On this episode of Molecular Moments, Dr. Jim McNally chats with DMPK Senior Director Dr. David Johnson, Ph.D., from BioAgilytix San Diego. They discuss how his childhood breakfast cereal formed an interest in science which eventually led to his pursuit of biochemistry and a career in small molecule therapeutics.  David, known as Dr. J to his friends and colleagues, shares his goal of helping people get a better quality of life through his work in the pharmaceutical industry and what it’s like working with small molecule drugs like aspirin or ibuprofen. They also talk about pharmacokinetics, how the industry has shifted over the years, antibody-drug conjugates in cancer treatments, LC/MS usage, and the increase in resources, tools, and knowledge to solve problems thanks to the growth of BioAgilytix.

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Dr. David Johnson Talks Frosted Flakes, Small Molecules, and Pharmacokinetics! .mp3: Audio automatically transcribed by Sonix

Dr. David Johnson Talks Frosted Flakes, Small Molecules, and Pharmacokinetics! .mp3: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.

Speaker1:
Welcome to the Molecular Moments podcast.

Jim:
In today's episode, we sat down with our guest, Dr. David Johnson, from Bio Analytics, San Diego. Welcome to the podcast, David. Good to have you here. Delighted to speak with you today. Looking forward to learning about you, your career, small molecule, bio analytics, something that we don't talk a lot about at bio analytics until recently as we acquired a new company. So give us a quick overview of your career, how you came to the small molecule, BIOANALYTICAL space in DMP space.

David:
Absolutely. Thanks so much for having me here. This sounds like such a fun way to get to know scientists at bio clinics, and I'm glad to participate. So how did I get into science? That's pretty fun. When I was a kid, I would start memorizing the ingredients on cereal boxes and then I would start describing what these ingredients were to my family members. I think it became apparent early on that I had an interest in science, and that certainly played through. I actually was going to become a medical doctor and I signed my early artwork as Dr. J. Ironic that nowadays that's a nickname that we have at my work because there were 25%. David's at the company at the time I joined, but carrying on through high school, it became apparent that I was more inclined to do scientific research as opposed to medical research. And so I went towards chemistry and this became really prevalent in college. Somehow my brain was able to work with organic chemistry. People still are befuddled at how how that even is possible. But it worked. It worked really well. So that got me into the science field and then the small molecule space where I'm at right now. And in addition to that, I became very interested in biochemistry. For some reason it really excited me to memorize all those biochemical pathways with enzymes and etc. in our in our body. And I became so fascinated with how complicated it was. There's so many enzymes. Even experts are befuddled at how all of these work together and how dysfunction in these enzymes and receptors are what cause disease. And the more we learn about these enzymes and receptors and how they're how they're broken and how we can fix them, that's where my interest in the field of pharmacology and pharmaceutics really became apparent.

David:
And that's the kind of the early buildings and beginnings of how I got into the field where I'm at right now. Then I decided to join a company called Hybrid Tech early on. It's one of the first companies in the San Diego area, and they were involved with doing diagnostic testing. And I got to work with radioisotopes, do some biochemistry, some robotics, learn how all these different sciences can come together in the pharmaceutical industry. And that was particularly exciting because I got to marry my fascination with technology, my chemistry, biochemistry. It all came together, all of it science, all of it different, but all of it to fill a purpose of how are we going to help people? And that also is super interesting to me. So it got me into graduate school because I liked it so much. I wanted to do more. And so I went to Minnesota and got my PhD in chemistry and after that I fell into a job doing drug metabolism in the pharmaceutical industry and I've been hooked ever since. So that was a while ago and I've been fortunate to be able to really expand on that knowledge, grow in my career and my ability to help other pharmaceutical programs get to market so that we can help lots of people get past these diseases, deal with them and help them get a better quality of life really kind of the end game and gives a very nice flourish onto the whole idea of being in chemistry and science. Get to use that at interest to to help people so very. Fascinating. And hopefully that gives you a small flavor of what actually got me into science. Why love it, crazy about it, and want to keep doing more and more of it now?

Jim:
That's great and what an amazing way to get started. I feel like I wouldn't be doing my hosting duties properly if I if I didn't ask, what's the first cereal that you recall reading the ingredients?

David:
I would I would guess that it probably was Frosted Flakes.

Jim:
All right. Okay.

David:
Great. If that doesn't eat me, I don't know what does.

Jim:
No, it's it's funny, right? And you think about it. Hopefully there weren't too many small molecules in the Frosted Flakes. Probably not a lot of polymers.

David:
There are xanthan gum. You know, there's all sorts of stuff that were in there. And so I was happy to explain, oh, what these things are to my family. And they shook their head. But, you know, you you deal with it. They just found out, oh, that's David.

Jim:
That's great. You know, I wonder how many scientists have, let's say, at least a similar kind of origin story here, not so much around reading cereal boxes, but some sort of fascination that caught their attention when they were young. And they continued to pull on that thread a little bit to eventually become a career. And I often find a lot of people in science have had some sort of early experience, whatever it is that triggered that, and they followed on it and they're so happy to do it because they've been passionate about it for almost their entire life. It's kind of great to see people that turn their passions into their career. So great to hear that story. So you're based in our San Diego facility. As I suggested, biologically, San Diego is new to the family, formally Micro Constance acquired in summer of 2021, which really opened the door to small molecule support, not something that biomedical had a lot of experience in previously, really focused on large molecules. So I'd love to hear some of your thoughts about working in the small molecule space, the type of work that you enjoy doing there, and maybe some of the particularly interesting drugs you've supported.

David:
Absolutely. Small molecules for people who might not be aware are like acetaminophen, ibuprofen. Many of the drugs that basically built the pharmaceutical industry back in the the mid to late 1800s. These companies that we know nowadays as Merck, Pfizer, Bayer, they were formed based on preparing and distributing these small molecules that found a good market. A lot of people did not want headaches anymore and they thought, take a little pill, don't have a headache as much anymore. And it grew and expanded on that. And that's the space where we are helping. We've addressed a central nervous system disease, oncology, antiviral, antibiotics. All of these different indications have been addressed by small molecule programs we've helped at the San Diego site, and my specific role has been a little bit early in the phase where we are testing the compounds in animals. Even before animals, we do a lot of in vitro assays here and we're investigating. Does this molecule have good drug like properties? Is it going to make a good next aspirin, which itself is actually not that great of a drug, but it probably wouldn't make it onto the market nowadays because it has so many off target effects that we take advantage of.

David:
But it's still a good drug. And we're we're looking to find drugs that behave in such a way that we'll be able to take one pill a day. And we are feeling good and it stays in the system. The right amount of time is not toxic. All of these types of general characteristics are what we investigate at the San Diego site, and we help our sponsors make those decisions to see which candidates might want to move into the next phase, where we're going to be testing them for safety. These would be in standard animals such as rats and dogs. And after they've been proven to be safe enough for the animal studies, then we get to go into the clinic and I do a little bit of work on that in my department, the DPC group, but it's not so much at that point. It's the handoff to the regulated industry. So we we all work together in different parts of the drug development program. And the end goal is to get it far enough along so that we're able to do the regulatory filings and get this medicine onto the market.

Jim:
Yeah, know a couple of interesting points there. I think some things that people don't often think about and aspirin or ibuprofen, great examples of things that people just take, right? I mean, they're accustomed to it. It's so widely available, so well defined, used so frequently. All of these things have toxic effects. Right? It's all about getting to the right dose. And that's an interesting part of your job and part of the role of people really that we all do in the pharmaceutical industry. We can make a lot of things and they can treat a lot of things, but finding the right amount to give to people to get just that right effect, just enough to get the intended effect without getting the unintended effects is a big part of what we all do, right?

David:
Absolutely. And it's super important we do that at our site in San Diego. It's called pharmacokinetics. We're measuring drug concentrations in plasma samples so that those drug concentrations can be correlated with clinical effects. They can then decide, well, at this concentration, we're able to see a clinical effect and then at a much higher concentration or or maybe even a slightly higher concentration, then we start seeing bad effects, the ones the effects we don't want. And as you alluded to, Jim, those would be the toxicities. And we want to really hone in on what dose levels and amounts of these compounds will make for a good drug as opposed to a toxin. We want to make drugs, not toxins. And as early toxicologists are saying, it's all about the dose.

Jim:
Yeah, the the old quote, the dose makes the poison or the dose makes the toxin is really true of almost everything that we put into our bodies, quite honestly, and something that we're accustomed to in the pharmaceutical industry. And not just a small molecule property either.

David:
Yeah, if you drink too much water, it will kill you. It will imbalance your salts and you will die.

Jim:
So if you the other interesting part of that is a concept that a lot of us that play around in this space certainly get. And we're getting a bit of a crash course globally around this thanks to the pandemic and some other things that have happened. These things are not just defined by one factor, right? It's about getting the dose to the right level and then combining it with an entire data set of other things that are being monitored. Right. So if you're looking at pharmacokinetics, you're also tying that data into a much larger package of safety evaluations, perhaps biomarker evaluations to see the actual effect of things. It's not just one piece of data that decides anything, right? It's really an entire package of information.

David:
Is a huge package of information. Most people are most people are lucky enough to never see a regulatory submission for a pharmaceutical or a biopharmaceutical. How many boxes do those companies write? It's a lot of boxes. And so the role that I play in in that box is small. There's a lot of hands that go into generating the data that is reviewed by the FDA or any other regulatory agency, as they considered. The basic question, is this compound safe enough to justify the risk of taking it? And that's where we're trying to get the compounds to the point where those decisions can be made. And to your point, it is quite a task to collect all the data, and I'm happy to be a part of it in any way. And it's actually nice that we're part of biological ethics now. We're able to address a larger part of the whole data collection package then than we were before. So that makes it even more gratifying to be a part of this because we we can address more of the regulatory space, more the science space. It's a lot of opportunity for us to help more programs get further and further into the market.

Jim:
Yeah, I agreed. The instant that we made public the announcement of the acquisition of MicroConf Biomedical in San Diego, I went on an internal team call with our team and said, look at the most basic level. We say no a lot less. Now there are a lot more things that we. Can do and combined. There's an amazing potential to impact an even larger part of the industry, which is for those of us that want to have positive effects on patient outcomes, it's a huge advantage and more things that we get to work on. And I think also incredibly interesting for curious scientists to just do something and think about something differently than they've done before. It's an awesome opportunity.

David:
It is so much of what I have learned as a small molecule drug developer is applicable towards the larger molecules, such as peptides, and then the modalities are just growing. Those peptides are getting conjugated to larger molecules like monoclonal monoclonal are getting conjugated to oligos. The types of drugs that are being called drugs are getting more complex, more sophisticated, and the skills that we have learned in both small molecule, large molecule are starting to get married. Their blending is getting harder and harder to tell the difference and the need to know both types of workflows. The small molecule and a large molecule is more apparent now than ever. If you just look at the the new drugs that are coming out and the type of science that's being developed to address the needs of those new drugs, it's fun, interesting and a great reason for large and small molecule to be together in one company.

Jim:
Yeah I guess it we'll continue the food taglines and it's to great taste that go great together instead of sure yeah I mean and that that's very true the drug modalities are becoming more complex so we're leveraging more tools. Things that you originally thought of as being small molecule are now used across areas. Large molecule tools are being used in the small molecule space platforms that have previously been used for this or being leveraged. And it's really an amazing time in the bio analysis space to to really think through how we're going to characterize all these new, slightly crazy drugs that people are building for sure. Let's come back to something because I do want to talk about LCMS use for large molecule and some of that just briefly. But but before we move off of some of the exclusive small molecules, but you made an interesting comment about the the aspirin and maybe something that wouldn't get approved today. And I'd like to get your perspective on this of how you've seen the industry change over time as far as the level of detail and rigor of getting drugs approved now from the earliest days when you got into it, maybe into now, how do you see the shift in the industry?

David:
It's a total shift. If you look at the number of SOPs that we had when I started at the San Diego site of 421 years ago, it would fit into just a couple of binders, the number of SOPs. Now, we don't even put it into a couple of binders, lots of binders. And we've done this for a few reasons. One is because regulatory requirements have grown and grown as we have learned what makes for good drug? What allows a drug to be safely taken by a person in combination with many other drugs? Polypharmacy is a huge nowadays. We have a large number of people who are on multiple medications for completely different indications. And we as a collective science team have found out that there are things we can do that make it safe for people to take all these medications. One of my tasks as a drug metabolism scientist is to study the enzymes that are responsible for metabolizing these drugs and determine which of them can be taken together. If they're metabolized by the same enzyme, then one one drug may be made unsafe by combat, combining it with another drug so that science has guided regulations and regulations have become more rigorous. And this is across the whole world. As And in response, the data we put into the packages have become extended and expanded in ways we couldn't have imagined 20, 30 years ago. So this is to make it safer for all these medications to come to the market. When you're taking that medication, that pill or that IV, the clinician, the pharmacist, needs to know information that will allow them to give it to you and say, hey, this is. Going to be safe for you. You are not going to go into convulsions and die or something. We are taking this medication and that desire to make it safe is the reason why the regulatory burden has greatly expanded.

Jim:
Yeah, you hear it all the time, right? You hear these ads for new pharmaceuticals on on television. And somewhere in the disclaimer lines, you get the if you're taking X drug, please notify your physician before taking this new drug that they're trying to advertise. And it's really that interaction and thinking about that many people, as you said, are on multiple drugs at the same time. And how do they all play off of each other? Incredibly important part of what you do and the type of work that really gets analyzed, because drug drug interactions are a big part of the small molecule space, a little less so in the large molecule space, although we're starting to see some of that for sure. But the big part of the small molecule space.

David:
Yeah, it's a very large part. All your drugs that you consume, you don't want to stay in your body and your body doesn't want them to stay in there either. You've developed a lot of clearance mechanisms for removing these foreign drugs from foreign compounds from your body, and those processes can be inhibited, they can be affected. And that's what causes the changes to the drug concentrations that would then make a drug rise up to the point where it could be toxic or fall to the point where it stops working properly.

Jim:
Finding that right balance. Right. That's the important part of really what we're all doing in this. So let's move on. You started to touch on some of the newer drugs that are combining things like large molecules and small molecules. One of the big examples really is antibody drug conjugates, ADCs, something we think about where monoclonal antibodies, so a large molecule, protein based therapeutic is used for targeting purposes. I mean, essentially to get the drug to the right cell or the right tissue and then it carries a payload that's often one of the small molecule compounds intended to kill or have an impact on the cells there. So brings together the best of both worlds, right? The characterization of small molecules, the characterization of a large molecule, and then that combo molecule, something that we're all very interested in. We're taking on some of our first projects here. How does that space look to you from the small molecule side of the fence?

David:
It's exciting. It, as you said, is quite the marriage between all the small molecule science plus ligand binding assays science. Both approaches are needed to address the needs for developing these types of antibody drug conjugates. We are looking at the load of the small molecule payload onto the antibodies and there can be multiple small molecules attached to these antibodies. So we're looking at the release of those small molecules from the antibody, hopefully by a proteolytic enzyme that is unique to a certain cancer. This is the silver bullet technology we're trying to take what is not a drug, it's a poison. It is being targeted at very specific cells. And the reason is because oncology before is a lot of people know that if you go and get chemo, your hair falls out, you get violently ill and sick throw up. It's extremely unpleasant to get traditional chemo because those drugs kill your healthy cells in addition to the cells you want to kill. Adcs antibody drug conjugates are trying to get that poison to very specific unhealthy tissue and the small molecule space where we're targeting the drug metabolism of those small molecules, the release of those molecules. And that is combined with the overall ligand binding assays that are designed to to see if the antibody is still in the body. And the science is becoming even more sophisticated because now we're learning that some of these antibody drug conjugates can be slightly metabolised to the point where they're less effective. But the ligand binding assay may not be able to tell the difference between the metabolic products and the original compound.

David:
So to your earlier point, you're wanting to know about how LCMS can address this space. We're now getting sophisticated enough equipment so that. We can look at the intact antibody drug conjugate and we're able to tell the difference between small changes in this antibody drug conjugate. So we can tell when it's metabolized and we can track it more accurately than some ligand binding assays that might not be specific enough. And this is the growth of the industry. Our equipment is getting more and more sophisticated and giving us the tools that we need to help our our sponsors with decisions regarding stability of their compound, release of payload. And those bits of data are useful for the decision making that goes into the design of safety studies, design a clinical trials, and we're leveraging the technology and all the past science so that we can keep growing and directing these programs into the future. And that is the exciting part of seeing these small molecule, large molecule science teams being able to come together at biologics, because collectively we know a lot more about how to deal with these new types of molecules because all of us have different tools to bring to the table. And when we talk about certain problems that programs are having now, all of us can collectively decide on some plan and some research that can be done to help clarify, Well, why are we observing this when we should be observing that we have more investigative tools and more people able to address those questions that might not have been as addressable before?

Jim:
Yeah, I completely agree. I think we have a larger pool of scientists now, all with maybe slightly different backgrounds, but good scientists. And I think in general good scientists are problem solvers. So when you look at a situation, it's simply a matter of figuring out what's the right next question to ask and then get the right tool off the shelf to use to ask that question. And luckily, we have great teams, both the San Diego team and all the legacy bio analytics teams. Also, the pull on it is kind of interesting that in the ADC space we're also looking at an extension of what we were discussing earlier about getting the dose right, you know, instead of the blunt force chemotherapy approach, really being precise about getting the least amount of drug necessary to kill a cell to the right place, we don't have to poison the rest of the body with it. And it's a great tool that we're seeing become more and more dominant. Let's talk a little bit about some of the large molecule LCMS uses, and it's something that's new to San Diego, new to overall biomedical optics and part of the expansion there. How do you see those changes in the San Diego site coming and where do you see that taking the San Diego site, too?

David:
That is going to be very exciting because the main tool we use to do large molecule LCMS is going to be our explorers to 40 orbit trap. It is purpose built to be able to handle both small and large molecules, and we are using this technology to look at both modalities. We're going to be able to do LCMS for these OLIGOS antibodies, antibodies connected to OLIGOS antibodies connected to small molecules. So where we're going to be able to mix and match the modalities with this piece of equipment and be able to address a chemical space that was just not addressable before, not at the San Diego site anyways, or booby traps have been around for a while. So I don't want to imply that this disability has not existed before.

Jim:
Yeah, right. Right. No, it's just an expansion of your services there.

David:
Yes. And so we see it as very exciting because at a time when we're getting the support to get this new piece of equipment, the people to run it, we are talking with clients that have a strong interest in using this technology because of getting the equipment and the people to run. It is not easy. So it often is much better to go to someone who is able to help with a specific problem as opposed to invest in that infrastructure yourself. So we are positioning ourselves to be able to help people who do have those specific problems and very excited. It has, as you pointed out, where we're going to be able to address a large number of programs that have very creative mix and matches between large and small molecules. Is stunning to see how we're being able to address targeting of drugs to very specific tissues by using our chemical knowledge and our biochemical knowledge. We're on the cusp of, I guess, the next revolution of drug design, where it's not small molecules is much. Many of those small molecules have gone towards what are called primary care programs. And the space like statins, those are mostly off patent. Now, there's not a lot of commercial incentive to go after those kinds of primary care markets because we have the drugs. We've we've done what we're supposed to do. We have the market exclusivity to the point where it is now off exclusivity, and we're able to use that molecule as its intended purpose. It's a general use medicine now, so we're getting more creative. These other modalities are much more targeted towards very difficult to treat diseases. And we're needing to have this science to do both small and large molecule LCMS to help those programs get the medicine to very targeted proteins or areas of the body that were previously addressable addressable by small molecules. And that, as you alluded to, is, is the real exciting next next step for what we're able to do.

Jim:
So what's the, I don't know, craziest molecule, new molecule, new modality that you've seen?

David:
Oh, we have lots of polymers. Believe it or not, antibodies are not a crazy modality. We can address antibodies very well. But there's are some polymers that are designed to extend the pharmacokinetics of a drug. Basically put a shield around the small molecule that allows it to be released. It's a time release capsule and they're dosing this instead of the small molecule itself. And then as your body digest is very large, complicated polymer, the small molecule gets released a little bit over time and you don't overload your system with this compound which may have toxic effects. Very creative, extremely difficult to look at analytically. So that would probably be the craziest one is mass of polymers connected to a bunch of small molecules.

Jim:
So that's great. So it's exciting to know that. Well, the folks out there in your team especially are really interested in playing with these new crazy molecules, the new modalities continuing to grow and gain experience out there and new branches. And then also all of us getting better at bio analytics as a whole by leveraging each other's scientific experience. I really want to thank you for taking the time to be part of the podcast today. David I'm glad that you sort of raised the Dr. Jay thing right out of the gate, because I thought for sure that would be one of the interesting things. It's always kind of funny. It jumps out at me. There are a lot of Davids in San Diego, so I do love the fact that you came with a built in nickname, but you had it before you even got there, it sounds like.

David:
Yeah, it was just a signature because I. I love art and so I would sign it to paintings and drawings that I did as a kid. It was just ironic. It wasn't because there's a lot of David Johnsons at the time. It just seemed to make a cool signature at the point. And then it was super funny that it ended up becoming a nickname early on at the San Diego site because of the lots of Davids. And when I was in graduate school in Minnesota, there was a small section of the phone book that was dedicated to David Johnson's. So yeah, it is a common name, but it's what I got. I like it.

Jim:
Well, it's it's great. It definitely sticks. And it immediately caught on with the rest of your colleagues here. And it's it goes hand in hand, I think, with the very kind and generous nature you've had of teaching and speaking with all of us. It's been a great collaboration over these past six or nine months to be part of the same team really enjoyed. Speaking with you today. Thanks so much for taking the time and hopefully we'll do this again. We'll follow up maybe somewhere down the road with another podcast on some other areas of interest for you.

David:
Absolutely. Thanks so much for having me. It was an absolute pleasure and I do look forward to the next time.

Jim:
The Molecular Moments podcast sponsored by Bio Analytics, is an ongoing conversation about the various nuances of drug development and bio analysis. In each episode, we sit down with a different industry leader to explore their area of expertise, the industry as a whole, and the mentors who help them become the scientists they are today. It's a podcast for scientists by scientists. Listen and subscribe to molecular moments today on Spotify, Apple Podcasts or wherever you choose to listen. Thanks so much.

Speaker1:
Thanks for listening to the Molecular Moments podcast.

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