Phil Dawson Interview: SPPS, Native Chemical Ligation & a Career in Peptide Science

Introduction

Annually, the American Peptide Society recognizes a scientist whose work has profoundly impacted peptide research by honoring them with the Bruce Merrifield Award. Named for the inventor of solid phase peptide synthesis (SPPS), this award acknowledges researchers whose work shapes the present and future of peptide science. The 2025 recipient is Phil Dawson, a Professor of Chemistry at the Scripps Research Institute in La Jolla, California.

Phil Dawson’s ties to Scripps run deep, having earned his PhD there in the lab of Stephen Kent. After spending time as a postdoctoral fellow at Cal Tech, Phil returned to Scripps as an Assistant Professor. He has served as the Dean of the Skaggs Graduate School, mentored many students and post-docs, and successfully run his lab, publishing over 200 papers to date. In addition to the Bruce Merrifield Award, Phil has received the APS Vincent du Vigneaud Award, the RSC MedImmune Protein and Peptide Science Award, and been named the American Chemical Society Cope Scholar.

Q&A

CSBio: Could you share a little bit about yourself, your research interests, and how you ended up studying peptides and working in peptide science? When you were applying to graduate schools and graduate programs, what made you say, “Oh, that looks cool!” ?

Phil: Right. Our research is broadly in the area of the chemistry of biological macromolecules (peptides, proteins, oligos, carbohydrates), focusing on improving our ability to manipulate them structurally and study them in complex environments.

I had worked in labs as a teenager, and I think I had thoughts of moving away from that area, doing some economics, or history was perhaps my best subject. I took chemistry to keep pre-med alive; I went to WashU, and I think every undergrad was pre-med. I took an intro chemistry class and sort of caught the bug again. I was fortunate to work with a bio-organic chemist working with DNA and it caught my interest, and I got really interested in the interface between chemistry and biology.

I think I was probably a rare person who didn't double major, but I took a major that was halfway between the two subjects. When I looked for graduate programs, you know, this was some time ago, I was looking for chemistry programs that incorporated biochemistry into the same program. In general, biology, chemistry, and biochemistry were all in completely different programs and areas. That's the sort of link I was looking at, and there's a few of them.

My advisor at the time gave me a brochure about a new graduate program that was starting at Scripps, and it was sort of an interfacial PhD: I think they called it macromolecular cellular structure and chemistry, so a bit of everything. The idea was exactly what I was looking for, so I applied, and had the fortune to be admitted. It was a bit of an unknown– the graduate program didn't really exist at the time other than a couple classes, it didn't actually have accreditation yet, but there were a lot of great people, and a lot of great science. I think there were probably 12 different labs I could see myself working in at the time, so it was a no-brainer to make the jump and join the program.

At that time, I'd certainly never made a peptide. I knew a little bit about peptides, but I'd probably done a little more in DNA sequencing and protein engineering, those sorts of areas. I had the good fortune in graduate school of meeting Steve Kent, who was pushing the envelope of synthetic protein chemistry. It's an area that I clicked in on very quickly and productively, and it's been a lot of fun being able to continue working in that field.

CSBio: Congratulations on the Bruce Merrifield Award. What does receiving that award mean to you?

Phil: Well, thank you. It's probably the greatest honor that I could receive. You know, this is a prize that is the highest honor of, essentially, my academic family. I guess I am a “grandson” of Bruce Merrifield through Steve Kent. The people who have received the award before are absolutely spectacular, some of my heroes. I went to undergrad with Garland Marshall's son, Lee, who actually started at Scripps as well. I've had connections with many of these greats in peptide science over the years. It's a fantastic honor.

CSBio: That's awesome. How would you say that your research interests have changed throughout your career? What has shifted in what you're focusing on?

Phil: You know, it's been one continuous journey that maybe circles a little bit. I think the general theme and curiosity have remained the same. We're interested in how the molecules of life work.

I certainly started off with synthetic methodology; we've gone through phases of trying to build unusual protein structures and understand fundamental forces like hydrogen bonding in proteins and enzymatic catalysis. It always brings us back to developing methods to be able to make more and more challenging proteins and different structures–we're always brought back into methodology.

We've done arcs in the areas of bioconjugation and unusual structures and proteins. More recently, I've returned to the oligonucleotide area, initially in the area of DNA-encoded libraries, which are chemistry performed on unprotected oligos or unprotected DNA. A lot of our lessons in chemoselectivity and how proteins and DNA and doing reactions in water and organic solvents, or, in that case, trying to get hydrophilic things into organic solvents all sort of came together, and allowed us to make some advances in that area.

I've worked a little bit in oligonucleotide therapy, and now we've come back into doing oligo conjugates and developing both oligos and peptides together as therapeutics. We're always moving forward and adapting, but I think our basic principles and interests remain fairly similar. The context changes, and we're always looking to be opportunistic and find something new.

CSBio: Can you share something that your lab is working on right now that you're especially excited about?

Phil: I think we're sort of at a rebuilding phase. I spent quite a bit of time doing probably a little too much administration. We have all sorts of new projects that are just getting going that we will probably be talking about in the very near future.

One that I think we’re quite excited about is a concept that we call stretching peptides. A lot of our work has been on proteins and large structures, but the small peptides are interesting and important as well, and a lot of the work in making mimics of peptide structures has been making loose macrocycles, doing stapling of helices and things like that, where you're taking two points that are a long way apart and bringing them close together to try to get the peptide to fold up in between. This is kind of the opposite; we take two atoms that are close to each other in space and try to push them as far apart as we can, which forces the peptide to be incredibly rigid in between. This gives us very locked-in structures, and we think this is going to be very useful for interrupting beta strand confirmations and extended proteins, as well as mimicking intrinsically disordered proteins and binding in the active sites of enzymes; when an enzyme works on a peptide, it usually opens the peptide and binds the backbone and a couple sidechains in a very ordered geometry. We're really trying to use this approach to make potent mimics of extended peptides to understand both biology and to develop bioactive molecules.

CSBio: Can you share some examples of different naturally occurring peptides that would do that?

Phil: We actually found a natural product. We were working in this area and thinking about things, and it occurred to us, looking at structures, that an antibiotic that inhibits signal peptidase would utilize one of the sorts of stretching types of approach on the backbone. Our linkage was much simpler; we decided that we would try to mimic that antibiotic using our particular approach, keeping some of the binding elements constant. That was an antibiotic called arylomycin: instead of having two aryl groups coming together, we had a diyne (two triple bonds) linked together that inhibited a protease.

I think these stretch peptides are going to be useful for inhibiting proteases. They all bind a hydrogen bonding pattern in the backbone that's quite conserved. The other area that I think these are going to be very useful for is interacting with amyloids, which are often beta strand structures, being able to stain them or inhibit them, or otherwise bind and then target these structures.

The final area that we've been focusing on is a lot of the enzymes that modify side chains, for example, SH2 domains that make phosphotyrosines and bind them. All of these peptides bind a bunch of one side chain and then a bunch of backbone. I think these types of structures are things that we'll be able to make potent ligands to. That's been very difficult to do with small molecules or even with larger peptides.

CSBio: What advantages do you experience using automated solid-phase peptide synthesis in your research? Has that changed the way you approach experiments? Especially starting out, the level of automation was probably not the same as it is now.

Phil: We always called it machine-assisted synthesis. At the end of the day, the synthesizers are different, but they're incredibly similar. Peptide synthesis isn't the most complicated, operationally, right? You can make perfectly good peptides with a fritted funnel and a vacuum source. We still do manual synthesis from time to time, but automation really allows you to focus a little bit more on what you're going to do with the peptides and how you're going to study them. When we do our chemical ligation work, we focus on how we're going to modify them and link them together, rather than the pragmatics of assembly.

What I've found over time is that what you really want out of a synthesizer is reliability and predictability.

CSBio: What are some of your favorite discoveries in peptide science, from your lab or from others?

Phil: There are amazing things every day. At the last meeting, Tom Muir shared his new approaches for splicing in little bits of peptide into proteins and cells, which was very exciting. I think from our own work, it's often these side projects that you end up getting involved in. We worked with a researcher at Vanderbilt, Billy Hudson, who had found an unusual link in collagen. They had a mass and some electron density by crystallography, but their initial guesses at the structure didn't entirely make sense. We worked with them and Barry Sharpless to figure out that it was actually a sulfilamine bond, so it was a lysine linked directly to the sulfur of a methionine residue. It turns out this crosslink is essential for every organism that moves; I think sponges don't have it, but anything that actually has motility has this crosslink, and they were able to do a lot of interesting follow up. They discovered that bromine was essential for higher-order animals, which was never known before. And all this sort of came from guessing at what a chemical structure was in a type of collagen. That was one of those small things that then led into a very big, exciting area. I think one of the most fun projects from my lab was building topologically linked proteins, things like catenanes and rotaxanes, and helping to discover sort of pseudoknots in peptides, the sort of linkages that nature usually doesn't explore too much.

CSBio: Could you say that there was a turning point in your career that has kind of defined where you are now?

Phil: I'm not sure I've really had a truly turning point. I've always had the philosophy of keeping doors open and looking for new opportunities, and taking advantage of them when they show up. So, I'm not sure I’ve really had the “aha!” and then change of direction.

CSBio: It's been rolling hills.

Phil: Exactly, we're on an adventure.

CSBio: Can you tell me about a time when something in the lab went ridiculously wrong, and did it result in learning something you hadn't anticipated?

Phil: I remember doing something very wrong in undergrad. I was working in a Physiology lab, and I was asked to make a bunch of agar plates for the lab, doing basic technician work. I decided that rather than making 50 plates, I'd make 100. I was being industrious and trying to show I was being useful. I poured all the plates and put them in the cold room, and I got a call from the PI the next day asking me to come in and clean up. I'd apparently poured 100 plates of broth without adding the agar. The PI had picked them up, and uh…everywhere. You learn that it's good to be industrious, but it's also very important to be careful and diligent, and, perhaps, follow a recipe.

CSBio: That’s a good lesson to learn early on though, right? That's a low-stakes situation. Nobody was in a lot of danger or anything like that. Better to learn that lesson in that way than….

Phil: Exactly. Yep.

And perhaps to be forgiving as well, when people who are new to things screw up–it's part of learning. In academics, as much as doing research, our job is training, right? Training people to be excellent scientists, so I think you always have to keep that in mind, that that's part of the job, as well as the discoveries.

We do have a certain element of serendipity in the research, and a lot of what we do is build large proteins using chemical ligation strategies; I guess the most challenging part of building the proteins has often been trying to figure out ways to make thioester groups at the C-terminus of the peptide, which is the part that's attached to the resin. The current approach that we use.… we weren't following that methodology at all. We were trying to do completely unrelated work, trying to modify a protein with 3 different dyes to do single molecule protein folding studies. And out of that came a beautiful new method for making thioesters that I think is now one of the most popular approaches. It's always good to look at your results broadly: you never know what you're going to find.

CSBio: Look at what the data are saying instead of what you want it to be saying.

Phil: Exactly.

CSBio: Where do you see room for growth in peptide science? Do you think that there are areas of study where we might be able to see an application for peptide science in which they are not currently very broadly involved?

Phil: Well, things are the same, but they're also changing, right? I think with the huge successes of the weight loss drugs in particular, this opens up a lot of people's eyes to the potential of peptides. I think that there's going to be a willingness to take a lot more risks on peptide-type structures, whereas even 5 years ago, people were skeptical if these things could be made at the scale necessary, or if they'd be immunogenic, or have other problems associated with them. I do think that it's a huge time of opportunity, where a lot of things that people might have been thinking about for the last 20 years, and sort of been told, “Oh no, that'll never work.”, that we can actually try again. I think that areas for growth are probably where peptides and biologics meet, folded large peptides. I think that's an area that we're going to see a lot of in the future, and it's going to be bridged with all the work on macrocycles that’s coming through the pipeline, but larger structures that are perhaps a little bit more folded, I think they're going to have their time come in the near future. I also think that getting active peptides into cells is going to start exploding soon, both small structures and large structures; I think for both discovery and for pharmaceuticals, that's an area that is going to be quite exciting.

CSBio: Do you have any concerns about any of these applications?

Phil: I don't have any strong concerns. I think that the field is going to have to adapt. Making things on a much larger scale, both in quantity and size, than we have in the past, and…. the world is more sensitive to doing this efficiently and not poisoning the world while we do it, but I think that the field is certainly up to the challenges. And, you know, I think everything will improve. I think with the investment being put into peptides now, it's all quite exciting. I'm very optimistic that we're going to be doing the business of making peptides a lot better in the coming years than we have in the past.

CSBio: Can you tell me about some real-world applications of your work that you feel particularly excited about or proud of?

Phil: The native chemical ligation suite of technologies. Every time I’m at a conference, I'll be pulled aside by people that I know and many people who I don't know, who have been using the methods to make peptides in their business or in their lab that's allowed them to do new experiments. You don't see a lot of products, but there's certainly a lot of people (CROs and other businesses) using the methodologies that we developed, making quite large structures. That's quite rewarding. It's my understanding that they scale up reasonably well, so that's good. I don't think the methods have necessarily matured, but people are emboldened by the success of Ozempic to make larger peptide structures and see if they work, so I think a lot of these products are really being of interest for the first time.

In terms of other applications, in the research field, it's been great to see how these methods have really helped in our understanding of epigenetics, how the proteins surrounding our DNA control function, and actually are somewhat inherited. These peptide ligation techniques have been great at modifying tails of proteins and the histones and all those sorts of things. It’s been great to see that field flourish largely anchored by a lot of the techniques that we and others developed.

CSBio: How do you build positive relationships between people in your lab, and what benefits do you see from spending time together, away from the research like that?

Phil: I mentioned that training is a critical element of what we do, and having a group that works together and cares about each other, I think, is essential for doing a good job. I've always felt that a healthy mind and a healthy body go together, so we try to get out and get some fresh air from time to time. We do beach walks; basically, you can go from the lab to the hang glider and down the cliffs, and then off to La Jolla Shores Beach. It's a good walk; if you hit low tide, you don't get too wet. We try to do that a couple times a year, other activities sort of go, depending on the group. We're hoping to get back into playing some tennis. I've been very blessed to have really great people to work with. Many of them have stayed in the field, and it's great to see them at conferences and see them do wonderful things in their independent careers. I think that all comes together by having a lab that…. you know, you don't necessarily want your whole social life to revolve around your lab, but having a good element where we can get on and do things, I think, has always been important.

CSBio: It's nice when you like the people you spend 8-plus hours a day with.

Phil: It does help.

CSBio: What would you say you love most about what you do?

Phil: I think it's working with early career scientists. I think back to when I was a grad student: it was an exciting time! I was learning new things, discovering new things. Trying to give some of that back, to provide an environment where people can be creative, be productive, and discover something new, I get to direct it a little bit and watch it, rather than getting in the lab so much: that's quite rewarding, seeing that journey of development.

CSBio: If you weren't working as a scientist, what other industry could you see yourself working in? At the beginning, we were talking about when you were thinking about where you were going to go to school, you mentioned a few other possibilities.

Phil: I would often give advice to new students when I was dean of the grad program, and one of those was that you have to figure out what you're interested in, what you're good at, and hopefully find where they intersect. I think I've been very fortunate to have found that. I certainly explored lots of things I was very interested in and not very good at, and a few things, perhaps, that I was pretty good at and really didn't care about. It's good to avoid being in any of those, so I think I am quite fortunate to have found an area that works for me in that sense. I'm not sure I would have been a very good historian or an economist. I can't imagine not being in the broad scientific area. I've done some work in biotech, and I think that's all very exciting. I wasn't set on becoming a professor, I was just trying to keep doors open and find something interesting to do. But I think I could always see myself involved in science.

CSBio: Very good. We really appreciate you taking the time to sit down and talk today.

Phil: Perfect. Right, well, my best to the whole team.

We appreciate Phil taking the time to sit down with us and reflect on his career so far, what makes him excited about peptide science, and sharing his enthusiasm for mentoring early career scientists. Our congratulations again to Phil on receiving the 2025 Bruce Merrifield Award—we can’t wait to see what’s next out of the Dawson Lab! Keep an eye out for our next discussion with leading scientists in peptide research.