The W. M. Keck Foundation has awarded Michigan State University’s Marcos Dantus and Elad Harel $1.3 million to start a new revolution in the way we use optical microscopes to understand the living world.

The philanthropic grant is one of six awarded nationally by the Keck Foundation in 2022 for science and engineering. This also marks the first time that scientists at MSU have claimed the award.

This also marks the first time that scientists at MSU have claimed the award. The Keck Foundation encourages creativity by rewarding transformative projects that other funding agencies might see as too ambitious or risky.

“This is a really remarkable achievement,” says Douglas Gage, MSU's vice president for research and innovation. “The Keck Foundation is a funder of scientific research, and they value one thing, I think, over anything else, and that's transformative innovation. They do not want to fund research that can be funded by any other agency.

“One of the things that it does for MSU is that it really validates the innovation that we have going on at the university. And we know that, but it's great to have a national organization really validate what we know about MSU. We're very grateful for this proposal and that it was funded. I'm convinced that the work that Elad and Marcos will do will indeed be transformational. If they can do the imaging of living systems at the resolution that they propose, that will be remarkable, and it will be indeed transformational. The innovation here comes from two very independently innovative scientists bringing together their ideas in really a novel way. I think that's often the seed that leads to innovation. We try to promote that at MSU, so we're looking forward to the outcome of this research. I think it's going to be something to watch.”

“Our key goal here is to see if we can see the machinery of life in action with a resolution of nanometers,” says Dantus. “And that would be thousandths of millionths of a meter. It's really tiny length scales. In most of the cases, our microscope will not look at a space much larger than the width of a hair. Most of the time, we're going to be way, way below that. So, our main goal is resolution in the nanometer scale and time resolution. If we get there, we both will be so excited. We will be jumping up and down. And I think a lot of our colleagues will be equally excited.”

“The challenge has been, as Marcos described, that we tend to think that we can see these molecular machines in motion,” Harel adds. “And the truth is we can't. What we can see are these kinds of static snapshots. And we infer; we're very good at inferring what happens from those static snapshots. It's like if you see a picture, you can infer a lot of maybe what's going on in the picture. But if you see a picture only every hour, you're really missing a lot of the details of what's happening in between. How are people communicating? What's the social structure? What's happening in that scene? And that's kind of where we are. We're very good at inferring, and enormous ingenuity has gone into figuring out the mechanisms of various biological processes. But it's a very, very slow discovery process because every kind of science that one does is only revealing a very small, narrow window into that process. By combining enough little snapshots of information, we can form a hypothesis of what's happening.

“That's really different than being able to observe it directly at the time scales that matter. There are different technologies for getting those snapshots. The technology that does not exist now and what's specifically addressed in this Keck Foundation grant is how do we make these movies at the requisite time and spatial resolution to see directly what's happening and to accelerate that discovery process? Because we are, after all, very visual. Human beings are just visual. We understand things through how we see them. That's still a very large missing piece.

“It's not just that we'll be excited to see better resolution. There's always a goal of improving resolution, but it's really to help aid our fundamental understanding of these complex processes so that we can advance science in general in ways just like microscopy advanced science 100 years ago. The advent of microscopy accelerated the knowledge of the microscopic world. That's the same kind of goal here. Just like astronomy where the more powerful telescopes are accelerating the discovery of the planets and the evolution of the cosmos, we would like to apply that to the nanoscopic world, the world in which molecules and proteins and cells live.”

“The biggest challenge is that we intend to use visible light,” continues Dantus. “Visible light has a certain wavelength, which is about half a micron, and so there is the so-called defraction limit that tells that you cannot resolve elements that are smaller than half of the wavelength. That's the number one challenge. We're going to be using ideas that are borrowed from magnetic resonance imaging, but that's the first challenge. It's like, who do we think we are that we can break the fraction limit?

“We think we have a new idea on how to do this, and if we are successful, we are predicting that our method will be less detrimental to molecules and will allow us to image with a very high-speed entire movies so that we can see this biology of life in motion. That's the biggest challenge that I see.”

“We have to kind of start with the most basic premise of the entire proposal, which is just distinguishing two things, two objects that are really close by to one another, closer than what the traditional limits impose,” Harel adds. “And then the question is, how do you extrapolate from that to, say, two dimensions or three dimensions or more complicated imaging scenarios? We really have to do some really basic research in terms of just showing what the limits are. The first MRI experiments were distinguishing two tubes of water. That's not terribly interesting. But someone said, ‘Wait a second. The brain is just a bunch of compartments of water, so can we extrapolate to that? What kind of contrast would we see in the brain or in the body, and under what circumstances do we need to enhance that contrast, or what kind of different pulse sequences can we use to see one feature and not another?’

“There were decades and decades of work to get to where we are today where that can be used as a diagnostic tool and as a routine tool that doctors who are not specialists in the technology of MRI can use to make medical decisions. That's going to be the same thing here where we have to prove that these techniques are going to give information that's useful and not distorted in some way, or at least that we know what the distortions are so that we can expect them and account for them. There's a lot of work just to be done in the verification step because we don't know what we're going to see exactly, which is what makes it exciting, but also, we have to appreciate that fact.”

“The first experiments will be on very small particles that are in the earth and static,” says Dantus. “But as soon as we can demonstrate that this approach works in one dimension, we already know exactly how to take it to two dimensions, and it will already have a huge impact. Our brains are now focused on getting that first step done.”

“As scientists, we're always greatly appreciative of the fact that external philanthropic sources appreciate the challenges that we have to face as scientists and the infrastructure and resources that we need to really test new ideas,” Harel says. “It's very gratifying and we're extremely appreciative of the fact that we're given that opportunity and that the Keck Foundation knows and understands the kind of challenges and the kind of risks that one has to take sometimes in order to make breakthrough discoveries.

“We're incredibly fortunate that we get to have that chance. That doesn't come along terribly often. We believe that something really good is going to come out of this and it's going to push science forward in one way or another. We really do thank the Keck Foundation, and we thank MSU as well for really being supportive of us and of the application and of the process to put forward the best application we could and to really be highly competitive with many, many other universities and very strong groups applying for this as well.”

“We’re proposing something that has never been proposed so it’s a high risk, but high reward,” says Dantus. “It's wonderful that there are institutions like the Keck Foundation that are saying, ‘If some scientists convince us that there is a possibility to achieve results that have never been observed before that could have a tremendous impact in science, we would like to facilitate that.’ That's really fantastic, and to be on the receiving end is just incredible. It's just a wonderful opportunity and one that we want to do the most for.”

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