Introduction to Proteomics in Proximity

Welcome to the Proteomics and Proximity podcast, where your co-hosts Dale Yuzuki, Cindy Lawley and Sarantis Chlamydas from Olink Proteomics talk about the intersection of proteomics with genomics for drug target discovery, the application of proteomics to reveal disease biomarkers and current trends in using proteomics to unlock biological mechanisms. Here we have your hosts, Dale, Cindy and Sarantis. Welcome to proteomics and proximity. I am Dale Yuzuki, your host with my two co-hosts

Sarantis and Cindy say Hi! Hey there. Oh, hello there. Nice to see you. For our inaugural episode. Yes, the very first episode. We'd like to go ahead and have you the audience know a little bit more about us and Sarantis, would you mind going first and telling us a little bit about your background. Yes, thank you. Thank you, Dale. Yes, yes. Tell us. I just start my bachelor and my PhD in Italy, in south Italy, studying Drosophila genetics and epigenetics. Oh, that's great. I yeah.

You're a real geneticist. He's a real geneticist. And then I moved to Max Planck Institute for epigenetics in Germany, where I joined the Lab of Dr. Asifa Akhtar , the director of the institute working on chromatin gene regulation and nuclear functions. And so wait a minute, wait a minute. Max Planck has a center for epigenetics. Yes, it was a center for immunobiology and epigenetics.

And I think one of the first worldwide nominated epigenetics institutes actually And I was really happy and it was really lucky because I got to work with Thomas Jenuwein Also was able to work with the famous SU(VAR)3-9, the code, the epigenetic codes and they was really, really nice times when epigenetics was emerging in the gene regulation field and after staying for quite a long time, scientists. How long's a long time? I More more a little bit more than seven years. I say, okay, actually.

And then I join industry and Activ Motif for doing consultant for Epigenetics Project and since December I am part of the great Olink team. as the scientific director for multi-omics where I try to match the proteomics and preach the importance of proteomics in multi-omics work. And I'm really proud and happy to see how people they like proteomics and how and what's expanding to. And the affairs of the heart Yeah, right Sarantis.

And this is true, this is true The affairs of the heart, referring to Cindy. Too, that he cardiology, cardio, metabolic, those that sort of broad umbrella of of disease types that that I think Sarantis has learned a lot about. So Sarantis what led you to industry? What made you decide to move from academics? That's great. So that's a great question.

I guess I’m always asking myself… why has this happened? That is to say I think the motivation and the thing and let’s say the general question to learn more and to get to know about novel technologies. I think at the point in the academia have reached my top level, my top level and I wanted to explore more fields. I want to explore technologies and how this can be applied to the day by day basis to the disease areas.

Right. And I think Olink offers me this possibility to apply my basic knowledge in science to application to translational medicine and to biomarker discovery. And that I can tell you it's a great journey already. Well, we're certainly luckily lucky to have you, and that's for sure. Very lucky with you. Was that a hard transition to capital? Was that a hard transition? No, actually not. Not at all.

Because, I mean, in industry we are doing science and we are doing the high profile science and we are dealing with high technologies and novel technologies. And it was really smooth. I never actually I feel like I never left academia because I’m always reading papers I try to be updated for the novel technology and discussion with scientists and discussion about projects and I'm bringing the value to the scientific life and that that's that's really amazing. It's really exciting.

I haven't seen any change in my daily life, that's for sure. I see. And officially, your title at Olink is? Scientific Affairs for Multiomics nd I’m also taking care of cardiometabolic disease areas Yes, I see. But this is scientific affairs which is a unique discipline within commercial activities. Yeah, yeah, yeah. I mean I breach commercial, R&D, marketing My goal is to preach about the use of proteomics to the multi-omics work and to match the basic research with translational research.

So that's yeah, that's my goal actually. Yeah. And getting back to your work at Max Planck as well as Active Motif was the main method of epigenetics looking at five methyl cytosine or were you looking at also histone modifications and the whole?

I mean, we are we are focusing mainly on histone modification, transcription factor binding Of course we have done studies on methylation but our main focus is on histone modification, histone code” accessibility of the chromatin and how these may interfere with the gene expression and how this regulates the gene expression. This was the main focus. So it's a really nice connection to the to the mechanistic sites, you know, of the nucleus.

Yeah. You can see accessibility of the chromatin and connect it to the gene expression. And now of course abrogates and now coming from the protein side You get the real phenotype right and. You get what all of those upstream aspects have affected. Right, which is exactly what I what I'm attracted to around proteomics as well. That's great.

And in all that work around gene expression, was there concern that the relationship between RNA presence or absence with all that complex epigenetics upstream of that, that connection between the presence of RNA and the actual protein, was that ever a concern of researchers in terms of that linkage? No, I haven't see the concern, and I don't think that's a concern because it’s, of course it’s a question The scientific basis depends upon the question that you have

Right. But there's a complementarity. There's a complementary because you learn different things from proteomics will have different things for transcriptomics they have quite an overlap. Not really nice correlation, not really high correlation to be correct. But this is normal because this is biology. There is a lot of steps from regulation to translation to translation to translation with protein translation.

There's transcription regulation for epigenetics of transcriptomics, but it's also the beauty of science in order to get a better vision and connect better genetics to phenotypes, I think you have to apply both transcriptomics proteomics and actually you have to apply multi-omics approaches, right. That's that's the really beauty of science.

Well, and we've seen we've seen this transition, of course, from bulk RNA as as the technology has evolved from bulk RNA sequencing to single cell sequencing, which I think is enormously helpful in understanding mechanistic biology. So I think, yeah, RNA is, is getting at real time biology and I think proteomics is as well. Yeah, that's so interesting, that background. Single cell is where the entire field is going. And though, I mean there's so much interesting biology to reveal.

Thank you, Sarantis. I know your background in epigenetics gives a unique perspective on this particular podcast. Appreciate it. Really does. And Cindy, what about yourself? So background. Sure. So I yeah, I did my undergrad in bio psychology, so I thought I'd be in neurology. I thought I'd work in that field.

I think I, I somewhere in my, in my final year, maybe my junior year, I realized that, that the tools were were hard to implement that there it was just really hard to to to get at what's happening in the brain. And and so I just started looking around for, for what was it about biology that was so fascinating to me. And so I, I actually have a similar background to you. I taught high school for a little bit while I figured that out, and then I went back for evolutionary biology.

So I became… gained clarity I should say around my fascination with understanding how we reconstruct what's happened in the past to understand systems today and ultimately did my Ph.D. in a in a biological system in the ocean. So worked for fisheries ended up working for fisheries for ten years like look at using genetics as tools. So I make the comment about Sarantis being a pure geneticist, right?

Because calling me a geneticist when I'm really just using genetics as a tool, you know, I've, I've thought about that a lot, but I guess, I guess we're all we're all pushing the field forward. Right. So wait, when you talk about fisheries, you're talking about places like in Maine or down in Florida. Gloucester. Right. Or or the coast of California or. Yeah, Newfoundland or certainly Iceland. Norway. Yeah. Some of your work took you or your research took you to far flung places.

I yeah, I was I was really lucky. I was really fortunate. Well, were you then involved in some of the grittier, dirtier aspects of the fisheries industry? By that I mean I can just imagine. Did I go on boats? Yeah, yeah. Specifically, that's what I think. I think I you know, I remember after my after my presentation for my dissertation, somebody said to me, so you just did one cruise? And I was like, Oh, I made a mistake. I really should have emphasized how many cruises.

I think there was eight cruises that that that contributed in some way to the, to the final, you know, dissertation. They would call it a cruise literally. I guess. Yeah. My association with cruises. Yeah. In fact we had cruise directors. Right. See I think about the Love Boat or something, you know, so when you're a kid But then you are collecting samples, are you collecting samples then? And you said. That's right. On tour, but you have it done.

So both adult samples and some cruises that that was the focus. And so there was actually a lot of scuba so working off of those NOAA ships, but also larval samples. So it turns out with some of these fish that live that are bottom dwellers, that you can't just collect them as larvae along the bottom. They're actually pelagic. They actually move through the water column as they develop and then eventually settle into places like kelp beds, depending upon the species.

And so we needed to understand their life history. You know, it turns out that, you know, people may not think about this. I didn't before I worked for the fisheries, but the burden of demonstrating that we're overfishing is on the managers of the fishery. And so collecting the information to demonstrate that is is essential, especially if you want buy in from the fishermen whose livelihood depends upon being able to have access to those fishery sites.

So a big part of my dissertation was looking at marine protected areas and characterizing the scale at which they could help reseed the fishery outside the protected area. Yeah, that’s cool. Wow. You've been places. You've seen things. So have you. You both have, right? I mean, I think I just have to emphasize that Sarantis wins the prize for knowing the most languages in this in this group. How so. Yeah. Sarantes. How many languages do you know?

Only three for the moment then Germany, Italy and Germany. A little bit. And I apologize again for my German friends. So I never managed to. I think, conversational and in German at the very least. But yeah. Yeah. Well I’ve to give Sarantis the most languages prize There we go. There we go. And I get the most cruises prize maybe. There you go. That's for definitely. That's for sure. Then how did you end up in industry, Cindy? You know, I transition to industry. It was a big surprise to me.

I had been suggested for a position at this little company that I thought was probably, you know, it had a lawsuit against it. It was I had a friend who worked there, this little tiny startup. I thought it was tiny, about 150 people. I guess that's mid-sized these days. But and so I she said this job would be perfect for you. And I said, I'm really looking for something an academic. And I had an eye on a couple of postdoc positions along the coast and of the U.S. on the West Coast here.

And and I said, well, I'll go interview just for the practice and I'll learn a little bit. And I was so blown away by the technology and just the ability to support technology. That is a rising tide that lifts all boats like that just blew my mind and it felt like an opportunity to learn so much about so many different fields.

And I think have after having been, you know, what it's like in a Ph.D., after having had your nose to the grindstone in a system and learning it to the extent you need to to be credible. And in getting that Ph.D., this was just so different and so it was just so awe-inspiring I was really excited about the technology. Cindy, what was the company? Well, you were there. So I asked. You couldn't tell me what the name of the company is.

It was Illumina. It was Illumina. And I ended up staying for 14 years. So it was it was such a good such a good time. So I joined in the very early days and. And for 2004. That's right. Yeah. I remember trying to negotiate. You know, you're coming out of a PhD in the industry like you got no no where to negotiate from.

Right. So I was trying to negotiate a little extra time before I started in the position and I got two weeks from the time I defended my dissertation to the time that I, I remember my mother and I went to travel in New Mexico. It was a fantastic trip. But yeah, I started, you know, almost right away. It was it was quite. Quite a New Mexico was how you spent those two weeks. Right, right. Sorry. Yeah, yeah. Okay. And yeah, but I. Was born in New Mexico, so. Oh, okay.

I'm guessing that there were a lot of DNA sequencing at the time. What was the most weird species that you were You were sequencing at the time? What was the most wierd projects that you had? One of your first let's say. One of the first projects? Yeah. So I'll tell you, one of my first projects was working with Decode Genetics.

And so I remember and I, you know, I had no idea the impact they had on, you know, steering or anticipating, I should say, you know, where the field might go and various. Sarantis, to clarify, right this is before NGS, so at the time Illumina was just offering genotyping. That's right so it was. Yeah so 2003 Illumina launched an 1152 plex, Golden Gate genotyping platform. And then Illumina was able to sew-up a lot of the HapMap projects that were going on.

And this was again after the genome project right to characterize variation across populations And Cindy, your first role was it as a Project Manager? Yeah, I was a project manager within the scientific team that delivered data to customers that were sort of testing out the technology in order to determine whether they wanted to invest in a BeadLab or a BeadArray Reader Now, the bead lab was the big genome center, you know, offering.

It was a million dollars. $1,000,000, a LIMS liquid-handling automation system. Yeah. Yeah, it was, you know, an I had not worked at that scale before. So seeing the number of samples and the number of variants within the genome that were query able at that point was just mind boggling to me. And the person that interviewed me was just such a, such a a great people person.

He just listened to all my, you know, objections or all my, you know, you know, questions about the technology was so patient. And I thought, you know, I could work for this person. Who was it by the way. John Stuelpnagel. Oh Okay One of the founders of Illumina. That's right. He was he was very, you know, just a great a great leader. Just a great person to learn from. And for those of you who may not be familiar with the name, he is the principal behind many, many companies After Illumina.

Successful companies. Many successful companies. Yeah, right. Yeah. And what's I find fascinating, right, is at that time 1152 Plex blew people's minds. as far as how many genotypes you can get at the time because people are used to like mass spec methods, right? From what is that San Diego company that whose name I can't remember. Sequenom. Right. Yeah, it was a handful, maybe ten or 15 SNPs at a time for a sample and you go from 15 at a time to over a thousand.

And then of course the first HumanOne Genotyping BeadChip which you know, I was involved in the development of that was 108,000. So you go from right one 1100 to 108,000 to the first HapMap chip that was over.. Remember, we had a we had the gene chip in between. We had a 10,000 chip in between. Oh I don't. Remember. Was gene centric. Yeah. Yeah. Okay. And there was the HapMap chip. But it didn’t it”

Yeah. Yeah. But then really quickly that 300 the HapMap 300 that was tag-based SNP selection you know intentional SNP selection to collection additional information beyond just the ones you're querying because you have some understanding of, of genomic diversity within the population that quickly overshadowed that gene centric chip. But I thought that gene centric chip with maybe it was 100,000, maybe that's the one you're thinking of to the.

Yeah, the what's interesting is the parallels to today. Right. Where Olink’s competitors on the low-plex side They do four plex, they do ten plex, they do 20 plex. And now Olink comes out with a 96-plex and then panels of 96 and then 1536 and then now 3000. Okay. May not have ramped as quickly due to the inherent challenges right of various complexity of proteins. They have a dynamic range, those little buggers.

Yeah. Yeah. And it's fascinating to think well we're on a similar multiplexing track here and right. and history is prologue. It really does give us ideas of where the future is. Yeah. And I think we can think about it quite a quite similar to genotyping right targeted locations in the genome. It's, it's a great way to get a general view of the whole genome. It's sort of like a satellite view of the genome before sequencing technologies evolved to be so accessible and so affordable.

And I think we're we're going to hopefully we see these technologies on the on the horizon that may offer a future of next generation proteomics or maybe next next generation proteomics that maybe one day we'll be able to sequence the proteome. I think the that mass spec is beautiful because you can see everything, but you're limited by how much you can push through. So those low, abundant proteins are really, really challenging with that technology.

So I think that's where we're we're nicely complementary to existing methods. I mean, here it is. Cindy, How was the transition for you, how to do you see genomics through proteomics? How was these transitions actually for you?

Yeah good question so so you know that that I got I was pretty clear about what was motivating to me about the genotyping technology and then ultimately the sequencing technology you know, I stuck around, you know, holding that tiger by the tail while, you know, it blew into the Illumina that it is today. And I, I really wanted a way to understand the the impact genetics is having on more real time health.

And so I actually had a stint at a company called Metabolon, looking at metabolomics now talk about complexity of of biological pathways. Right. And, and I was there until I saw the launch of the NGS readout on the proteomics at Olink and that NGS readout, I was an AHA for me and I thought, well, I can, I can help with that. And I'm excited about that.

You know, specificity, you know, the quality of the assay, which I think I think is, is exciting because you want to be able to make discoveries and then drill in to those discoveries and focus in on on individual targets. Right. So that's the that was the attraction. And I actually approached Olink and said, you should hire me. Just like that. So cheeky, right? Never, in… a million years would I expect myself to have done that But yeah, they were, they were very amenable.

I had a great experience with that. And I will say working for a Swedish company with a U.S. representation is, is a really nice it blends some nice qualities. It's remarkable. Before I joined Illumina in 2003 I was at QIAGEN a German company, for four years representing their commercial efforts. And this is, of course, to 1999 to 2003, where I saw through the whole genome project from the lens of a sample prep provider for the Human Genome Project.

Of course, at that time Affymetrix had just grown like gangbusters.

And all this interest in whole genome transcription expression analysis via microarrays and coming back to a company that's from Northern Europe and it just the precision in and QIAGEN was wonderful because the engineering mentality” is very much exhibited, right, the precision of their, of the assay development and of the product development and at Olink I see shade of that as far as very disciplined approach to accuracy, to the quality of their product. There is a lot of care taken, right.

And it's a great cross-functional collaboration here at the company. And I think we all know that the more contribution you get from diverse opinions, the better your products going to be, provided you also have that discipline to ensure that you've got the specificity. So anyway, it's a it's a fun, fun ride. Sarantis, I'm curious what you're so what you're most excited about in the coming year at Olink, in your role.

I am really excited to see that data integration” of really multi-omics data coming true, you know because we hear a lot of multi-omics we hear a lot of this buzzword multiomics, but we are not still there, you know, the different regions and I think Olink offers the perfect tool being an NGS-based assay mainly to create this, multi-omics approach in life, to bring it to life And I'm really excited to see projects coming really multi-omics projects

that they have epigenetics, they have transcriptomics, they have proteomics, they have genomics, that it will be really the future of of science. What do you think has held that back so far? Like why do you think now is the time? Right. I have this this sense that we're in an inflection point. Right? There's this there's this energy for sure when I go to conferences. Sure. And so I'm curious. You're your perspective on that Sarantis.

Now, I'm really happy to have your feedback on that because it's really an open discussion. I would really like to know from your side, say this, I see that I think that people in regards of proteomics the making, let’s say the Mass Spec assay was must because it was really difficult to break into the multi-omics work.

I think having an NGS-based approach to this makes things easier I suspect big data, you know, having expensive experiments, the sequencing is is a quite is not an easy experiment to do you need bioformatics tool, we need bioformatic analysis you need the specific platforms that they can integrate this data that they are not very well advanced. Let’s say their data analysis. Yeah. They are not so well advanced in the sense that they are really not easy, accessible to everybody in this respect.

Of course they are advanced, but not the science that will be accessible to everyone, it has to be easy for everybody and they are not there for the multi-omics approach but we hope soon Yeah. What do you think from your side?

Yeah, I was just going to say, I think I think you touched right on what I when I come across a lot is this analysis piece and having having tools to make those analyzes happen where you're integrating these data because some of the platforms allow the data to sit by side by side. But, but actually having scripts and tools that are that are bringing those data together in a multi-omics analysis is not trivial.

But I think maybe part of the as you were talking, I was thinking maybe maybe part of this sense of urgency and excitement is, is all that's happened in the UK Biobank in the last five years. Right. The exome sequencing, the whole genome sequencing. Now the proteomics that's coming out of the UK Biobank and making those data accessible means that there is a playground for people to advance their skills, to integrate those tools.

And it's very cohort projects as well, you know, not just the UK Biobank, but it's certainly the buzz at ASHG every year. Sorry, go ahead. It is ‘the’ definition of big data Right. Is volume, its velocity and its variety. So we have a big data problem, right. Was we have whole genomes at scale. You've got whole transcriptomes at scale. We have whole epigenomes And now we are going to overlay proteomes? You know, these are different types of data in large scale, in multiple dimensions.

Yeah. And I think I think that back to Sarantis comment about mass spec. I think that was the barrier maybe is that you know mass spec it's hard to get a lot of samples through under this sort of service wrapper conditions where you're you're controlling variability and then and then feeding it into what you're talking about Dale, integrated project with, you know, 50,000, 100,000, ultimately, you know, half a million samples. It's and we can't talk about mass spec as a monolithic item, right.

Because of all the infinite amount of varieties of. GC, LC, tandem. Yeah And timsTOF, I mean you just go down the line in terms of everything from sample prep all the way through the technology, all the way through the analysis, bottom up proteomics, top down proteomics and everything in between. Yeah, it gets really complicated from even the analytical chemistry side. Yeah. Is absolutely that monolitic is really a lot of advances. Also the single cell proteomics space, right?

I mean the single cell proteomics protocols, they're designed to done by mass spec. Nowadays I think there are different questions and there are different scientific questions that I think get different answers from a Mass Spec and Olink approaches PEA approach, I think they can really nicely complement And that's, that's the beauty of science, right. That isn't out there. Really nicely complimenting can take really nice and integrated information. So that's. That's right.

That's right. That tied right up. Oh, there's all this great stuff. Alas, we just have a few minutes left. Does anybody ever ask me about my background? I can ask before I wanted to ask you that question. QIAGEN was your first, it was your first?” That was my first. That's correct. Well, before that, I was a manager of a small laboratory in Santa Monica.

I worked for a P.I., Dave Hoon, whom we worked on tumor immunology back” in the late nineties when nobody worked on tumor immunology except for Don Morten there at the John Wayne Cancer Institute in Santa Monica, and then Rosenberg here at the NCI though They were the only two working on tumor immunology And now how I look at it now, wow, you were a pioneer. Incredible.

And then that time at QIAGEN was fascinating because I started with customer service – technical support, 1-800-DNA-PREP And the manager of that department is Kirk Malloy, who ended up joining Illumina at the end of 2002 and invited me to interview, invited me to take a tour, and I’ll never forget the tour I had because he showed me the ‘Oligator’ the Vacuum Box and all of its 96-well glory.

And this was, Sarantis, their secret sauce Illumina's the ability to make very inexpensive oligos at scale. And so they developed this method, and Cindy is putting up her little.... That's me! A piece of history. Illumina. Different haircut, you know. That led to the coincidence of the fact that we're side by side, we're right next to each other and that yeah. So those were kind of, like Cindy said, kind of scary days, right? Because it was a small company that had...

We had a lawsuit, remember, there was a lawsuit over... There are several lawsuits. Actually, there was a lawsuit there was from another company. And I learned now that, you know, maybe that's a badge of honor sometimes. But I didn't know that then. I thought I thought it was going to be, you know, the death of us. You know, I had no idea. And then there was a there was another lawsuit.

I can't you know, both of them ended up being, you know, just just indications of success, I think, when we look back. But, yeah, yeah, yeah. I think the secret sauce. Right. Was not just the right technology, really, it's the people behind the technology. It's also the creative thinking of people behind the technology in terms of what are the critical things to work on, what is the critical fundamentals of the business to make it successful?

And I can say career wise, right, I've I've been in a lot of different genomics companies. It was 17 years from that time leaving QIAGEN, and then to come back to Olink yeah, the 17 years and the in between so much I've learned in the genomics realm. And then now to bring it back home to proteomics. Yeah, bring it back to very close to common disease, very close to rare disease, very close to population health, very close to wellness, very close to aging.

Do you realize the advances we've made in cancer have been remarkable because of a focus on therapeutics and prevention? Can you imagine doing the same thing to longevity and aging to make similar advances? And we're on the edge. Of prevention, right? There's the potential. Yeah. Yes. It's remarkable times we're living in from the point of view of measuring proteins at the scale that we're talking about can have true impact on cardiovascular disease like matter. Matters of the heart.

Just as well as right population health with the UK Biobank, like you mentioned, Cindy, what a amazing resource. I mean, yeah, what is it? 500,000 healthy individuals measured from 2006 onward. Yeah. And not checking. In. Go ahead. Not to forget or to close the loop. You know, we're right back with Decode Genetics. Right. They're also very engaged. So what led you to industry, Dale?

I think what it was was an opportunity, the opportunity to apply a lot of what I know as a scientist, a lot of what I value in terms of learning about science in a new way. And that is the combination of science with business. And it's fascinating, right?

Some of my favorite classes as an undergraduate were in psychology, and now I get to use that every day in a marketing role because I'm thinking about the psychology of buying behavior, the psychology of, you know, what messages resonate, the psychology of, okay, if somebody's searching for solutions from a search engine, what terms do they use to find Olink Proteomics? I mean, yeah, it's yeah that's part of my day to day believed. Is understanding people's motivations.

Yeah back to the people right. Back to the people. And I think what's fun about the a holding a podcast and this proteomics and proximity is that we get to talk as people about science. We will interview people as scientists, we will go ahead and talk about papers that people have written, their conclusions, their ideas.

And so it's I think there's going to be a lot of fun to talk about sort of papers in the context of like a journal club, I think will also be really interesting to bring in guests. and certainly Sarantis and Cindy you have some ideas of who you’d like to bring on in this remote kind of personal and intimate environment. And then we can just the three of us talk a lot about fish or larvae… or what’s it like to scuba dive in Nova Scotia or wherever it was you were.

Yeah. Or maybe what's it like to work for one of the leading institutes in Germany? They're on a true model organism from a true geneticist, no doubt. Right? Yeah. And if we can give some perspective to maybe graduate students who are who are finishing up their Ph.D. around ideas of what it's like to be in industry, I'd love to contribute to that as well. I'm pretty still pretty passionate about working with students. Great. Well. Again, people, right? People and people.

Well, we got to get that in there. You got to get in there. All right. Well, until next time, take care audience. Thanks for joining. Thanks. Thanks. Bye. Thank you. Thank you. Thank Thank you for listening to the Proteomics in Proximity podcast brought to you by Olink Proteomics. To contact the hosts or for further information simply email info@olink.com.