Neuroscience Widens Its Investigations of Disease Mechanisms

A systems perspective informs the work of Neurocrine Biosciences, which seeks new treatments where neurobiology interconnects with endocrinology and other disciplines

Nerve cells firing
The nervous system’s connections are dauntingly complex, even if one considers only the connections between neurons. But of course, there are many other connections, some of which reach from the nervous system to other systems, including the immune system and the endocrine system, or even the gut microbiome. To map obscure but essential connections, researchers are adopting multidisciplinary approaches and deploying powerful computational resources. [Science Photo Library-Pasieka/Getty Images]
When scientist-sage Richard Feynman said, “Nature uses only the longest threads to weave her patterns,” he wasn’t thinking of neuroscience in particular, but his words certainly apply to the discipline. In neuroscience, threads of various kinds are proving very long indeed, long enough to run from the nervous system to the immune system, the endocrine system, and even the microbiome.

Kevin C. Gorman, PhD
Kevin C. Gorman, PhD
Co-Founder, President, and CEO
Neurocrine Biosciences

To tug at these threads and make sense of the tapestry they form, neuroscience is applying new tools, such as optogenetics, chemogenetics, imaging technologies, and artificial organs. It is also becoming increasingly interdisciplinary, reaching out not just to immunology, endocrinology, and microbiology, but to branches of mathematics and computer science such as artificial intelligence. To help us appreciate the neuroscience tapestry that is now emerging, GEN spoke with Kevin C. Gorman, PhD, co-founder, president, and CEO of Neurocrine Biosciences. He expects that close study of this tapestry will reveal once obscure disease mechanisms and lead to new treatments for a range of maladies.


GEN: What key advances have been made against neurological diseases since 2000?

Gorman: First, a better understanding of systems biology as it deals with the brain and the different cell types. Second, the development of new therapeutic modalities. Third, all of this ties together because we have seen that a different way of thinking about therapeutic approaches has led to an explosion in innovation in the area of immuno-oncology.

Think about it. Fifteen years ago, when you had cancer, what you got was a collection of intravenous drugs that would poison you just this side of death. You were subjected to a brute force approach, a nonspecific hammer that would try to kill as many tumor cells as possible but as few normal cells as possible. It wasn’t specific at all.

Contrast that with the way it is today. You are diagnosed with cancer, and the first thing that’s done is that the genome of the cancer is sequenced—not the whole thing, but enough to type the cancer, that is, to reveal the molecular organization of the cancer. And then you have tailored therapies: the checkpoint inhibitors, the monoclonal antibodies, the bispecific antibodies, and the tethered toxins that are targeted just to the tumor. It’s a completely different way of approaching the treatment of cancer. And that is what has happened. I think neuroscience right now is where oncology was about 10 years ago.


GEN: What research trends will emerge over the next 10 years?

Gorman: Forgive me if I sound a little repetitive, but research will improve our understanding of neurological systems and other systems and how they interconnect. Some of the emerging technologies for understanding systems are actually going to work as therapies. Neuroimmunology is going to be a key area of research. If you step back 30 years, no one knew that the nervous system and the immune system engaged in crosstalk.

Now we know the nervous system and the immune system are highly interconnected. What we don’t know are the molecular mechanisms responsible for that connection. As that gets revealed over the next few years, that is going to give us some of the most interesting targets to tackle among the most serious diseases that we have in neuroscience and neurology. I should add that you can’t talk about the nervous and immune systems without mentioning the gut axis, including the microbiome.

Those three systems are going to be found to be tightly interconnected and to add another layer of complexity.

You’re already talking about having 80 to 90 billion neurons in the brain, and you have about 80 to 90 billion other cells in there. Most of them are immune cells. By the way, there’s no receptor in the gut that isn’t also found in the brain and vice versa. So, from a receptor standpoint, they’re replicates of one another even though their functions are so dramatically different.


GEN: How might the trends you’ve mentioned be driven by emerging technologies?

Gorman: In neuroscience, it was not that long ago that you chose your targets based on brain region, and there were about 50 brain regions mapped out. Now, we have uncovered several hundred brain regions, and we want to know, where are the neurons projecting down to? Each individual neuron is different and has a different function, even though its cell body and its projections go to the same place. Several technologies are being used right now to study these neurons and their functions. These technologies include optogenetics, chemogenetics, imaging technologies, and artificial organs.

Both optogenetics and chemogenetics are going to provide great insights. Advances in optogenetics allows us to work with ion channels and make them optically sensitive so you can turn them on and off with light, both in vivo and in vitro. Chemogenetics has allowed us to more effectively target G protein–coupled receptors by engineering them with a sequence that allows them to be selectively turned on and off with a drug or a molecule. This approach can be taken in vivo or in vitro to help us understand the functioning of single cells.

The imaging technologies that we have now, such as magnetic resonance imaging, are being utilized along with our understanding of systems biology to better understand positron emission tomography ligands. We are now able to develop an agonist or antagonist to a system that we want to examine. Doing so allows us to assess the functions and study the effects that are taking place in the brain in real time.

Brain organoids or the use of artificial organ systems can also provide clues to how the brain works. These systems allow us to compare normal states and disease states. This is an exciting area in science that will advance our understanding of disorders.

We are only at the beginning of understanding neurons and their individuality and function in the body, and we are hoping that new technologies will give us better insight into developing treatments for patients.


GEN: Which neurological diseases will be most tractable? Which will be less so?

Gorman: The most tractable diseases/disorders will be the ones for which relatively noninvasive treatments are available and for which the most information has accumulated. At the top of the list, we’re going to see diseases involving a system that we’ve known for at least as long and as well as any other—the endocrine system. We’ve understood for a long time that there’s a hypothalamic-pituitary-gonadal axis and a hypothalamus-pituitary-adrenal axis. Everything starts in the brain, and the key to discovering therapies will be to tease those axes apart and find multiple places of intervention, even outside the brain.

The second one is monogenic diseases because they lend themselves to a precision medicine approach in neuroscience with the use of small molecules and gene therapies. Orally active small molecules can precisely target the aberrant protein, whether it’s one that has a gain of function or a loss of function. That’s particularly evident in epilepsies now. With gene therapies, obviously, you’re going to try to precisely target one gene. We are also interested in silencing the gene in areas where we don’t want that gene expressed. We can design vectors to a specific brain region with genetic information that will help dampen or silence cell types where you don’t want the gene expressed.

The diseases that are going to be much more difficult to tackle include neuropsychiatric diseases. They are clearly not monogenic. This is true systems biology going on here. Another reason they are more difficult to treat is that the way of classifying and recognizing the disease involves points-in-time observations, and they can’t be all put in the same bucket. For example, with movement disorders, you can’t treat a tic disorder, Parkinson’s disease, tardive dyskinesia, and even certain seizures all identically, just because they present as abnormal movements. When we’re talking about psychiatric diseases, we need much better classification criteria than those informed by points-in-time observations.


GEN: Why are you confident that the future looks bright for the treatment of neurological disorders?

Gorman: I’m an immunologist by training. My doctoral advisor, William R. Clark, PhD, at the University of California, Los Angeles, always taught immunology while conveying the subject’s historical background. He did it not by giving you a timeline of facts, but by showing you experimental data and then interpreting that data, which then led to an understanding. Then the next experimental pieces of data led to a new understanding. When you take a historical perspective, you can see that almost all the really salient discoveries were made by non-immunologists.

Today, we are multidisciplinary in ways that we never thought we would be, and neuroscience is at the nexus of that. We have neurologists and immunologists poking their way into the brain, radiologists who have developed techniques that are going to be absolutely critical for what we’re doing, mathematicians who are working on areas of interest, and artificial intelligence gurus who are stepping in. We have physicists, mathematicians, computer scientists—and I haven’t even mentioned engineers.

On top of all this, wearable devices can have a huge impact on our advancements in neuropsychiatric diseases. Being able to access electronic observational data that is collected 24 hours a day will help us identify phenotypes and subsets of phenotypes, which will allow us to improve our understanding of what’s happening on the genotypic/cellular level. Hopefully, we’ll be able to treat patients much more precisely, safely, and effectively.

When you have that kind of cross-pollination of disciplines and technologies, the odds of success go up logarithmically. That’s what we’re seeing here, and that’s why you’re going to see the rapid pace of discovery that’s going to take place over the next 10 years in neuroscience.

We are fortunate here at Neurocrine Biosciences to be at the forefront of these new discoveries. We are involved in the many of the areas I have talked about today, either internally, in our research, or externally, through collaborations with other biotechnology and pharmaceutical companies as well as with phenomenal academic research labs. It is a very exciting time for us, and we are looking forward to continuing advancements in neuroscience to help the many patients with serious, challenging, and under-addressed neurological, endocrine, and psychiatric disorders.


To help us preview the future, we asked opinion leaders, all from outstanding technology companies, to discuss a range of new initiatives. The full list of articles is below.

Leroy Hood: Reflections on a Legendary Career
Uncharted Territory: Top Challenges Facing Gene Therapy Development
Envisioning Future Trends in Regenerative Medicine
Engineering Biology—Accelerating Transition
Bioprocessing in a Post-COVID-19 World
Sustainability and the Synthetic Biology Revolution
Sowing the Seeds of Agricultural Biotechnology
Neuroscience Widens Its Investigations of Disease Mechanisms