Expert Interview: Marc Allaire

Aliyah (00:09):

Hi, this is Aliyah Kovner from Berkeley Lab Strategic Communications Team. I’m here with Marc Allaire, head of the Berkeley Center for Structural Biology, to talk about how he and his colleagues use the Advanced Light Source to enable incredible research in fundamental science that has high impact applications such as drug discovery. Hi, Marc. Thanks for being here.

Marc (00:28):

Hi. Hi. Nice being with you.

Aliyah (00:31):

Can you tell us a little bit about the techniques that you use at the Advanced Light Source to study biology?

Marc (00:36):

Yeah. The techniques that we’re using is really x-ray crystallography and the small angle X-ray scattering. So basically we’re taking advantage of the light or the photons that the ALS is producing, which interact with the, the biological molecules that we’re looking at. And then it’s giving us a lot of details about molecular details, atomic details about the, those biomolecules: protein enzyme, DNA, RNA. So to give an analogy, it’s like if you’re in a plane and then if you’re flying and then you’re seeing down on the ground, and you, you may see cities, but you know that these cities are basically made of many houses. And you may want to know if there is some some car or truck park in the parking lot. So this is an example where a small angle X- ray scattering could be used where you would differentiate the size of the, the size of the molecules, the size of the car or the truck. And then the crystallography could even tell you that there may be some flat tire on one of the <laugh>, one of those cars or truck. So, so that’s the kind of thing that we’re looking at. So I think we’re trying to look into details at the molecular details, atomic details, the way that the, the proteins are folded in three dimensions, and that’s the kind of things that is really helpful from using these experimental techniques of macromolecular crystallography and small angle X-ray scattering.

Aliyah (02:03):

What are the strengths of crystallography versus small angle X-ray scattering? Where would you use one versus the other?

Marc (02:09):

Certainly the word of X-ray crystallography, there is crystal in it. So clearly you need to bring your proteins or biomolecules to crystallize so that you can get access to the diffraction data out of it. So you get really atomic details and near-atomic details using crystallography. But there is a, the caveat is that you don’t see the protein in solutions. The beauty of small angle X-ray scattering is that indeed you could have your biomolecules in solution, or closer to the native state of the of the protein. And then from that you can get access to some structural biology information, not to the details that you get in the crystallography, but good enough to find, for example, the conformation of the protein, or if you have a protein complex, this is a good technique to look at how those two proteins would interact together, which is going to give you information about the mechanism of the interaction between the two proteins. So those are definitely complementary techniques.

Aliyah (03:12):

So what is kind of the, the special sauce that separates Berkeley Lab’s capabilities in these areas from other institutions?

Marc (03:21):

Yeah, so our group, the Berkeley Center for Structural Biology, which operates many beamlines at the at the ALS we’re part of the Molecular Biophysics and Integrated Bioimaging division of the Lab. This group has been in existence for the last 25 years and focused on helping scientists and pharmaceuticals basically to use to get the structural biology of their favorite proteins. So we develop a lot of expertise, experience. We pioneered the automation at the beamlines to the point now that we, people are sending samples and then we’re providing experimental data directly. And this is done completely automatically, leaving the scientists to work on additional structural determination that they need to do. There’s a lot of new development at the ALS that were pioneered also by the ALS and BCSB like the development of new type of X-ray source. And that’s the kind of thing that the expertise of the group is just outstanding, and I’m quite privileged to work with all these people.

Aliyah (04:38):

Can you give us a few examples of a discovery or breakthrough that came from work on these beamlines?

Marc (04:44):

Sure. I would have a two or three. So certainly there was a, a big effort that was done by the group of David Baker, Dr. David Baker at University of Washington. He had the idea of developing a new design of biomolecules for new functionality. So of course, when you do that, then you want to be sure that the the structure of the proteins or the new, new biomolecules that you’re designing is indeed the one that you are targeting. So he was designing those from scratch and basically confirmed those through structural biology on our beamlines. So for this, he was co-awarded the Nobel Prize in chemistry in 2024, the last one, basically. So this has been a tremendous tour de force and starting, starting on this was something that nobody could think that it’s possible to do, but he was able to show that basically. So that would be one of the example.

Marc (05:45):

Certainly, we had a few example during the time of the COVID where basically drug discovery were done using information on our beamlines, experimental data from our beamlines to be able to develop drugs again, this fight of the virus. But I would give a more recent example from the company Gilead Science. I think they develop a new inhibitor, which is called lenacapavir, the trademark is known as Sunlenca, which is a drug against the HIV virus. So the beauty of that drug is that that’s targeting the capsid protein. They identify the molecules that binds the capsid protein, and then the capsid proteins with this binding the virus cannot replicate or cannot enter the cell. So that’s the kind of thing that were developed on our beamlines. And there’s would be a many, many example like this where companies are using the BCSB Beamlines at the ALS.

Aliyah (06:47):

Can you tell me a little bit about some upcoming work that you’re excited about?

Marc (06:51):

So, yes, I can I’m going to give you two different answer to that one, which is more on the technical side, and then the other one, which is another collaborative project, which is really exciting happening. So let’s start with the technical side. So I think the one that I’m most excited about right now is the project called Gemini. So we’re basically trying to extract a second beam from the same source, the same ALS photon source an undulator source. So this would be a good way to double the productivity of the light. Basically, it’s a cost effective way as well. So this could become prototypes for a future beamlines, for example, after the ALS upgrade which is upcoming in a few years from now, basically. So,

Aliyah (07:40):

Wow. Awesome.

Marc (07:41):

And then the other one, which is from the group of Rebecca Abergel, which is working on these heavy atoms elements the elements the chemical elements that are radioactive in nature. I think there’s a lot of understanding of these chemical elements that are not always clear, especially when it’s time to understand how they coordinate with the other atoms surrounding them. So, so then the group of Rebecca found a good way to use in the X-ray crystallography to load the proteins, which are bound to, to this radionuclide in order to study this this mode of interaction that these are. So this this interest is certainly important because could feed a tremendous beautiful effort in trying to, for example, purify the site radionuclide site, or people that are affected by radionuclide, as well as in cancer therapy. Basically you could probably deposit this radioelement, this heavy atom element on some sort of a chemical that would bind to a protein, and then the protein would be targeted directly to, let’s say, cancer cell. And then this would certainly deposit the energy of the radionuclide directly on the cancer cell, then kill those cancer cells independently of the regular, the normal cells, basically. That’s a great effort, which is ongoing right now. And we’re quite excited about that.

Aliyah (09:15):

That’s very cool. Sounds like really promising research with a lot of, a lot of different applications.

Marc (09:19):

Yeah, that’s right. Exactly. I think they are doing great.

Aliyah (09:23):

So, to close out, what is the number one thing that you would like the public to know about the biological research that is happening at the Advanced Light Source?

Marc (09:31):

Yeah, so for me it’s the, the impact that the ALS and the X-ray crystallography has on the, on the drug discovery. And the drug discovery process is a long process in trying to find a chemical that binds to a protein or enzymes. And some analogy, I would basically compare that to a key where you’re trying to find a key to open the lock. So you may have a million keys on the, on the table, but it may be a challenge to find the one, the real one that you have the lock. So if using X-ray crystallography, I, I can basically show you the in and out of the lock, then you would be able to find the keys that bind the, the lock. So that’s the kind of thing that drug discovery is using as a technique. So that’s, in my opinion big part of the ALS and it has been a big part for the last 25 years and will continue to, to be as is supporting academia, but then also the biopharmaceuticals to to fight the disease.

Aliyah (10:33):

Well, thank you so much for taking the time to talk with me today.

Marc (10:36):

You’re welcome. It was great talking to you.

Aliyah (10:39):

To learn more about the Advanced Light Source Beamlines, the research they enable or how to access them for your own investigations, visit als.lbl.gov. This is Aliyah Kovner from the Strategic Communications team at Berkeley Lab.