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10x Genomics Blog

Every day, young neuroscientists around the world step into the lab, don their lab coats, and put on their thinking caps to tackle the mysteries of the brain. The breakthroughs they make today and in the coming years will change how we understand and treat neurological disorders, improving the quality of life for those living with Alzheimer’s disease and related dementias (ADRDs). To honor and support a new generation of investigators on their journey deeper into the complexity of the brain, we launched the Early Career Investigator Award (ECIA), which recognizes one exceptional early-stage researcher who is advancing our understanding of the pathophysiology of ADRDs.

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With so many inspiring nominations, it was a challenge for our panel of leaders in the field of ADRD research to pick a single winner! We are pleased to announce David Michael Gate, PhD, an Assistant Professor at Northwestern University, as the inaugural ECIA award winner. Continue reading to hear more about Dr. Gate’s neuroscience career and his insights on the future of neurodegenerative research.

### What drew you to study Alzheimer's in particular?

**Gate:** I'd say a lot of it was serendipitous...I was coming out of college looking to gain research experience. I wasn't quite sure if I wanted to go to medical school or graduate school. I was hired in a lab that specialized in Alzheimer's disease (AD) research, and it became really clear to me very quickly that I wanted to go the scientist’s route and not the physician’s route.

Alzheimer's disease, I realized, was a growing health concern for our population. You could even argue that we're in an epidemic. So, I became passionate about it because it seemed like it was this huge problem, and we had \[made very] little progress toward solving it... there were no treatments. So, I just fell in love with the research and fell in love with studying AD simultaneously.

I also had a peripheral interest in the immune system, just from my graduate work being tangentially related to immunity so I sought out a postdoc with Tony Wyss-Coray, who was one of the few people at the time studying both immunology and neurodegeneration. And you could argue that he's a pioneer in the study of neuroimmunology in Alzheimer's disease. That's how I got into my current focus.

> *“David has been an absolute pleasure to work with and learn from; I think his pioneering approach to collect and characterize cells from cerebrospinal fluid at the single cell level–instead of throwing the cell pellets from CSF collections away–will have a huge impact in studying immune–CNS interactions in neurodegeneration and other brain diseases. I’m thrilled he received this award and wish David all the best with his new lab at Northwestern!”* 
>
> *\- Tony Wyss-Coray, PhD, Stanford University*

### You are now about to start your own lab. What is it that you hope to focus your lab on?

**Gate:** There are a lot of animal studies, a lot of mouse work in the neurodegenerative research area. I'm mostly interested in working with human specimens, human tissues, patient brain imaging, and patient fluid cells, like the immune cells in the blood and cerebrospinal fluid. My lab will take genetic, genomic, and proteomic approaches to studying the genes and the proteins, which really are the movers and shakers of this disease—to study not just Alzheimer's disease, but other neurodegenerative diseases, as well. This is really why I was so intrigued by Northwestern neurology because they have so many patients and so for someone like me, who wants to study human specimens, I was looking for a university with a large patient clinic and I couldn’t be happier with where I landed.

I'll have access to these patients and have already started writing grants that are focused on studying these diseases using the techniques that I've mastered during my postdoc. I was the first to sequence immune cells from the cerebrospinal fluid \[CSF], and it's revealed some very interesting things with respect to the immune response in the cerebrospinal fluid. And I think that we can use changes in the immune system to, perhaps, someday, diagnose and predict if a person is progressing towards neurodegenerative disease.

### What does receiving this Early Career Investigator Award mean to you and your research moving forward?

**Gate:** It's huge. I mean, I was really humbled to receive this award because I know how many talented young researchers there are in this field. I work with some of them and, of course, I have read their papers. So I think more than anything, it was really humbling to be acknowledged in this way by some of the leaders in the field. The people on the selection committee are some of my scientific idols, to be frank.

For my lab, it provides me with funding for doing some of the experiments that I'm really passionate about. And 10x Genomics technology has been integral to my research projects. A lot of these technologies came on while I was doing my postdoc. I was midway through my project, and we were at a standstill where we wanted to look at the CSF, but we just didn't have the tools on hand.

Going forward, I think, it opens a lot of doors. As a new PI \[principal investigator], you're restricted with what you can do financially. You're given a startup package, but you're always looking for other sources of research support. So, to get that directly from 10x Genomics and to be able to use their technology even more, it's huge for me.

### Is there any technology that you haven't tried yet, but you are particularly interested in exploring?

**Gate:** Yeah, that's a great question. I think the developments in the spatial transcriptomics area are really exciting. I think the technology is just in its infancy, and I'd love to try spatial transcriptomics assays on human brain tissue specimens. These technologies are now allowing us to use tissue specimens that have been preserved over decades. So, it opens a lot of doors for going back to a large number of historical samples, and you don't necessarily have to only work with prospective samples that you'll be getting down the road.

And of course, as the technologies get better, we're able to capture more genes and be able to tie them to single cells within the tissue. It's a really exciting technology. And it's something I haven't used yet, but I absolutely plan to employ in my lab.

### We're excited to see what you do with it. You've been talking a little bit about the new connection to Alzheimer's. Are there any other recent discoveries in the field of Alzheimer's that you're really excited about?

**Gate:** Dr. Michael Heneka is a researcher in Germany, someone I really have a lot of respect for. He's shown that the response of the immune system connects Alzheimer's amyloid plaques to tau pathology. This was published in *Nature* and it's a really exciting finding because it really shows how integral the immune system is to the disease. In the past, I think, people observed all these separate aspects of the disease, where you had the amyloid, you \[had] the inflammation, and you had the tau. It turns out, the inflammation and the immune response actually connect all these things. It's not just its own pathological entity, but it's really a mover and shaker of the disease process.

Dr. Christian Haass has always been one of my favorite researchers. He's really done a lot of very good biochemistry and has found that this particular gene *TREM2*, which is a gene expressed on the brain's immune cells—microglial cells—is involved in the disease. He's done some really elegant work there.

And then there is Dr. Mathias Jucker who has done some really interesting research showing how amyloid can spread in the brain, where if you even just introduce a tiny amount of amyloid into a mouse brain, it will spread much like a prion, as Stan Prusiner showed in mad cow disease.

This disease is so much more complicated than just one part of the brain or one type of cell. So, we really need all hands on deck, as many experts as we can. And there are some really talented people coming out of these labs that I just mentioned that are training these young researchers. I think there are a lot of trends in this field that are promising. It's a very scary disease and the numbers are looking more scary by the day, but there are also very talented people working to solve this disorder.

### How do you see the field evolving over the next few years?

**Gate:** We've now entered the era of big data, as I would call it, where you can take these multiomic approaches to study these diseases. And I've been mentioning the advancements in genomics and how important they've been to understanding the disease, but also advancements in the study of proteins, which is really important if you think deeply about it. The protein is the end result. Now you have the genetic mutation, you have RNA, but the protein is really what makes the disease happen. And we're just now getting these really impressive technological breakthroughs in the study of proteins.

I can imagine, and I've done some of this myself in my own studies, where you're doing these big data projects on large numbers of patients where you're looking at a large group of patients, both healthy and diseased, and you're measuring essentially everything you can possibly look at. You're looking at CSF, brain tissue, blood immune cells, proteins and genes, within all of these compartments. And that's how I think we're really going to make major breakthroughs. If what I think is true and there are different forms of Alzheimer's disease, that's how we're going to find that out.

You're going to see out of these 1,000 patients, this group of 200 is really distinct. They have this component of the disease, it's much more inflammatory and we think that's directed by their genetic mutation. And so those people probably should be given a drug that targets what we think is causing their disease, and these other people, perhaps, should be given a different therapy.

### On the topic of big data, how important do you think multiomic characterization—looking at those different analytes within the same cell—is going to be to tease out the complexity of Alzheimer's?

**Gate:** Yeah, it's critical. I think this trend has already started where we're finding things that were lost in the weeds previously because our techniques were limited. And I've been hitting on this, where if you're looking at a couple thousand genes in a person's genome, you could find a mutation that has been previously undescribed, and you can then follow that all the way through. You can manipulate that gene in a mouse to test therapies, and then you can treat those particular patients in a targeted way. A lot of these mutations, they're genetic and so they're familial. So, you then have a therapy for a particular family or for a particular patient group, and I think this is really important.

### One last question. Do you have any advice for young researchers looking to delve into Alzheimer's or any other type of research?

**Gate:** Yeah, I love talking to young researchers. I think it's an arduous field. Getting a PhD is difficult; succeeding in a postdoc is difficult. You often feel like you're sort of on the bottom of the societal totem pole, because researchers are not paid vast sums of money. You don't get the type of notoriety that professional athletes get. You're not a rock star by any means. But, in my opinion, the journey has been worth it.

It was always my dream to have my own research lab and it's not like there weren't struggles along the way. It's not like there weren't bumps in the road. It hasn't always been a smooth, rosy journey for me. But if you stick with it, if you work hard enough, if you align yourself with the right mentors, and if you follow the advice of the people that you've entrusted with mentoring you, then good things can happen. I don’t think I could have chosen a better mentor than Dr. Wyss-Coray, who provided me with a master class education in how to manage a research lab.

I also tell people to not follow the dogma. If you read something or if you find something in your own data that bucks the convention, don't be afraid to follow up on that and try to make your claim.