In this interview, Chris told me about his rich career, the automated patch clamp race, the role of a CCO, the value of an MBA, and his dream for a handheld patch clamp device. The story of Chris is full of interesting facts on the development of the first automated patch clamp systems and I think many patch clampers will find it very informative.

Have a good read.

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So, Chris, in your LinkedIn account I saw that you had a varied and rich professional career as an ion channel scientist, product manager, marketing director, chief commercial officer… I’d really love to hear your story.

Sure. I think, my first exposure to electrophysiology was when I was an undergrad at Stanford University, at Hopkins Marine Station, which is a part of the Biology Department of Stanford and is based in Monterey, California. Beautiful location. I took a 15 credit research course there and each of the professors at Hopkins would show you what they did in their labs. And two outstanding ion channel scientists, Stuart Thompson and William Gilly (“Gilly”) were there as professors. Stuart Thompson is famous (in part) for his K-current publication in Journal of Physiology in 1977, and Gilly together with Clay Armstrong did a lot of work on ion channels in squid. I was fascinated by watching how Stuart and Gilly were measuring conduction velocities in squid giant axons. And I was amazed by how they would turn the dials and knobs to measure everything. I was like: “How did they know what to turn?” Later, as a patch clamper, I realized they were just turning the dials until the recording worked!  So, that was my first experience with electrophysiology and I was hooked.

Later, I started my PhD in Neuroscience in Pancho Bezanilla’s lab at UCLA (he was there at the time). I really fell in love with ion channels when I was taking Pancho’s class on electrophysiology with Julio Vergara. It was a great class, we essentially went through all the original Hodgkin-Huxley papers in detail; we did electronics, we built circuit boards, and it was just fantastic.

So I did a project in Pancho’s lab and in collaboration with Dr. Richard Weiss we studied sodium currents from skeletal muscle fibers in normal and dystrophic (mdx) mice. I did macro patch recordings on the muscle fibers and I also had the opportunity to build my own temperature controller (although I didn’t build the whole patch-clamp rig as many of my advisors did).

At the time, I had a young family, my wife and our son, and we decided that we weren’t so excited about living in smoggy and giant Los Angeles. I wondered how I could finish my PhD with UCLA and be away from Los Angeles. And so, I talked to Pancho and I talked to Stuart Thompson (who I knew from my time at Stanford) and we made an arrangement for me to go to Hopkins to finish my PhD thesis project. It wasn’t easy due to administrative reasons and I couldn’t have done that without Stuart and Pancho’s support. So I went to Hopkins Marine Station and studied voltage-independent calcium currents in neuroblastoma cells. We provided evidence that this was one of the first examples of a store-operated calcium current in a neuronal cell. This was at the time when I_CRAC had been discovered by Richard Lewis and Reinhold Penner and their assertion was that I_CRAC was only in non-excitable cells. But we showed that it also existed in excitable cells. It was different though and it was found to be regulated by cyclic GMP. I really enjoyed working at Hopkins Marine Station and so I stayed there a bit more and did a postdoc with Bill Gilly. With Gilly I worked on potassium channels and we did some projects in collaboration with Clay Armstrong, and also with a good friend of mine, Dr. Mathew Brock, who’s now a lead scientist at MyoKardia. So that was a great time.

I was only in Gilly’s lab for about a year when a new opportunity arose. At the time, there was an emeritus professor at Hopkins named Daniel Mazia. He was a very well-known microbiologist at the institute, and I really enjoyed conversations with him. One thing that he said to me really struck me and I think about it these days with the COVID-19 crisis. He said: “It’s not amazing that people get sick. It’s amazing that people don’t get sick all the time, because of all the microbes and viruses and bacteria.” That was very interesting to me. So, he came up to me and said: “You know, one of my former postdocs is now a professor in Germany and he’s looking for a postdoc. Would you be interested in going there?” Later that day I said to my wife: “What do you think about going to Germany for a postdoc?” And she said: “Let’s go”, and essentially started to pack our bags! I was amazed, like: “Okay, wow, let’s do this!”

When I started thinking about the opportunity I thought: “Well, I would like to study I_CRAC some more.” So, I reached out to Dr. Reinhold Penner, who is a very interesting character. Reinhold was fantastic. I remember the first time seeing him at a conference when I was a grad student. He came to my poster and he was so critical, very direct and blunt. I just thought: “What a terrible experience.” But when I contacted him and asked if he needed a postdoc, he said: “Yeah, absolutely.” So, I got a Humboldt Fellowship and started to work in his lab. He ended up being one of the best mentors I’ve ever had. He was so supportive. I learned that once you’re on Reinhold’s team, you’re going to be successful. I had a great time in Germany as a postdoc. Great experience; loved Germany. We were in Goettingen, essentially the birthplace of patch-clamp, and this was in the department of Prof. Erwin Neher. So I got to spend some time with him and people from his lab. Fantastic experience.

When I was early on in my graduate career, everyone was excited because all the professors were supposed to be retiring. And there were supposed to be many jobs available. Well, they didn’t retire, they stayed around…

CHRIS MATHES

In 1997, Reinhold got an appointment in Hawaii. He offered for me to join him and continue a postdoc in Hawaii, but I decided to apply for junior faculty positions in the US mainland. But the late 90’s happened to be a tough time to apply for a professor position. When I was early on in my graduate career, everyone was excited because all the professors were supposed to be retiring. And there were supposed to be many jobs available. Well, they didn’t retire, they stayed around, and so there was a backlog of postdocs. And I was one of those postdocs…

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As I was looking for a faculty job I noticed an advertisement for Axon Instruments. They were looking for someone to be an Applications Scientist to provide technical support for patch clamp amplifiers. That was kind of interesting, and I did some soul searching and I thought: “Well, you know, I think the world will probably be okay if I don’t do academic research. The world will probably go on.” Actually, it was a tough decision, it was agonizing to leave academia. Maybe it’s not so tough these days as more scientists go into industry, but for me at the time, it wasn’t something that happened very often. And I really wrestled with it. But I talked to some people and I thought: “Well, I could give it a try for a couple of years.” So, I joined Axon Instruments and never looked back.

The founder and CEO of Axon was Dr.Alan Finkel, a very charismatic, very smart engineer and scientist, who started the company in the early 80’s (just after the explosion of patch-clamp electrophysiology). He started by building AxoClamp and Axopatch amplifiers “in his garage” and grew the business quickly. He hired PhD scientists to do technical support and he said: “When you’re helping customers, try to find out what their needs are and try to look for new product opportunities.”

One fateful day we received a call from a scientist named Dr. David Owen from a British company, Channelwork, which was a spinoff of biotech CeNeS. And they had claimed to have developed an automated patch clamp system. Their technology was called the Interface Patch; cells at the air/liquid interface of an unpulled patch pipette were patched with an upside-down patch pipette (and no microscope!). I was very skeptical about this idea at first and when I spoke with David Owen, I said: “Come on, David, there’s no way you can do automated patch clamp. I’ve been patch clamping for several years and it’s hard enough to do it manually.” And he just replied: “Come see for yourself.”

So, together with some excellent Axon engineers, we went out to Cambridge, UK, and saw the automated patch clamp system in action, and we were fairly impressed. But of course, being the confident engineers and scientists at Axon we thought we could do better. So we decided to embark on a planar patch clamp project ourselves. First, we thought that it was important to remove the electrodes, the pipettes. We thought that was kind of a bottleneck for higher throughput patch clamp. And so we stuck to the idea of planar patch clamp. And I’d like to mention that our team of engineers was led by Dr. Yuri Osipchuk, a Ukrainian trained biophysicist, really interesting character and great engineer. And, whenever I talked about our “new” planar patch-clamp idea, Yuri reminded me that the first experiments were done in Ukraine by Kostyuk, Krishtal and Pidoplichko in 1975. So, I cannot fail to mention this here, and I have great respect and admiration for Ukrainian biophysicists.

In the late 90’s, there were several companies that were developing planar patch clamp systems. And it was really exciting. It was like the space race – who could come up with a system first?

CHRIS MATHES

At the time, in the late 90’s, there were several companies that were developing planar patch clamp systems. And it was really exciting. It was like the space race – who could come up with a system first? There was Cytion, Nanion, Flyion, Channelwork, Axon Instruments, Molecular Devices and Sophion. Very exciting times. And at Axon we were also collaborating with a group from AstraZeneca that had developed an automated oocyte clamp system. We came up with an idea for automatically recording from up to 8 oocytes at a time. We actually got the oocyte system, OpusXpress, to market in 2001 and the project was led by Dr. Cathy Smith-Maxwell.

And I think technically it was the world’s first commercially available automated electrophysiology system. It wasn’t patch-clamp, but it was electrophysiology and an important first step. The lead engineer on this project was Richard Lobdill (who also designed the famous Axopatch 200B with it’s cooling headstage for low noise single channel recordings).

Technically, the OpusXpress was the world’s first commercially available automated electrophysiology system.

CHRIS MATHES

At that time we learned a lot about automation. This was something Axon had not done before. Axon was all about amplifiers and no moving parts. So that was all new for us. But finally, one of our engineers, Dr. Nick Byrne, built a prototype, called PatchXpress Jr. It had the robotics, it had everything that was needed to perform measurements but we had to improve our planar electrode. And I must say that the planar electrode was very tricky. We collaborated with Prof. Fred Sigworth (Yale University) on the development of PDMS electrodes for our planar patch clamp system but it happened to be very challenging. IonWorks, by Molecular Devices, was announced at the Society for Biomolecular Screening conference in 2001. This was a conference where everyone was so excited about their new developments: Nanion had a poster where they showed data from planar patch clamp, Axon had the gigaseal recordings from planar electrodes, but Kirk Schroeder and Molecular Devices were showing off their IonWorks. And they were way ahead of everyone. And we felt so much pressure because of it. So we started looking for other companies that had more robust planar technology to put into our PatchXpress system.

The team at Axon had gone to many demos to see planar patch clamp electrodes work in person, but we never experienced a successful demo. Obviously, companies like Nanion and Sophion, they got it to work (and quite well!) but in the early 2000s it wasn’t optimized by any means. And so, when we visited Aviva Bioscience in San Diego, we were amazed when we saw a demo that worked. We set up a partnership with them and integrated their SealChip into the PatchXpress. We quickly put together a prototype, but … Molecular Devices was poised to release their IonWorks machine. I’ll never forget it.

I heard from a friend of mine at a pharma company that Molecular Devices was taking orders for their IonWorks system sight unseen, even before they were commercially available; they cleverly developed a waiting list for purchases of the IonWorks. And I thought: “Wow, we need to do that too.” So we started having people visit Axon for demos and we started to get people lined up for selling the PatchXpress system. And it was such a great time because Molecular Devices was in Sunnyvale, California and Axon Instruments was in Union City, about 30-45 minutes away from each other. So people came from all over the world, and they would visit Molecular Devices for a demo and then they come to visit us. And we had very different company cultures. Molecular Devices was mostly led by people in business suits and ties. They would let people watch their controlled demo in the back room. Very secretive. At Axon, we were very open; we would have espresso in the lab and we would give people an oscilloscope and say: “Check it out.” And it worked out well for us because electrophysiologists liked that culture better. So we were able to secure some sales and by early 2004 we had sold 20 PatchXpress systems.

We did a press release announcing this success, and shortly thereafter Molecular Devices acquired Axon Instruments. I stayed on with Molecular Devices for about six months and then went to Sophion Bioscience to lead the set-up of the US business for them in New Jersey. With Sophion it was so interesting because it was like setting up a business without so much risk (because we had the backing of the parent company in Denmark). I got my MBA from Rutgers at that time and I was there for seven years making the US division a profit center for the parent company.

So, after Sophion, I went to ChanTest and that was my first experience in the drug discovery research world (as opposed to instrumentation). ChanTest, a great ion channel company founded on hERG testing, was actually a customer of mine when I was at Sophion. I had known Buzz Brown, the founder of ChanTest, for many years. There were about 60 people in the company, a lot of good ion channel scientists: Drs. Jim Kramer, Yuri Kuryshev, Glenn Kirsch and more. Great team. And my role at ChanTest was to help them to grow the business so that we could sell it by 2016. But in the end, we were able to grow quickly and sell to Charles River in 2014, for over $50 million. And so, I found myself in Charles River and it’s an excellent company. It’s like a family business with over 10,000 people! The founder, James Foster, is a very down to earth person and a savvy business person . His father was the founder. And I was impressed by how many people in the company have been there for over 30 years. It’s amazing. I’ve never seen such a big company with people that stay that long. Great company and I really enjoyed my time there. I stayed on there for a couple of years and then I joined Icagen, a great ion channel biotech that has been around since the 90s.

After my time at Icagen, in January 2018, I started my consulting business, Candidate Biopharma Advisors. In May 2018 I joined AnaBios as full-time Chief Commercial Officer and I continue working for this amazing company to this day.

Wow. That is a really interesting story and an amazing career. So, you were working as a Chief Commercial Officer at three companies. I’m curious, what’s the typical day of a CCO?

I manage the business development and marketing teams, which are responsible for customer connections and commercial growth. I also manage accounts and relations with some customers, too. I’m responsible for the marketing message and also the sales process. As we’re developing new products, there’s a lot of customer conversations. So I’m involved in those meetings with scientists who want to send us their compounds for testing or partner with us. My scientific background allows me to understand what they’re doing, so I can translate the message to our management and R&D team.

When I was at Axon Instruments, there was a language translation needed between the customers and the engineers developing the devices. The users would say they want everything and the engineers would say that they can only do some things. So I had to negotiate between them, I was kind of a mediator. Now I use my science background to again, really talk to the customers and establish credibility. Scientists really want to talk to a scientist when it comes to specialized scientific experiments. For example, another person on my team at AnaBios is Dr. Richard Kondo, and he’s a PhD scientist with a cardiac physiology background. He’s an excellent business development person because he really understands the science, and he speaks the scientific language and develops strong relationships with the scientists. That’s a very important part of business development in the scientific industry.

You said that while working at Sophion you earned an MBA degree. Was it valuable?

Yes, during my time at Sophion I was fairly new to management, so my boss, Dr. Torsten Freltoft said: “Why don’t you think about some management training?” And I said: “Well, how about an MBA?” And so, they sponsored my MBA at Rutgers University. It was an executive MBA, so I could do that at the same time as working full-time. And that was a great experience and it’s been extremely valuable. I learned a lot about strategy, business development, partnerships, negotiation, accounting principles and the language of finance. So, you know, I don’t consider myself a finance expert by any means, but I know how important it is to get a good CFO for a company! Strategy was one of my favorite classes. We went through many case studies of companies and discussed how they evolved and adapted. And now, in the time of the COVID-19 crisis, we can see how important it is for companies to adapt to the changing market dynamics.

For example, one thing we’ve done at AnaBios is to increase the number of our sponsored webinars. Before the crisis, we generated new opportunities primarily by attending scientific conferences. We were only doing one webinar every quarter, and now we’re doing one or two every month. And the webinars that we do are very much a public service. We get top-notch academic speakers and I usually moderate the session. And it’s a way that we can expand the base of people that know about us, our community.

Tell the truth, provide the data and develop trust with customers.

CHRIS MATHES

But, you know, I think my business development training really started when I was at Axon Instruments, where I was selling PatchXpress systems without knowing I was a salesperson. The idea was just to present the science behind the system and let the customer decide. And it’s a principle I use even today: tell the truth, provide the data and develop trust with customers.

One of your patents is called “Handheld device for electrophysiological analysis“. I’m curious, do you really have a handheld patch clamp device? Why haven’t we heard about it?

Well, the driver of this idea was Nick Byrne and together we formulated the idea in a patent when I was at Sophion. So, the idea came from a commercially available hand-held cell counter and we thought: “Wouldn’t it be nice to have a hand-held patch-clamp device that a molecular biologist can use to get data?  It would be super easy to use, like a pipettor!” We started imagining a small hole and pulling cells up and patching… We had a version of a prototype that didn’t go very far though. And, in the end, Sophion decided to focus on the higher throughput system instead. But it’s still an idea that’s out there and I think it has great potential.

Could you tell me about AnaBios, the company you are working for now? How can AnaBios help ion channel scientists in their research or drug development?

AnaBios is a great company. It’s a human tissue company, but what makes us different is that we do physiology with the tissues and cells from human organs recovered ethically from consented donors. We have a very extensive network of hospitals and transplant centers in the US. Obviously, transplants are the top priority, but if transplant cannot happen for medical or logistical reasons, then we can recover the organs for research to help create new medicines. We work extensively with human hearts, dorsal root ganglia (DRG), lungs and other organs. We can isolate the cells, create cultures and do patch-clamp recordings or calcium imaging with electrical field stimulation, for example.

So this is a great way to study ion channels in the native environment. Let’s say that you’re studying the role of sodium channels in pain. We can develop assays with our DRG platform that would allow you to develop compounds that would target those sodium channels. And our assays can help differentiate the effects of Nav1.7 or Nav1.8 based on TTX resistance, for example. So, we can help ion channel scientists by doing very target focused experiments and very information-rich assays in real, adult primary neurons.

There’s so much interest in human translation these days, and more and more scientists are now using human stem cells in their research. But the problem with stem cells is that they still lack key proteins. No matter how hard scientists have tried, they haven’t been able to exactly replicate the adult phenotype. And not only the phenotype but the complexity. So, for example, in our human DRG cultures, we have approximately 25 different types of neurons expressing different channels and receptors. And there are groups that are developing stem cell neurons. But which one of those neurons do you develop? Are you going to develop a mixture of 25 different types? So, it’s very challenging. Therefore, adult human primary cells have become a really valuable tool at AnaBios. And when we test compounds using human cells, we actually get a sense of the right dosages for clinical trials, too. That’s amazing.

Unlike stem cell cardiomyocytes, for example, which have immature phenotype and beat spontaneously, missing some key ion channels, the adult primary cardiomyocytes have the full deck of ion channels. So, it’s an ideal system for testing cardiac safety or even drug discovery and we’re working with companies all over the world for discovery efforts and cardiac safety. We’re also working with many groups involved in pain research in the pharmaceutical industry and we’ve gained a lot of experience in the pain area ourselves.

So, as I understand, you perform contract research, but do you sell the material?

Yes, we provide the material, which could be flash frozen, formalin fixed or in RNAlater, for subsequent biochemical assays. But AnaBios is primarily a contract research organization (CRO). We test compounds for partners. We work mostly with biotech and pharma companies, but we also do some work for academic labs. We do have some internal programs as well – some pain assets and one atrial fibrillation compound that we in-licensed from Sanofi.

And what about cell cultures? Do you provide cultured cells for patch clamping?

That’s more difficult. Previously AnaBios attempted to ship cultures and plates, but the cells happened to be very fragile. So we decided not to ship cell cultures for the time being. We are looking into ways to be able to ship cultured cells but we are not there yet. There are ways that you can put them in hydrogels, for example, to protect them during shipment. That’s something we’re working on.

As you got a lot of experience in the pain area, I’m curious to know what you think about Nav1.7 analgesic failures.

I wouldn’t count sodium channel blockers out, even Nav1.7. We’re still working on Nav1.7 internally and one of our pain assets is mixed Nav1.7 – Nav1.8 blocker. In fact, we looked at some of the pain molecules that failed in the past and what we realized is that it’s very important to know the therapeutic area. In some cases, companies were just going after the wrong indication and if they had gone after some other indication, some other type of pain, then it might have been successful. And I think that our human models will help us find the right indication for those promising compounds.

Well, that was a very interesting discussion, with you telling me about both science and business. And, honestly, that surprised me, because I was preparing to talk with a 100% commercial person. But during this interview, I discovered that a scientist lives inside of you. So, are you a businessman dealing with science or a scientist doing business?

Oh, I think I’m both. I think of myself as accidentally entering the commercial side. At Axon I was doing sales and I didn’t realize it. Doing sales for me is just promoting science. It happens naturally. So, I would say that I’m a hybrid of a scientist and a business developer.

Patch clampers are all about instant gratification. We sit down and we know if it’s going to work or not in ~ 20 minutes.

CHRIS MATHES

I’m excited to be with AnaBios and it’s been a great career, but I want to tell you that I really enjoyed my time as patch clamper in graduate school and as a postdoc, and I still consider myself a patch clamper, even though I haven’t done experiments in a while. One thing that I like about patch clampers is that we’re very opinionated. I always say you can put a group of 100 patch clampers in a room and everyone will have a different way, their own way to patch-clamp. And they’ll claim that’s the only way to do it! So it’s a really interesting group, very different from molecular biologists, for example, who do long experiments and processes over several weeks. Patch clampers, to me, are all about instant gratification, so to speak. We sit down and we know if it’s going to work or not in ~ 20 minutes.

When I was a grad student, I tried once to do a northern blot for one of my experiments and after one month of work I looked at the blot and it was just meaningless. And I thought: “My gosh, how do they do this?” So, cheers to this very unique group of patch clampers and I commend you for setting up the IonChannelLibrary to bring together these people and to strengthen the ion channel community.

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I’m thankful to Dr. Chris Mathes for taking the time to talk with me and sharing his interesting story and insights.

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Images by Chris Mathes