Diagrams of the Brain Paint a Colorful 'Brainbow' Researchers have developed a new technique to label individual neurons in the brain in different colors. This method, which the scientists have dubbed 'brainbow,' could help shed light on brain function in a way that traditional staining methods don't allow.
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Diagrams of the Brain Paint a Colorful 'Brainbow'

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Diagrams of the Brain Paint a Colorful 'Brainbow'

Diagrams of the Brain Paint a Colorful 'Brainbow'

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A little bit later in the hour, we'll be talking about diet, obesity and disease. But first, you know, we've all seen beautiful full-color maps of the universe, the oceans, the Grand Canyon, well, why not a beautiful map of our brain in living color. Well, that's just what my next guest has done. Armed with genes that gives coral their color and jellyfish their glow, and the latest in microscope technology, he's turned a few genetic tricks to produce an absolutely stunning full-color map of the brain.

Each neutron gets its own color - think of a jumbo box of Crayolas and then some - resulting in a brain map that is much art as it is science. But science it is, this new map dubbed the brainbow - like a rainbow, a brainbow - allows the researchers to trace the path of a single neuron and see how that neuron connects with others to form a brain circuit. Studying the brain at this level could help scientists better understand how it develops, how it works and how problems in that wiring cause the disease.

If you'd like to actually see the brainbow, it's on our Web site at sciencefriday.com. We have a still picture on the right side of the page, and you can click on the left side to see a video, a three-dimensional video of the brainbow. And research is out this week in the journal "Nature," and one of the researchers joins us now to talk about the brainbow, Jeff Lichtman. Dr. Lichtman is a professor of molecular and cellular biology and member of the Center for Brain Science at Harvard University.

He joins us today by his office from there. And if the truth must be told, Jeff is the father of Flora, our video producer here. So welcome to the program, Dr. Lichtman.

Dr. JEFF LICHTMAN (Molecular and Cellular Biology Professor; Member, Center for Brain Science, Harvard University): Thank you, Ira. It's a pleasure.

FLATOW: Thank you for Flora.

(Soundbite of laughter)

Dr. LICHTMAN: Well, we're very proud of her.

FLATOW: Let's talk about what we're seeing in these images. They're absolutely stunning images of the brain. How did you do that?

Dr. LICHTMAN: Yeah. It's just molecular biology. It's taking genes that evolution has developed to make bioluminescence in jellyfish and that kind of genes that give corals their beautiful colors, and putting them inside nerve cells in the brain of mice.


Dr. LICHTMAN: And when you put them in there and then shine light of the right color on these brains, they fluoresce and they give off these beautiful colors.

FLATOW: And if you go to our Web site and you look at these pictures on the Web site, you see pictures of the brain tissue. You're saying each nerve cell has a unique color.

Dr. LICHTMAN: Yeah. It's a very simple idea to explain, a little harder to make. But the idea is to take advantage of the simple fact that every computer monitor has, every television has - that if with just three primary colors, red, green and blue, you can generate a true rainbow of colors by mixing different ratios of the red, green and blue at each place. And so each of these nerve cells has its own unique mix - a blend of the red fluorescent protein, a green fluorescent protein and a blue fluorescent protein - and that gives each cell its own unique color.

FLATOW: Mm-hmm. And because each neuron is a different color, you can actually trace its path back in the brain there?

Dr. LICHTMAN: Right. You know, there've always been techniques that would allow you to look at one neuron, if nothing else was labeled, and follow its path, so that's been around for over 100 years, ways of staining cells. But if you had a lot of cells stain the same color - let's say all of them green or all of them black - then where their processes cross, you'd kind of get lost about whose process belongs to which cell. But now, you can get a pretty dense labeling and still, each cell is traceable because it's got a different color from its neighbors.

FLATOW: Can you also see how the neurons actually connect to one another by following the colorful trail there?

Dr. LICHTMAN: Yeah. If you follow the long process of the neuron called its axon - long enough, eventually, that process will branch into little terminal endings where it makes synapses on target cells, which are the dendritic processes, the short processes, coming off other neurons. So you can actually see those synapses and just tell which particular neuron gave rise to those synapses because they have a particular color.

FLATOW: Mm-hmm. I'm fascinated by how - you described a little bit before how you were able to do this. Can you describe in a bit more detail?

Dr. LICHTMAN: Yeah, I guess I can. It's like a game of chance. It's actually sort of like a slot machine, if you will. Jean Livet, who is a postdoctoral fellow here and soon to start his own lab in Paris, and Josh Sanes, who is a another professor, and I, have collaborated on thinking about ways in which to - it could be possible to generate a kind of game of chance for single cells. And Jean came up with really clever idea of forcing a neuron to choose which particular color it wants to express, and it can express red, green or blue.

And it makes that choice multiple times because there are multiple copies of this little genetic cassette. So it's sort of like pulling a slot machine lever in which a recombination event takes place in the nerve cell. And if, let's say, two lemons and a cherry come up, two yellows and a red, the cell will be sort of a light orange. But if two reds and a blue come up, it will be a mauve color.

And, in fact, we don't have just three colors but actually more like nine or ten different things that are spinning around before the cell finally decides what color it makes. So that's what we - gives us this very large spectrum of colors.

FLATOW: But you've also taken foreign genes, genes that are expressed in animals like jellyfish and coral, and you put into mammalian nerve cells.

Dr. LICHTMAN: Yeah. This is a funny thing. You know, this loaded term, intelligent design, this is a form of, at least, human-based design of animals. You know, evolution would probably never put jellyfish genes. They'd never find their way into a mouse. And yet, if you do that, the mouse seems to tolerate these fluorescent proteins quite well, probably because they're so foreign that the cells don't even know that they are there and know what to do with them.

So, in fact, you make these animals that seem perfectly happy, that live normal, long lives, but when you put them under fluorescent illumination light, their brains truly light up in these remarkable colors.

FLATOW: So how did you get them into the mice?

Dr. LICHTMAN: So these are transgenic mice, which is a now quite a common technique for generating molecular changes inside mice. And it - for medical research, it's a very valuable tool to test the role of particular gene products on cells, for example. And we just used that general technology to make lines of mice that just express fluorescent proteins. And their offspring do as well. So these are actually, you know, mice - you wouldn't - if you had it in your house, it would just look like a regular mouse. If you put it under a fluorescent light, you'd see something quite extraordinary.

FLATOW: You mean the mouse itself on the fluorescent light?


FLATOW: You've tried that on a mouse?

Dr. LICHTMAN: Well, yeah, I mean you just see the glow through the skin, so you wouldn't see these beautiful pictures. But you would certainly get the sense of the fluorescence inside its nervous system.

FLATOW: I see a Christmas product here.

(Soundbite of laughter)

FLATOW: Something for someone who has everything.

Dr. LICHTMAN: Yeah, I guess that's right. If you have everything, this might be something you would want.

FLATOW: Fascinating. Talk a bit about more - now that you can do - you make the mice light up in fluorescent lighting. What do you do with these brain maps? What use are they?

Dr. LICHTMAN: Yeah. Well, I think there are three or so things I can think of right off the bat. I think one is that if you think of wanting to know how something works, let's say a television, and you opened it up, or a radio -maybe a radio would be a better, more apt technology in this particular situation. You open up and you see all these wires and they're all the same color white. You'd have a time kind of tracing out the circuits.

But if someone had gone to the trouble of making every wire a different color inside that radio set, it wouldn't be that hard to figure out the wiring diagram. And in a brain, it's exactly the same issue, except you don't have hundreds of wires, you have hundreds of millions of wires. And so if you ever have a wish to understand literally what the wiring diagram is of a brain, what nerve cells are connected to another nerve cells, you've really got to use a tool like this…

FLATOW: Mm-hmm.

Dr. LICHTMAN: …something that would allow you to trace them out. So, for one thing, it's very useful to see the way the brain is kind of wired up and give us some principles of the organization of synaptic circuits. And I think there are two other things where it's also useful. One is that there are probably diseases of the nervous system where brain function is abnormal, perhaps because there are wiring abnormalities, things that I would call connectophaties, pathologies of connections.

Those sorts of diseases or disorders would be hard maybe to study without tools like this, what maybe autism spectrum disorders, for example. So if you had an animal model of such a disease, this would be a good tool to study such a model.

FLATOW: And your…

Dr. LICHTMAN: And lastly, I think, for me, most interestingly, the brains of mammals, including human beings, undergo rather dramatic changes in the wiring between birth and adulthood. Now, anyone who's had a baby or seen a baby knows they don't work like adults, you know? They start out, they can't walk, they can't even turn over, they don't talk, they don't see very well. And then all these things must happened to them that kind of change them into something else, a more mature state, and that's almost certainly changes in the wiring, pruning of some connections, additional connections are added at other places. We think this is the tool of choice to study that event.

FLATOW: So, you could watch the wiring change as the animal grows.

Dr. LICHTMAN: Absolutely. The nice thing about watching it is that these animals are pre-stained, that is they already have the colors in them, so one could watch over time.

FLATOW: Wow, is that what you're going to do next?

Dr. LICHTMAN: Yes, that is definitely what we are going to do next.

FLATOW: Any preliminary results so far?

Dr. LICHTMAN: Well, you know, we've looked at the wiring of some young animals and it's promising, this technique works pretty well once animals are born. The colors kind of get going about the time animals are born. And at earlier stages, the colors are not quite bright enough to see very well. But after birth, in the week or so, the colors really come on nicely. So, it's promising.

FLATOW: Mm-hmm. These pictures look spectacular, but I read from a scientific standpoint they're fairly low resolution, right?

Dr. LICHTMAN: Well, it depends what you mean by low resolution. For a light microscope, they are as good as one can do with present technology. The sad fact is that the circuitry of the brain is so dense and so finely grained that ultimately, to see every last little bit of that circuitry, one might have to use techniques that are just being developed now.


Dr. LICHTMAN: High-throughput serial electron microscopy is one, another are these very fancy microscope techniques called nanoscopy that break through the diffraction limits of the light microscope.

FLATOW: Well, we'll see if we can get you one of those for the holiday.

Dr. LICHTMAN: Thank you, I'd need one.

(Soundbite of laughter)

FLATOW: Thank you very much, Dr. Lichtman, for taking time to talk with us and good luck to you.

Dr. LICHTMAN: Thank you very much. It's been a pleasure.

FLATOW: Jeff Lichtman is a professor of molecular and cellular biology and a member of the Center for Brain Science at Harvard in Cambridge. He joined us by phone from his office there.

Stay with us, we're going to come back and talk with Gary Taubes, author of "Good Calories, Bad Calories: Challenging the Conventional Wisdom on Diet, Weight Control, and Disease." Our phone number: 1-800-989-8255. See you on the other side of the break.

(Soundbite of music)


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