Understanding the human brain: a work in progress or an impossible ambition?

by Emily Ferenczi

Flying home to England for the holidays I began chatting with a friendly fellow passenger in the aeroplane seat next to me. On discovering that I study neuroscience, my neighbour asked “Is it really possible that we will ever fully understand the brain – or is it just too complicated?” It is not the first time anyone has posed this question, but it gave me pause for thought, as there is still no readily accepted response. The brain remains one of the greatest mysteries of the human body. Our understanding of brain diseases, including psychiatric disease, lags far behind those of other medical fields such as cardiac disease or cancer. This makes it an enticing field for research, with a lifetime’s worth of questions and so many untraveled paths for discovery. Sitting in lab day after day, often finding more questions than answers, I wonder if we ever will unravel and expose all the secrets of the brain. If so, how long is it going to take? And are we sure we really want to do it?

Data, data everywhere

I tried to explain to my aeroplane neighbour how exciting the field of neuroscience is right now – that we have reached our “golden era” where new tools are being invented faster than you can read about them, large quantities of money are being invested and the brain is now getting the recognition that it deserves. Fresh from the biggest neuroscience conference in the USA, with 30,000 attendees, my immediate impression is that it is a field flooded with new data and ideas and enthusiasm from transparent brain (click here to see a movie through a CLARITY cleared brain) to new understanding of the neural underpinnings of sex and violence.

However, the sobering realization for neuroscientists is the sheer immensity of the task at hand. The brain stores incredible amounts of information and performs countless computations in a very small space using only ~20 Watts. Professor Jeff Lichtman from Harvard University described in his Society for Neuroscience Presidential Lecture how with high throughput microscopy and computational techniques we are now able to reconstruct mouse brain tissue to a resolution of 4 nanometers (enough to visualize tiny sacs inside cells that contain neurotransmitter chemicals (synaptic vesicles)). So far, one billionth of a mouse brain has been reconstructed – with the resulting conclusion that even this tiny fraction is so incredibly complicated and full of “stuff”, we are struggling to make sense of it!

Image of the hippocampus (part of the brain involved in learning and memory) of a transgenic Brainbow mouse in which different cells appear in different “colors” depending on the fluorescent proteins that they express. Professor Lichtman was one of the inventors of the “Brainbow mouse”, a tool which holds promise in helping us to understand the complexity of the brain, however even he admits that so far it has “proven to be incredibly useful...as a screensaver!” (Society for Neuroscience Presidential Lecture, San Diego, 2013).

Image of the hippocampus (part of the brain involved in learning and memory) of a transgenic Brainbow mouse in which different cells appear in different “colors” depending on the fluorescent proteins that they express. Professor Lichtman was one of the inventors of the “Brainbow mouse”, a tool which holds promise in helping us to understand the complexity of the brain, however even he admits that so far it has “proven to be incredibly useful…as a screensaver!” (Society for Neuroscience Presidential Lecture, San Diego, 2013).

On the plane, we are still waiting for takeoff. My neighbour complains that “for diseases like depression, to me it seems more like an art than a science – the doctor prescribes a drug and says ‘see how you feel on that’ and if it doesn’t work you go back and he tries something else.” It is hard to treat these conditions, as we do not really understand what causes them. But how do we understand what causes them if we don’t even understand how the brain works normally? There are so many levels at which to understand the brain – genes, proteins, cells, circuits, animal behavior and the question of where to begin highlights a major debate in neuroscience. If we were to have the “blueprint” of every cell and its connection to all other cells, would we understand how the brain works? The assumption that it would indeed help us to decipher the emergent properties of the brain and even the basis of consciousness underlies a number of large scale, multi-center, billion-dollar government-funded initiatives such as The Blue Brain Project in Switzerland – which aims to “reverse engineer” the brain using knowledge of the molecular and circuit properties of neural tissue to build a virtual brain inside a supercomputer. Across the Atlantic ocean, The Human Connectome Project – an NIH-funded Harvard/MGH-UCLA consortium, is using neuroimaging methods in combination with genomic data to develop an extensive map of how the brain is intricately connected or “wired”.

Image of white matter fiber tracts (the high-speed pathways that connect different brain areas) in the brain using advanced imaging techniques from The Human Connectome Project. Neuroscientists hope that having these intricate wiring diagrams of the brain will help us to understand how the brain is connected normally and how it may be disrupted in disease.

Image of white matter fiber tracts (the high-speed pathways that connect different brain areas) in the brain using advanced imaging techniques from The Human Connectome Project. Neuroscientists hope that having these intricate wiring diagrams of the brain will help us to understand how the brain is connected normally and how it may be disrupted in disease.

However, there is no guarantee that knowing the wiring diagram and all the components of the brain will actually tell us how it functions. This argument is reminiscent of early debates surrounding the Human Genome Project – having all that genetic data doesn’t tell us what all those genes actually do.  Few would now deny that the Human Genome Project has already proved its worth but perhaps the greatest discoveries are still to come as we realize that we are barely scratching the surface of understanding the genome and the epigenome. The same potential could lie in store for a “brainome” of whatever sort.

The debate about how to best investigate the brain (big national funded wiring diagram projects versus smaller scale studies guided by animal or human behavior and disease) form a fundamental platform for discussion of Obama’s new Brain Initiative announced earlier in 2013. The neuroscience community was pleasantly surprised by the announcement that $100 million dollars were to be dedicated to understanding the brain and brain disorders, although in reality, it will probably cost a lot more than that. What remains to be decided is how the money will be spent and by whom.

One important step forward is ensuring that we have the tools necessary to probe the brain at the level at which complex computations are taking place. We do not yet know how many neurons are needed for complex (yet everyday) tasks, such as making a cup of tea, or remembering our mother’s birthday. A good starting point would be to expand the number of cells that we can record from simultaneously, from several (the status quo until recently), to hundreds and thousands. For observation of the activity of thousands to millions of neurons, new tools such as state of the art microscopes and genetically encoded calcium sensors (GCaMPs) are set to be major players. Here you can see a video of the activity of neuronal cells in the hippocampus in the mouse – a region of the brain involved in memory, learning and navigation. These images were taken through a tiny microscope fixed to the head of the mouse, allowing recording of the brain activity as it freely runs around the arena.

A laboratory rat implanted with an optical fiber in the brain ready for an optogenetics experiment

A laboratory rat implanted with an optical fiber in the brain ready for an optogenetics experiment

Another important step is to be able to understand the causal influence of specific groups of neurons on brain activity and on behavior. For this we need to be able to control and manipulate the activity of neurons in a precise way. A technique known as optogenetics, first used in neural tissue in 2005, has already been a key advance in probing the causal mechanisms underlying conditions such as Parkinson’s disease, anxietydepression, obsessive compulsive disorder amongst many others. Optogenetics harnesses microbial proteins called opsins (similar to the light-sensitive rhodopsin protein found at the back of your eye) which act as light-sensitive “switches” that can turn neurons on or off in response to pulses of visible light with millisecond temporal precision. Using viral technology, we can now make these proteins appear in the brain cells of awake animals and use fiber optics to deliver light deep into the brain to activate them (as depicted in Figure 3). Genetic techniques allow us to specify exactly which cells contain these proteins so that we can control their activity with exquisite spatial and cell-type precision. These techniques of calcium imaging and optogenetics are so far largely limited to animal models such as worms, fruit flies, zebrafish and mice. To understand the whole brain of any of these creatures would still be a staggering achievement. However we must remember to continue straddling the evolutionary divide. Its not enough to understand how the mouse brain works – we need to persist in our goal to translate this knowledge back to humans. Human brains are 3000 times larger than an average mouse brain, containing 1000 times as many cells and 5000 times as many connections. The emergent complexity is reflected in diseases that in many ways can never be captured in the behavioral repertoire of a mouse, such as disordered thinking, low self-esteem, disrupted empathic ability.

So returning to my aeroplane neighbour’s initial question – we may never fully comprehend all the mysteries of the human brain, and in our attempts to do so we will face a myriad of ethical challenges that shall require discussion and resolution. However with a projected spend of 3 billion dollars by the US government, and 1.1 billion euros in Europe in neuroscience over the next 10 years, by 2024 we should expect to have made great strides in finding better treatments for millions of individuals worldwide for devastating conditions such as depression, schizophrenia and Alzheimer’s disease.

Emily Ferenczi is a 2010 fellow of the Fulbright Science & Technology Award Program, from England, and a PhD candidate in the Neurosciences Program at Stanford University.

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