also, people had assumed that the liver’s immune cells were dying and disappearing in fibrosis. But that was because of how people usually visualize them: using proteins on the surface of them that they can label. But [when the liver becomes fibrotic,] those are not there anymore; they are downregulated. The macrophages are still there, they’ve just lost their identity. I think one of the reasons we were able to find everything we did was because we did a lot of in vivo imaging.

And one of the things you found was that even though these Kupffer cells stop functioning, the liver has a backup system of sorts, right?
Exactly. The fascinating adaptability of the liver is something I’m continually amazed by. I’ve been working with the liver for so long, but that was still surprising.

Now, this was in a mouse model. Would you say there are clinical implications?
Well, we saw a very similar phenomenon in humans. The question becomes: With all the information we have now, how can we help mice and potentially humans overcome this whole architecture change of the liver? How can we potentially use what we’ve learned to help with infections and liver function? I think the findings so far don’t necessarily give us the answer, but we definitely have more information now about what’s going on. Now the knowledge can move forward and eventually get to a therapy or something more clinically related.

What’s next for you?
I’m working on another project, which is my baby. It has been my main project for a while. It’s also, of course, liver-related. But it’s focused on understanding how the liver and the same macrophage population play a role in neonatal infections. We already know that the cells don’t work as well as in adults. Now we are investigating why, to understand why babies are way more susceptible to infections—and these macrophages in the liver play a big role in that susceptibility. And hopefully we can use that [information] to better deal with newborn and neonatal infection, which is a huge problem.

I think it’s very important to highlight how these foundational blocks of knowledge are important. Because I feel like people in general, they rush to get to the clinic and unfortunately, sometimes things don’t work because we don’t have the knowledge we need first. People have to have patience.