Massachusetts Institute of Technology scientists examining the intricate network of brain cells that underlie sight, thought, and psychiatric disease had a running joke in the laboratory: let’s just make everything bigger. If they could simply enlarge brain cells, they reasoned, the task of mapping the circuits would be easier.
Now, they have found a way to do just that, using a technique that has shades of a 1950s science fiction movie.
But instead of spawning killer ants or a 50-foot giantess, the researchers have found a controlled way to cause a tissue sample swell to roughly four and a half times its size -- enough to make features of brain cells or cancer cells discernible under conventional microscopes.
“One of our lab’s strategies is to do the opposite of what everyone else seems to be doing,” said MIT neuroscientist Edward Boyden. “One of the ideas we were kicking around was if you make a sample big enough, could you take a picture of viruses or something else really small with your cell phone? We’re nowhere near that, but it’s the kind of thinking we’re exploring now.”
In science, the minutiae is often what counts the most and for years people have been building more capable microscopes.
In 1986, a team of scientists was awarded the Nobel Prize for improvements in microscopy, including the invention of the electron microscope, which has allowed scientists to see viruses, molecules, or the structure of an insect’s eye that wouldn’t register on a conventional light microscope. In 2014, a team of researchers shared a Nobel for a new type of optical microscopy that allows scientists to see detailed features of cells and proteins at the nanoscale.
The new technique flips the typical approach on its head: instead of providing ever more detailed close-ups of the sample, why not just magnify the specimen itself by essentially blowing it up? About a year ago, Boyden and two graduate students, Fei Chen and Paul Tillberg, decided to give their fanciful idea a serious try and Thursday in the journal Science, they reported that their counterintuitive new approach works.
The new technique, called “expansion microscopy” can’t yet reach the level of fine-scale resolution of electron microscopes or the super-resolution microscopes that won the Nobel last year. But it may offer an inexpensive way for people to examine fine cellular structures at a detailed level using off-the-shelf ingredients.
“It is encouraging to see out-of-the-box ideas that can still push measurement limits in microscopy, [since] it is after all an old subject,” Partha Mitra, a neuroscientist at Cold Spring Harbor Laboratory who was not involved in the work, wrote in an e-mail. He added that the technique may have a “sweet spot” because it will bring into focus some components of cells that can’t usually be seen with conventional light microscopes.
Researchers first attach glowing tags to the particular molecules they are interested in seeing -- for example, they might choose receptors found on the surface of a particular kind of cell. Next, they add the building blocks of a polymer that is more commonly found in baby diapers, used to absorb moisture.
A substance that Boyden compares to meat tenderizer is used to strip away molecules that could constrain the tissue from expanding. Last, they add water, which is absorbed by the polymer and swells up.
The swollen tissues can then be examined under microscopes commonly found in research facilities. In the paper, the researchers meticulously checked to make sure that the expansion occurred evenly in each direction and found that it did -- within 1 percent to 4 percent.
Boyden sees the technology’s strength in allowing three-dimensional analysis of tissue. For example, it could reveal the choreography of signaling molecules and cellular interactions that cause a cancer to spread or offer a new way to map the brain.
His team will publish a website explaining exactly how to perform the technique, in the hope that it will be widely adopted by scientists. The team is also applying for a patent on the technology, in case it can be further developed for medical applications.
It falls into a family of new techniques being used to visualize the brain in new ways.
Two years ago Karl Deisseroth, a neuroscientist at Stanford University who was Boyden’s postdoctoral adviser, developed a powerful technique called CLARITY that turns brains transparent using a similar process. Deisseroth said in an e-mail that the researchers had noted then that the process enlarged the brain tissue moderately, which was a problem they needed to correct. They added an additional step to shrink it back to normal size.
The new paper shows that what was, in a different experiment, a quirk of how materials behave that had to be fixed can now be harnessed for a completely different and novel use.