He turns color into a precision tool to untangle the ‘dance of molecules’

ASHBURN, Va. — Luke Lavis paints the insides of cells, but he’s not an artist, he’s a color chemist.

As head of molecular tools and imaging at Janelia Research Campus, Lavis is responsible for helping to bring varicolored detail to the hectic, colorless tangle of biological systems.

During a recent interview in his lab, he talked about how the colored dyes his team creates could be useful for drug discovery, why he loves giving them away for free, and how color can reveal life’s spark. This interview has been edited for clarity.

If you look at color in marketing and it uses a bright palette, it’s meant to grab your attention. How is that same palette useful to science and how does it help us see in a different way?

One of the great things about color is that it allows you to differentiate between different things, right? We color-code files. We sort our Legos by color. The question is: Can we do the same thing inside a cell?

A typical human cell really doesn’t have inherent color. And so we have to engineer different ways to add color to structures inside a cell.

The beauty of modern molecular genetics is that we can fuse a fluorescent protein, or a tag, that will grab a fluorescent dye, onto a particular structure within a cell or a specific protein inside the cell. And because of that we can then color in that particular structure or that protein and then watch these individual molecules as they move around.

The cell is made up of a bunch of different molecules and so the ability to image and track the behavior of different molecules in the same cell and watch how they interact really allows us to untangle the complicated dance of molecules in a biological cell. It’s sort of like putting numbers on a ballroom dance contestant. We’re trying to basically tag each one of the partners and watch how they move around — we are giving them really colorful ballroom dresses.

Why is color such an important part of what you do?

So our dyes, our colored molecules, are not just colored, they also are fluorescent. That means they don’t just absorb light, they absorb one color of light and they emit another color of light. And that phenomenon is incredibly useful for studying biological systems. You can shine one color of light on a biological specimen that has a fluorescent molecule in it and you can see that molecule in a sea of billions of other molecules that are not fluorescent, down to this single molecule level.

What can we color inside the body?

Modern genetics allows us to color different cells in the brain, so we can color neurons and not color other cells like astrocytes, glia, etc. We can color specific sub-cellular structures, like the nucleus where the DNA is housed, and not other portions of the cell. We can even go deeper and color specific molecules that control gene expression or molecules that are part of a particular organelle or particular sub-cellular structure, and then just look at how those molecules move.

It seems like you’re trying to develop a more painterly palette for the sciences. Why?

We’re trying to expand the palette because everything has to work together: the microscopes, the molecular biology to express the tags and other proteins inside the cell, and the data analysis. The ability to tune these dyes allows us to better match different limitations in the optics and the lasers, and the molecular biology.

And so the goal of my lab is to figure out: Can we squeeze in a different color? Can we extend it farther to the red to give another channel? Fine-tuning these molecules gives us options, so we can work with microscopes and biologists to try and get as much information out of a single experiment as possible.

What does it feel like when one of your dyes has hit its mark?

The first time we ever made a Janelia Fluor dye, I remember looking over and thinking: “Wow, that looks like a really bright.”

When we sent it up to some collaborators at Harvard, I got an email back saying “my postdoc just texted me and they said these dyes are so bright, [they’re] crying at the microscope.” And at that point, we realized that we might actually have something here.

What’s the most enjoyable part of this kind of work?

One of the great things about Janelia is that we actually get to give away a lot of our technology. That’s one of the mantras here. That allows us to send out thousands of vials of dye around the world every year. The ability to send these things out is enabling science and a lot of people are very grateful, very surprised. I’ll get an e-mail and sometimes the stuff will be in their lab the next day. (Author’s note: Luke’s email, incidentally, is [email protected].)

And the most rewarding part of this is when it’s a postdoc who’s desperate and I send them some stuff and I get an email back a week later saying, ‘thank you, you’ve you’ve rescued my project.’

What are your future hopes for the dyes you’re creating?

Right now our molecules that we’ve made are really focused on basic research and understanding how molecules behave inside a cell, but these improved imaging technologies could also be used for other things. For example, most drug discovery high-throughput screens are done with fairly low resolution, very slow imaging technologies. And so if we could adapt these very bright dyes and these improved microscopes to drug discovery, you might be able to find new drugs that are modulating really fast interactions inside a cell that can be the cause of certain cancers.

Another thing is just understanding how the brain works. We’re actually moving toward using our dyes in conjunction with protein engineering to fashion new sensors that sense brain activity voltage changes. Basic research in the brain could ultimately lead to research on different dysfunctions in the brain, like neurodegenerative diseases.

What’s the thing that you’d really like to do that you can’t do right now?

We’re making all these wonderful colors and in many cases we don’t have enough ways to attach these molecules to proteins inside a cell. We have maybe three or four different methods to attach these dyes and we now have many more colors. So one thing that we can’t do is utilize this [full] palette of dyes that we’ve created.

What did you see in color chemistry that gave you enough conviction to continue on with it?

I think one thing that I’ve learned from biologists is that they’re always pushing the envelope, always right at the edges of what’s possible using the tools that are available. To a chemist, if you make a dye that’s five or ten-fold brighter, that’s kind of incremental, but to a biologist all they say is, ‘now I can do so many more experiments.’

How would you categorize the things that you’ve been able to see with the system color tagging that you’ve helped create?

Looking at images, using our dyes, it’s amazing the choreography that occurs inside a cell. You think it’s just this jumble of molecules and in many ways it is. But then you see these definite tracks. This thing is hanging out over here and then suddenly it moves. It stops at a particular place in a cell — there are there are barriers to diffusion. There are different things going on and we don’t understand how they work or what they’re really doing.

As a chemist you realize that a cell, in all this wonderful complexity, is just a collection of molecules, and we need to understand how those molecules move and interact because that’s basically the the spark of life — it’s how living systems work.