Research
Making brains with more neurons: from the womb to the grave The human brain is the most complex organ in our body and, as far as we know, in the universe. Lucky to own one, in the lab we (occasionally) use it to understand how such a jelly and slimy machine arose in evolution, forms during development and functions throughout life. Why do we do that? Because answering these questions might cure diseases, enhance our cognitive abilities or revert aging (already done, Fig 1A, n=1). Minor details aside, we just have fun doing it.
First things first This is a lot of work, so we got down to business starting with a fundamental question: given that the whole brain arises from a few neural stem cells (NSC) during development, how do these little fellas decide when the time has come to stop proliferating and start generating the diversity of neurons needed for a brain to work? We are molecular cell biologists so we did what Flo once suggested: “we sequenced the sh*t out of those NSC”. This revealed tons of genes, non-coding-, circular-RNAs, epigenetic modifications and all kind of weird stuff that, though nobody ever heard about before, orchestrate the process of neurogenesis. In other words, we opened the instruction book telling NSC when to stop making copies of themselves and start producing neurons in order to make the most complex machine in the universe! (Fig 1B). Nobody really wants to read an entire instruction book, so we ended up focussing on the few pages that instruct NSC on when to stop multiplying and start producing neurons (Juli, 2013; Bene, 2015; Juli again, 2015; Martina, 2019; Flo, 2019; Martina again 2020, among others). This is probably the most important decision taken during brain development, as it defines the final number of neurons in the brain: the more a NSC multiplies beforehand, the more neurons it can produce afterwards. Not clear yet? Watch Sara’s explanation.
Getting the time right As speculated in ancient books (Fede, 2003), one key factor telling NSC when the right time has come to start making neurons is having the right TIME to do so. Cells measure time in terms of cell cycle: short cycles are enough to copy themselves, easy; but making neurons is extra work, hence extra time. Knowing that, we sped up their clock using our magic 4D-powder and kept them busy making copies of themselves. Then, after removal of 4D-powder they would start making neurons and, because there were more NSC, once they differentiated they made also more neurons (Christian, 2009) (Fig 1C). You may find it’s crazy, and you would be right, but it worked and we found that mice whose brains generated more NSC and neurons in the womb were born with bigger brains (Miki, 2013; needless to say, it was called the Miki mouse). Scientists keep telling that the bigger the brain the smarter we are… but how do they know? this provided us with an amazing tool to answer that question! However, given the experience by Wyatt et al. (The Rise of the Planet of the Apes. Century Fox’s, 2010), we thought not to take any risk and sent Miki mouse out to space to colonize other planets (Fig 1D).
Making old brains young again Brains are smart machines that retain a few NSC throughout life in specific brain regions. Therefore, we decided to use our 4D-powder to increase them during adulthood (Bene, 2011) and check whether we could improve brain function. We don’t like easy, so we started by challenging the most sophisticated sense in mice: the smell. And yes, adding more neurons to the brain area discriminating odors turned out to sharpen olfaction (Sara, 2019; the paper is too long… just watch Sara’s video). Improving a function that milions of years of evolution brought close to perfection drove us through half a dozen editorial rejections, but also a Nature highlight, an EMBO J cover, a top-98% ranking in Almetric and to take our first steps in Hollywood with our first movie (Fig 1E). While Sara’s mice kept dining with fine wine, terrible bills from the animal house were piling up and we were reminded that we were paid to develop therapies, not to turn mice into sommeliers. So we faced the ultimate challenge: revert aging! As we grow old, neurons decay and our brains start forgetting trivial things such as how to drive home. Luckily, the brain area responsible for navigation keeps a few NSC. The rest was trivial: we pimped old mice’s NSC with the same 4D-powder and came up with the ultimate brain rejuvenating treatment (Gaby, 2020) and a sequel movie.
Time for criticism OK, we generated the brainy Miki mouse that is now conquering outer worlds. We outsmarted evolution improving the most sophisticated function of the mouse brain. We rejuvenated cognitive abilities and made old mice young again... But let’s be critical: First, it doesn’t take much nowadays to manipulate NSC to get smarter and tougher. X-Men, Deadpool, the Apes and many others have done it. Second, while our mice enjoy fancy wines, computer nerds are bringing Robocops and AI to the streets, neither of which give a damn about our NSC. Worse still, third, after more than 10 years of work we still did not get any closer to answer our original question: How does the brain work??? Gaby says this is all about indexing, but we still have to understand what that means… In the meantime, measuring neuronal activity changes in normal vs. brainy Miki mice could help us understanding how the brain works (making our previous 10 years of work not absolutely useless). Even more, by decoding these signals with the help of computational biology, we could simulate brain activity through AI and even restore brain function after disease (Fig 1G).
So, if you 1) got the message, 2) are as passionate as we are for understanding brain function and 3) think you can contribute with your skills; no matter your background, join forces and contact us!