Lighting the Way to Better Understanding of the Brain
We are enamored by our brains. Arguably the most complex system in the universe that is made up of over 80 billion neurons, the brain is a complex organ that can be a source of marvel and devastation, from human consciousness to neurodegenerative disease. The triumph of overcoming brain disease and injury is captivating: Neuroscientist Jill Bolte Taylor’s personal story of stroke survival is the second most-watched TED talk of all time.
President Obama’s April 2 announcement launched the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, which is starting with $100 million in funding from National Institutes of Health, the Defense Advanced Research Projects Agency, and the National Science Foundation. With this national-scale neuroscience program, our brains will be the subject of even more fervent discussion.
At the Institute for Systems Biology, where I’m working toward my Ph.D., we think this national attention to neurobiology research comes at a crucial time. Because the brain is so complex, fresh, more comprehensive approaches to research are needed and we believe systems biology is the answer.
How difficult is it to understand the inner workings of the brain? Even after decades of brilliant research, our current understanding is like the illuminated spaces around 100 candles in a pitch-dark auditorium: We know a lot about a few specific processes, but no one knows what the whole room looks like. Systems biology can provide the tools needed to see the whole space.
To illustrate the interrelated layers of biological information that must be coordinated to produce brain function (or malfunction), one can think of the brain as a “system of systems,” within the larger system of the human body.
You recall that for many diseases, gene mutations, deletions and copy number variations can be linked to clinical disease phenotypes. The complexity lies between the genome and the outward disease phenotypes.
For example, the regulators that switch on and off specific genes in the genome in a spatiotemporally defined pattern are just one of many systems governing brain function. A hairball-like network of genes and regulatory proteins invites simple mutations to amplify and explode in their effects on health and brain function.
This system of DNA and protein is vulnerable to the influence of external environmental factors (like toxic fumes and diet), and in turn, it is part of a larger system of proteins, specialized brain cell types and neural networks.
Cell types and neural networks form a system that enables information transfer within and among regions of the brain, and this crosstalk governs myriad other processes in the body.
Whether something is awry at the genetic, protein or neural network level, the result can be debilitating.
The gauntlet is twofold: Where in the brain’s systems is the problem located, and what’s the best way to target the problem for improved health? Systems biologists work from the idea that we need to understand the biology of each brain system, and we need to know how those systems work together at multiple scales. In short, we need the candles, and we also need to light the space among them.
To do this, systems biology combines rigorously tested biological concepts with new discoveries from massive datasets collected at all levels within the brain – genes, regulatory networks, proteins, and cells. In an iterative cycle of biological inquiry, technology development, and computational modeling, new and old data are integrated using algorithms that are guided by existing biological knowledge to make new discoveries while gaining a clearer picture of how all the systems work together.
For example, the Allen Brain Atlas is a trove of mRNA measurements at 60,000+ genetic loci, from ~1,000 locations throughout the brain. This RNA-level resource was integrated with spatial anatomical data and cell-type information to reveal cell-specific proteins.
The punchline is that a few of these cell-specific proteins are present in peripheral blood, and may act as sentinels or biomarkers of an individual’s current or future disease symptoms. Disease phenotypes could be traceable, through blood proteins, to a single cell type in the brain.
Integrative neurobiology research like this is increasingly common, and requires intensive cross-disciplinary collaboration among biologists, engineers, physicians, and computer scientists. The President’s intention to back a decades-long effort to map the activity of the entire human brain is a timely testament to the need for this new A-game in brain science.
Critics doubt that current technology and resources can handle the task of producing value-adds for the steep $3 billion price, and thus the pace of new technology development and collaborative innovation will determine when and if the challenge is met.
Obama’s proposal aside, systems biology is the science of breaking down and making sense of complexity, for better health and better environmental stewardship. The brain is complex, but more importantly it’s personal and in a league of its own among organs. We have much to gain from bringing systems biology to bear on its mysteries.
The upcoming symposium on systems biology and the brain at Seattle’s Institute for Systems Biology will highlight new advances and will foster a dialogue on deciphering even more of the brain’s complex secrets. The light in the auditorium is dim now, but it brightens every day.