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The BRAIN of the operation

A decade from now, scientists could be well on the way to developing a human brain cell census that may provide revolutionary advances in the treatment of brain disorders, a leading US scientist has told the Medical Independent (MI).

Dr Gregory Farber, Director of the Office of Technology Development and Co-ordination at the US National Institute of Mental Health (NIMH), spoke to MI about his leadership role in a 12-year research initiative aimed at advancing neuroscience and developing therapies for brain disorders.


Dr Gregory Farber

The BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative, which was launched three years ago by US President Barack Obama and runs until 2025, with funding of over $300 million for this year alone, has been compared to the Human Genome Project that ushered in a new era of genetics-based medicine.

“We really think that we will have a mouse brain cell census delivered by 2022 or 2023. In the meantime, we will be funding further technology developments to make the technologies that are good enough in the mouse, which has a much smaller brain, to move them into bigger brains.

“If I were talking to you in 10 years, I would be incredibly disappointed if we weren’t well on the pathway to having the human brain cell census. I think that’s going to be one of our biggest deliverables.

“I do think that this first signature deliverable will be something that I think most people will be surprised that we don’t already know. We know how many different types of cells there are in a heart or liver and their different functions. We understand those organs. But with the brain, we don’t have very much of an idea how many different types of cells there are.”

The hope is that such a census will answer many questions and open the door to enhanced, even potentially revolutionary, treatments and technological tools to deal with a range of brain disorders.

Dr Farber and his team are responsible for co-ordinating all technology development and bio-informatics activities at the NIMH, including managing the NIMH component of the BRAIN initiative and managing the Human Connectome project that aims to map the neural pathways that underlie human brain function.

‘If I were talking to you in 10 years, I would be incredibly disappointed if we weren’t well on the pathway to having the human brain cell census. I think that’s going to be one of our biggest deliverables’

The US National Institutes of Health (NIH), which the NIMH is part of, hails the initiative as revolutionary. “By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space.”

Such a picture, it says, will fill major gaps in our knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilise, store and retrieve vast quantities of information, all at the speed of thought.

The central aim of the BRAIN initiative, Dr Farber stresses, is to speed-up development of new imaging and mapping technologies for studying the brain and improve the treatment of such brain disorders as Alzheimer’s, schizophrenia, autism, epilepsy and traumatic brain injury.

“What the BRAIN initiative is really focused on right now is developing the tools to understand the brain. Our overall understanding of the brain is really very limited so if you view the Human Genome Project as giving you the lists of all the things you would need to get a complete understanding of an organism, the BRAIN initiative is going to give us the tools we need to understand how the human brain works. So there’s a very logical connection there between the BRAIN initiative and the genome project,” Dr Farber told MI.

“Financially, also, the investment that is hopefully going to continue to be made in the brain initiative is about the same size as that made in the genome project,” he said, adding he was confident that would continue, regardless of any changes in the make-up of the US Congress or White House after the November elections.


Some neuroscientists, however, question whether the BRAIN initiate is the best way to proceed and are concerned that it could cannibalise funds for other brain research. But if the BRAIN initiative, which is expected to cost in the region of $3 billion, does turn out to yield results as revolutionary as those that emerged from the genome project, it will prove an efficient use of resources.

The Human Genome Project cost $3.8 billion. It begun in 1990 and its goal of mapping the complete human genome, or all the genes in human DNA, was achieved ahead of schedule, in 2003. A US federal government study of the impact of the project indicated that it returned $800 billion by 2010.

“Most of the BRAIN initiative is really focused on developing new tools and these are tools to monitor cells and circuits, either in intact brains or in model systems,” Dr Farber explained. “There are a variety of genetics and optical tools and tools for non-invasive modulation of brain activity. Those are all very much in the development stage. There are some really exciting advances, though it’s still many steps away from treatment or anything along those lines.

“Part of what we’re doing involves new imaging technologies — you see a signal in an FMRI and want to understand what really is the root cause of that signal; can you really use that as a biomarker? All of this has been just about impossible in the brain until now. I’m not suggesting we’ve solved that problem but I do think the new tools are going to help with those sorts of questions.”

In the last decade, scientists have made a number of landmark discoveries that now create the opportunity to unlock the mysteries of the brain — including the sequencing of the human genome, the development of new tools for mapping neuronal connections, the increasing resolution of imaging technologies, the maturation of nanoscience and the rise of biological engineering.

These technological innovations have contributed substantially to expanding our knowledge of the brain, Dr Farber noted, but breakthroughs in how we treat neurological and psychiatric disease will require a new generation of tools to enable researchers to record signals from brain cells in much greater numbers and at even faster speeds. That’s where the BRAIN initiative comes in.

“We are looking at new approaches as well as improving existing technologies,” he stressed. “Part of the reason the research community felt that now was the time for the BRAIN initiative was that there have been a lot of advances in nanotechnology that scientists haven’t really taken full advantage of.”

Confidence in the initiative has grown exponentially since its launch in 2013. “We were unsure when we started out three years ago how fast the project would grow financially and we limited all of our funding-grant awards to three years. Now that first round of awards is finishing up and we are looking at the results from that first round and thinking about a second round of tool-development awards.

“Before the BRAIN initiative, there weren’t many specific projects that were aimed at developing new tools or set aside money for that. That’s really the space that we’re in and why the BRAIN initiative involves multiple agencies and multiple parts of the NIH so that everyone can make use of the new tools.”

‘Part of what we’re doing involves new imaging technologies — you see a signal in an FMRI and want to understand what really is the root cause of that signal; can you really use that as a biomarker?’

Advances in the initiative so far have been primarily at the cellular circuit level, Dr Farber told MI. “That’s partially because of where we started and we do need to understand things at the cellular circuit level before we can realistically hope to move them up to a functioning level. That’s why this is very much a long-term project.”

New therapies

As the initiative gets closer to the 10-year mark, he expects it will have moved along the road quite considerably by then in terms of having new therapies and new technologies. “That’s certainly our hope. We really do hope by that point that we will be beyond technology development and will be moving into applying the new technologies to really understand, for example, what are the true underlying issues that happen for those who are mentally ill.”

Such understanding, he said, could also revolutionise attitudes to conditions like Alzheimer’s, autism, schizophrenia and other neurological conditions. “I think a lot of people just don’t understand that something like schizophrenia, for example, really is a brain disorder. Until you have a test or something that says ‘look at this test, it’s really clear that they’ve got something that you don’t’, I think that will all help at the treatment end.”

Once the initiative delivers that cell census, Dr Farber believes it will solve many issues regarding treatment. “I think it will go along very nicely with all of the tools we are developing, because many of those tools are being targeted to fix some classes of cells. If you really understood that a small part of the brain or a circuit of cells throughout the brain were behaving inappropriately in a particular disease, the hope would be that the census allows us to get a good idea of which cells are not performing correctly and the tools help us to adjust these cells so they come back into line.

“I have real hopes that the understandings we are going to get in the model systems and the tools that we develop to alter cell function in model systems may actually end up being things that we really could use in humans.

“You can imagine a nano particle that would have the ability to alter the function of a cell and would also have on it the ability to attach to a particular sub-class of cells.  Getting back to the cell census, if you knew all of the cells that ‘type x’ had and you knew that they were misbehaving in a certain way, maybe you could just inject nanoparticles that would find the cells that aren’t behaving right and then you would turn on a radio frequency from outside the brain, or light stimulation or whatever it was that induced the nano particle to act, and maybe you could do a world of good. It’s not science fiction but it’s not fact yet either. In a couple of years we will have learned a lot from the mouse and we will be much further along with tool development.”

The future looks promising, but it could also throw up unforeseen challenges and unexpected questions. “We have a really good plan of attack but if it does turn out that we’re being too simplistic in our thoughts about how the brain works, that is if it’s not so much about single cell malfunction but about huge numbers of cells that come together and work together in ways that aren’t so obvious, we will have learned an awful lot but we will have a lot of additional work to do. We’re setting out on an exploration. We have a good road map. We’ll see how good that road map turns out to be.”

Results to date

So far, the exploration is yielding some interesting results. One study emanating from the BRAIN initiative and which was published in the neuroscience journal Neuron showed that neuroscientists were able to manipulate a mouse’s brain circuitry accurately enough to turn behaviours both on and off.

The study detailed how the mouse stopped at a bowl of food and ignored it and then scampered back and gobbled it up. The point was to perfect a technique for identifying brain wiring underlying any behaviour and control that behaviour by activating and deactivating neurons.

If scientists are able to do that for the circuitry involved in psychiatric or neurological disorders, it may lead to new therapies. That approach reflects a shift away from linking such illnesses to ‘chemical imbalances’ in the brain and instead tracing them to miswiring and misfiring in neuronal circuits.

The technique used to control neurons is called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Brain neurons are genetically engineered to produce a custom-made ‘designer’ receptor. When the receptor gathers in a man-made molecule, that fits like a key in a lock and the neuron is activated.

Because the receptor does not respond to other molecules, including natural ones in the brain, the only way to activate the neurons is via the man-made one. DREADDs allow scientists to manipulate neurons without implanting anything in the brain.

DREADDs, invented about a decade ago, had been used to turn neurons on or off, but not both, Neuron reported. Targeting hunger-promoting neurons, the scientists made mice ignore food bowls or dive into them. Targeting movement neurons, they made mice scamper or stop.

When President Obama launched the BRAIN initiative in 2013, he also directed a Presidential Commission to explore the ethical, legal and societal implications raised by the initiative and by neuroscience in general. Indeed, ethical issues stemming from his work were also on Dr Farber’s mind.

“They are quite significant ethical issues as we think about these new tools. We have an ethics advisory board and we are paying careful attention to those issues. The new tools are going to be great, we think, but there are significant ethical complications in many that we might end up developing.”

The timeline for the remaining nine years of the BRAIN initiative covers technology development and validation from 2016 to 2020. The application of those technologies in an integrated fashion to make new discoveries about the brain will be the focus of the initiative from 2020 to 2025.

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