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by Kelsey Tyssowski
figures by Krissy Lyon

In the 2013 State of the Union address, President Obama announced a boost in scientific funding aimed at mapping the circuits of the brain in hopes of treating disorders ranging from depression to Alzheimer’s. This promise has developed into the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, a scientist-led, goal-oriented plan that makes brain mapping seem achievable.

The BRAIN Initiative is the Obama administration’s first push for science funding, and it’s therefore something of a test case for how well his other projects will fair. Now about three years in, the first round of BRAIN Initiative-funded projects are just starting to yield results and more project proposals are scheduled to be submitted soon. I sat down with Josh Sanes, director of the Center for Brain Science at Harvard University and member of the BRAIN Initiative working group, to discuss his hopes for the initiative and how we’re doing so far. He’s excited about what this can accomplish for science, medicine, and society, and here’s why:

1) It provides funding for projects that wouldn’t otherwise be funded

Technology development is important for making new discoveries, but it isn’t always well funded. The Human Genome Project, the government’s last big push for scientific funding, spawned genome-sequencing technologies that have revolutionized the fields of biology and medicine. One only needs to look as far as human genomics companies like 23andMe or whole research institutes (e.g. the Broad Institute) dedicated to sequencing to see the effects of this technology on not only biomedicine, but also the economy.

Despite these advances, most funding agencies are reluctant to fund technology development projects. Instead, agencies like the National Institutes of Health (NIH) prefer to fund “hypothesis-driven research,” meaning that the researcher proposes testing a specific scientific prediction. A hypothesis is something that can be proven true or false, and, according to the NIH, serves to focus the research. The researcher will reach the end of their project with some kind of answer even if their hypothesis is wrong. On the other hand, technology development is risky: the researcher will either emerge victorious with a new technology or have nothing.

The BRAIN Initiative’s focus on technology is where it distinguishes itself from the normal grants that scientists usually get. And Sanes told me that the BRAIN Initiative is already living up to its potential here: while many researchers were already developing technologies, these projects were not well funded. “So I think it gave lots of groups a real push,” he says. Examples of funded technology development projects range from better ways to measure the activity of neurons in the brain to new ways to study the molecular characteristics of one cell at a time in order to evaluate the diversity of cell types in the brain.

Sanes hopes this investment in risky projects like these will serve to transform the field of neuroscience like the Human Genome Project revolutionized biomedicine.

2) It will bring us much closer to treatments and cures for psychiatric disease

Sanes argues that when it comes to finding treatments for psychiatric disease, we’re “clueless because we don’t understand how the relevant part of the brain works.”  “It isn’t one of those areas where you feel like somewhere in a biotech company they could just mix a few more liquids together and they’d have the next cure.”

Instead we need new technologies to reverse engineer the brain in order to understand how it works. Sanes compares it to understanding a radio: “If you want to understand how… a radio works, you need to know the wiring diagram, and you need to know the nature of the electrical currents that are passing through it, and then you need to be able to make a hypothesis about how that wiring makes the radio play the Patriots game, and then you need to be able to test that hypothesis by… cutting a wire, putting a wire back, moving a wire around. And at that point, an engineer would say, ‘if someone brings me a broken radio, I’m going to be in a position to diagnose it and fix it.’”

Right now, when the brain needs to be fixed—when someone has depression, Alzheimer’s, post-traumatic stress disorder, addiction—we can’t just find the missing wire. Not only can we not find the missing wire, but also in most cases, we don’t even know where to start looking for it. In order to figure out what’s going wrong in these disorders, we will have to understand how the firing of specific neurons making specific connections results in a specific behavior.

Sanes is hopeful that in three to four years, we may be able to do this in a vertebrate animal: a zebrafish, an animal that is commonly used in research. That is, scientists will be able to record all of the electrical activity of every neuron of a fish as it goes through its day, akin to an understanding of the electrical currents move through the radio’s wires. (We’re already well on the way to this). And then they will then be able to take that very fish and map how each neuron connects to every other neuron in the entire brain, essentially figuring out the wiring diagram, also known as the connectome.

After scientists have this diagram, if they take a behavior, say the fish flapping its tail, they could look at what neurons are active during that behavior. Then, researchers will be able to manipulate those neurons and control the tail flapping, showing that they truly understand what’s making the tail flap (Figure 1).

Figure 1: Reverse Engineering a Zebrafish Nervous System. Scientists hope insight gained from mapping the brain of model organisms like the zebrafish will help them to understand the human brain. Here’s one way researchers could map the zebrafish nervous system: (A) First, scientists hope to get a neuronal firing map of the zebrafish nervous system—which neurons are firing as it goes throughout its day? Because zebrafish are transparent, researchers are able to make use of genetically engineered zebrafish whose neurons light up upon firing. This way, scientists can record which neurons fire when and correlate that information with what the fish is doing at the time. This allows them to make predictions about which neurons direct which behaviors. (B) Next, scientists can take that very fish and use powerful microscope technologies to determine the physical map of the fish brain, figuring out which neurons are physically connected. (C) Finally, researchers can test the predictions made after the first two experiments by experimentally controlling neuronal firing using light, a technique known as optogenetics. In this technique, when they shine light on a neuron, the neuron will fire. Therefore, if the researchers think they have found neurons that are responsible for some behavior, like making the fish’s tail move, they can activate those neurons using optogenetics. If the optogenetic activation makes the tail move, they will have strong evidence that their prediction is correct.
Figure 1: Reverse Engineering a Zebrafish Nervous System.
Scientists hope insight gained from mapping the brain of model organisms like the zebrafish will help them to understand the human brain. Here’s one way researchers could map the zebrafish nervous system: (A) First, scientists hope to get a neuronal firing map of the zebrafish nervous system—which neurons are firing as it goes throughout its day? Because zebrafish can be transparent, researchers are able to make use of genetically engineered zebrafish whose neurons light up upon firing. This way, scientists can record which neurons fire when and correlate that information with what the fish is doing at the time. This allows them to make predictions about which neurons direct which behaviors. (B) Next, scientists can take that very fish and use powerful microscope technologies to determine the physical map of the fish brain, figuring out which neurons are physically connected. (C) Finally, researchers can test the predictions made after the first two experiments by experimentally controlling neuronal firing using light, a technique known as optogenetics. In this technique, when they shine light on a neuron, the neuron will fire. Therefore, if the researchers think they have found neurons that are responsible for some behavior, like making the fish’s tail move, they can activate those neurons using optogenetics. If the optogenetic activation makes the tail move, they will have strong evidence that their prediction is correct.

Sure, making a zebrafish flap its tail is not curing psychiatric disease, but it’s a lot closer than we are now. The principles and technologies discovered from experiments like these are the first step to attempting a similar feat in humans and figuring out which neurons, which connections, and which brain activities make a person have, for example, PTSD. And figuring out what’s wrong is the first step towards curing psychiatric disease.

3) It is funding development of much-needed tools to study the human brain

According to Sanes, we’re just three to four years away from reverse engineering a zebrafish brain, but we’ll need much better technology to apply those findings to humans. The current best technology for reading the activity of a human brain is functional magnetic resonance imaging (fMRI). The smallest unit that can be measured by fMRI is, as Sanes explains, “tens of thousands of neurons of hundreds of different types. … It’s hard for me to see how that level of map in humans is going to end up leading to clinical advance, frankly.”

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Figure 2: What kind of map will we get from the BRAIN Initiative? Before the BRAIN Initiative began, we already had a basic map of the human brain. In each brain region, we knew that there were a handful of different types of neurons, we had a basic map of connections between brain regions, and we knew that certain brain regions were important for certain tasks. For example, we know that the prefrontal cortex (highlighted above) is important for working memory. The goal of the BRAIN Initiative is to add detail to this map by figuring how many different types of neurons there are within each region and determining a more complete and detailed map of connections between regions. In addition, the initiative aims to add functional relevance to this more detailed map: which neuronal types and connections are responsible for certain behaviors? So, by the end of BRAIN Initiative, perhaps we will know that our working memory is driven by a specific group of connected brain regions (circuit), made up of specific cell types in those regions.

While it is not realistic now, or even in ten years, for us to have a comprehensive map of the human brain, the BRAIN Initiative aims to develop human brain recording and imaging technologies alongside those used to study model organisms that will get us a lot closer (Figure 2). Among the funded grants in this area are projects that aim to use non-invasive ultrasound devices to stimulate specific groups of neurons in the human brain, allowing scientists to figure out what not just brain regions, but neurons in those regions, do. Researchers have also proposed adding electrodes to Deep Brain Stimulation (DBS) devices that are already FDA approved to be implanted in the brains of patients with Parkinson’s and depression. These electrodes will permit recording of the electrical activity of neurons in the brain of a person on doing normal every day tasks, bringing us closer to the activity-behavior connection.

Scientists are excited about human brain mapping because there are already examples of how primitive maps have lead to clinical advances. In the case of Parkinson’s disease, an understanding that a certain movement control center of the brain is underactive has allowed DBS of that area, which increases neuronal activity, to provide relief to patients.

However, other disorders are likely more complex than dysfunction of a single region, rendering current brain maps inadequate. Sanes gives the example of schizophrenia, for which there is not one clearly affected brain region. With current cutting edge technology, we may be able to figure out exactly which types of brain cells are different between schizophrenic and healthy brains, but that information is hard to use unless you put it into context. It would be helpful to be able to merge this information with “maps that would tell us what do those neurons actually do, and that would lead us to a new way of thinking about therapy.”

4) Understanding the brain is understanding ourselves

“There is essentially nobody who isn’t interested in their own brain. Because we all know that we are our brain in a way that we are not our kidney, and we’re not our liver.”

Because we are our brains, a better understanding of our brains has potential to shape society in a multitude of ways outside of science and medicine. Sanes gives the example of the law: “The more we understand how behavior that we think of as being free will behavior has true biological causes, we’re going to have to think about how we deal with people who misbehave in a slightly different way.”

Already there are examples of how understanding neurobiology has had the effects he’s talking about. Mapping the brain circuits underlying addiction has lead to the understanding that addiction has a biological basis and not a moral weakness. This has opened new research into pharmaceutical treatments for addiction and has lessened the stigma against addicts.

The BRAIN Initiative will give us a much deeper biological understanding of how the electrical activity and connections within our brains underlie our thoughts and actions. We’re still far from understanding the human brain as well as we understand a radio or a computer, but the initiative will bring us closer to a meaningful understanding of why we think what we think or do what we do.

“You know, and you can go to anybody, and you can say, if my kidney were transplanted into you, you would still be you, but if my brain were transplanted into you, it’s not so clear who you’d be…. It’s … maybe the greatest remaining scientific mystery.”

Kelsey Tyssowski is a PhD student in the Biological and Biomedical Sciences Program at Harvard University.

This article is part of the April 2016 Special Edition on Neurotechnology.

Further Reading:

To read more about Josh Sanes’ research, see his lab website here.

To read more about current research projects funded under the BRAIN initiative see the NIH website here.

The policy side of the BRAIN Initiative is covered in another article in this special edition.

For more information about how the BRAIN initiative will help treat psychiatric disorders see: Bargmann CI, Leiberman JA. What the BRAIN Initiative Means for Psychiatry. American Journal of Psychiatry. 171:10, October 2014. doi: 10.1176/appi.ajp.2014.14081029

 

One thought on “4 Reasons You Should Be Excited about the BRAIN Initiative: Updates and insight from a conversation with Josh Sanes

  1. This is great news. I hope that funding for work like this keeps flowing in a generous cascade. So useful and positive.

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