Q&A with Dr. Luke Esposito

Tell us about yourself – what is your background in and how did you end up in your current position?  


Human biology has always been a huge fascination for me. So perhaps it’s not surprising that for most of my career, my scientific interests have been directed at understanding mechanisms of human disease, so that we can hopefully devise better treatments for devastating illnesses like Alzheimer’s and Parkinson’s disease. 

My Ph.D. thesis was aimed at understanding how deficits in cellular energy production that results from dysfunctional mitochondria, the energy-producing centers of the cell, and the resulting increase in oxidative stress, can result in tissue damage and “mitochondrial disease”. Since the brain utilizes a lot of energy, mitochondrial dysfunction was proposed to be linked to, or even causal in, neurodegenerative disease. After my Ph.D. I did a postdoctoral fellowship at University of California San Francisco, at the Gladstone Institutes, to test this mitochondrial hypothesis of neurodegeneration in an Alzheimer’s disease mouse model that has extensive deposits of a sticky misfolded protein known as amyloid beta (or Abeta). As it turns out, Alzheimer’s disease is multifactorial and extremely complicated, but we showed that there was an impact of damaged mitochondria on brains of mice with Alzheimer’s disease, including how amyloid is deposited in the blood vessels of the brain. 

After completing my postdoc, and given my expertise with misfolded proteins, I was recruited to a startup biopharmaceutical company in the Seattle area. I spent 10 years in this industry, leading drug discovery programs aimed at targeting and detoxifying the misfolded proteins that cause Alzheimer’s disease (Abeta), and Parkinson’s disease (alpha-synuclein) as well as other more rare diseases. In addition to the scientific and regulatory aspects of drug discovery, I worked intensively on the business side of drug discovery, including business development, fiscal management and research operations in general. Overall, I really enjoyed the “chase” of drug discovery and development, but I had always had my eye on the cool work happening at the Allen Institute.  

I had the very fortunate opportunity to meet Hongkui Zeng, the current leader of the Allen Institute for Brain Science, and after speaking, I became very excited about how I might contribute to the mission of the Institute. I wanted to understand the brain in health and in disease- and to do so in an “open science” fashion, since nearly everything in the biopharmaceutical industry is proprietary and confidential. In 2017, Hongkui recruited me to lead Research Operations for the Structured Science unit within the Allen Institute for Brain Science. At the time, Structured Science was a group of roughly 100 scientists, research associates and engineers responsible for large scale data generation and analysis projects, also known as our “pipeline” projects because large amounts of data are generated in a standardized way and “flow” through the pipeline, and are ultimately disseminated to the scientific community. 

When Hongkui stepped up to lead all of the Allen Institute for Brain Science, in March 2020, she asked me to elevate my role, too – and lead all of Scientific Operations for our organization of  about 250 people. I jumped at the opportunity to increase my influence and impact. My extended team includes our Program Management team, our Engineering team, our Molecular Biology team and our transgenic colony management team.  Part of what makes this job so exciting is working with this diverse set of talented people who are all devoted to our mission and committed to the principle of team science. 

You’ve been at the Allen Institute for the past 5 years: what has been your experience and the focus of your work there? 

 
My work is essentially at the interface of science and business.  I work closely with a very diverse set of Allen Institute teams, from scientific, to financial, to administrative. One of my primary goals is working to ensure that we execute on our science to meet our ambitious scientific goals and in doing so, are good stewards of our resources and assets. For example, I am responsible for building our annual budget and ensuring that we manage our budget. I work with our program management team to monitor and evaluate progress toward our scientific goals. In doing so, I aim to be an unbiased arbiter of fairness whenever possible. I also play a central role in our internal and external reviews, for example, meetings with our Scientific Advisory Council and Next Generation Leaders.  I work with our human resources team to ensure that we have an engaged workforce, and I work with our legal team on our research agreements and contracts.  I also work very closely with the operations directors of the other science units to achieve our Allen Institute-wide common goals. Perhaps most importantly, I serve as an advisor to Hongkui Zeng, in addition to directing the administrative and operational functions of the organization.  

Can you tell us about the BRAIN Initiative?


The BRAIN Initiative stands for, “Brain Research Through Advancing Innovative Neurotechnologies,” and to me, it is an explicit acknowledgement by the U.S. government, especially former President Obama, that to understand the brain and how it works is really difficult.  To meet this challenge, the government has made a long-term commitment to support and fund basic research and the development of new technologies. I think the use of the word neurotechnologies in the name is significant, because neuroscience has evolved from a discipline focused largely on anatomy to one that approaches the study of the brain and the broader nervous system using a wide range of techniques, data modalities and hence technologies. This includes leveraging the massive power of the (relatively new) single cell genomics revolution where we can look at thousands of genes across millions of individual cells to define their molecular identity and glean insight into their function. 

In addition to technologies needed to probe the brain in the lab, we need improved ways to analyze the massive data set we generate, i.e. computational power. So I think part of the BRAIN Initiative is to encourage the development of technologies that are capable of converting massive data sets into useful knowledge. The BRAIN Initiative also acknowledges that a truly reductionist approach is required to understand the brain. By this, I mean we need a high-resolution understanding of the basic components of the brain, also known as the cell types, in order to understand how they connect to one another to form functional circuits and ultimately to act as a massive computer of sorts, taking in information, forming models about the environment, and informing action, while at the same time driving the fundamental processes that we don’t “think” about like breathing, heartbeat, digestion, involuntary movement, etc. It’s pretty amazing stuff.

Tell us about the brain cell census and the Allen Brain Atlas?


The Allen Brain Atlas was the first, and still most widely used, open access gene expression resource the Institute generated to accelerate research across the neuroscience community. When developing the Atlas, the Institute went gene by gene across the young adult mouse brain using a technique called in situ hybridization. What made this so ground-breaking was the Institute was using this (at the time) relatively new technology at a massive scale, to essentially demonstrate the anatomical landscape for each and every gene in the mouse genome. The work was enabled by the mouse genome project which was completed in the early 2000’s. This meant that for the first time in the history of neuroscience, we had a complete list of all the genes that could be expressed in any given region in the young adult mouse brain. 

This project was not only important for the scientific community (as I said, it’s still the go-to tool for anyone who wants to know where a given gene of interest is expressed in the mouse brain), but also for the Institute itself. While I wasn’t here at that time, I believe this early success demonstrated that the Institute could accomplish these impactful large scale projects, on time and on budget, in an efficient way, therefore justifying additional generous support by Paul G. Allen, which then enabled work across other species, ages and disease states. 

The Brain Cell census takes brain cartography (or atlasing) to the next level. Instead of going gene by gene across the brain, the cell census goes cell-by-cell. Since each cell expresses thousands of genes and can have many connections, the level of complexity, and size of the datasets increase exponentially. The Brain Cell Census work reached an inflection point last fall, in October 2021, with the publication of a detailed cell type based atlas of cells in the primary motor cortex, which is involved in voluntary movement. Using a variety of techniques and working across species, the work provided unprecedented detail into the cell types of this region and showed that this work can be extended across the whole brain, first in mice, and eventually in humans, which is where we are heading now.

As a researcher on neurodegenerative diseases, how do you hope to see the Brain Atlas utilized?


To understand the diseased brain, we need a comparator, which of course is the healthy human brain. So I believe that by defining and understanding the cell types of the brain, including the neurons and the non-neuronal cells which are increasingly known to be involved in human disease, we will make huge strides in understanding what goes wrong in disease, and hopefully early in the disease, so that we might intervene at a time that such therapies will have meaningful benefit to the patient by preventing further degeneration and decline. 

We are already seeing proof of the utility of this approach with our recent release of cell type data derived from Alzheimer’s disease patients at different stages of the disease. By using our data from a region of the brain known as the middle temporal gyrus, which is part of the cortex, we can compare healthy cells versus ones from a person suffering from the disease. Indeed, we see some interesting disease-related changes in the composition of cell types and changes in the genes that define those cell types that wouldn’t be possible to see without the healthy comparator.

What is the reasoning behind mapping primate, human, and mouse brains? 

Evolution is truly amazing. There is a remarkable conservation in some of the basic elements and architecture of the brain, from mouse to non-human primate to human. Nature is a master recycler of sorts. But of course it’s not all the same, and things change significantly over millions of years of evolution, otherwise this interview might be with a mouse instead of with me.  But there is enough similarity that we can glean insights into humans by studying model systems such as mouse and non-human primates like marmoset and macaque.  The mouse brain is of course much smaller (by more than 1000-fold by weight relative to the human brain) so it’s more tractable. We can also apply technologies such as transgenesis to mice (i.e. transgenic mice) to be used as research tools or use optogenetic techniques that we would not do in humans. We can also map circuits more easily in smaller brains. We can link cell type identity, structure and function in a highly detailed way in these model systems and then generate testable hypotheses of how these findings might apply to humans. In essence, we can understand the function of cells and circuits in humans by understanding how we evolved into humans and what elements of the brain are unique to humans and thus responsible for imparting truly human characteristics.

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What promising discoveries are on the horizon for neuroscience?**

I think we will learn a lot about the human brain and how it is wired in the next few years. We will convert a relatively coarse understanding of the brain’s cells and how they organize into functional circuits, and turn that into a high resolution functional map of the brain that will lead to circuit-based therapies. We will also learn to effectively deliver therapeutic genetic cargo to specific regions of the brain. By this, I mean gene therapy for complex neurological disease. To date, we have been limited in our ability to safely and sustainably deliver a gene, in the correct amount, to the precise regions of the brain where we want it to be while sparing regions where it might have a deleterious or negative effect.  I envision a complementary approach to treating human brain diseases, where gene therapy adds value to the traditional “small molecule” drug approach and the more recent antibody-based therapies currently in use.

What is your single biggest motivator when you come to work each day?

 
It’s the people that I have the privilege to work with. It’s a truly amazing group of dedicated, intelligent and respectful people who are devoted to our mission of making discoveries that may ultimately lead to improvements in human health.

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