Vince Mendenhall Podcast

Ken Mullinix: Thank you for joining us for the first recording of The Exchange, a podcast series focusing on casual conversations with notable life science contributors. I am Ken Mullinix. A little background on me. I’m the US Head of Surgical Services at Biomere. Prior to this, I was a consulting preclinical orthopedic spine surgeon, and before that, I was a clinical orthopedic spine researcher. I met our next guest on an orthopedic knee case, and I’ve since had the privilege of calling him both a mentor and a friend. He’s a man of over 40 years of preclinical research experience. He has an amazing wealth of knowledge, and he’s also humble. So, without further ado, let’s introduce our very first guest on the Exchange, Dr. Vince Mendenhall.

So, this is Doctor Vince Mendenhall, with a wealth of medical research knowledge. I’ll let him take over from here. Vince, why don’t you tell us a little bit about how you got started in the CRO world?

Vince Mendenhall:  Well, I’m a veterinarian, and, of course, like all people who go to vet school, I originally just thought I would have my own practice and all that. But I had always wanted to be in surgery, before I wanted to be a veterinarian. And so, I only really went to vet school because my first wife convinced me that it didn’t take as long to become a vet. So then we could start having kids earlier. And so, I really got into vet school just by accident as well. I almost quit the first week when I got to go put my hand up a cow’s rear. And I said, “You’ve got to be kidding”. But I managed to finish it and actually ended up liking it quite a bit. I’ve always liked animals a lot. I hadn’t really had much experience with them, so it was just an accident. But I’d still wanted to do just surgery. And vet school didn’t teach much surgery, except for spays and neuters, especially back in those days. So, I actually graduated quite young; I was only 23. And so my wife had a job opportunity open up in New Zealand.

So my wife and I went there for three years. It was mostly our general practice. But it was also socialized, so in other words, veterinary medicine for livestock and working dogs in particular was free, paid for by the government. So we got to see a lot of things that American large animal vets don’t get to see. In other words, you got to see cows when they were just starting to get sick rather than just before they were starting to die. And for the working dogs, most of their issues were broken legs. I got to do quite a bit of surgery that I first started, although orthopedics with veterinary orthopedics was not that big at the time. I just had to transfer and got a lot of information from orthopedic physicians or orthopedic friends of mine. All that was in New Zealand. I could do quite complicated fracture repairs in dogs for no cost to the client. And that’s where I really got interested but also found out that I didn’t know what I was doing. I decided I would try to go back to get an internship and become board certified in surgery. Unfortunately, New Zealand did not have a vet school at that time.  I wanted to stay in New Zealand, but I couldn’t unless I got rid of my American citizenship. I didn’t want to do that, so I came back to the States, to Colorado State, and then it turned out I didn’t have good enough grades to get into the internship program. But I did have good enough grades to get into the research program. So, thank goodness I didn’t have good enough grades in vet school, because my colleagues that were getting board certified were spaying dogs and cats, and I ended up doing triple spun electronics, spinal cord repair, and heart-lung transplants. So, I landed where I exactly wanted to be. See how that works? 

Ken:  Yeah. 

Vince:  And it was just like I said , “How did I get into the CRO business?” Well, that’s how I got into experimental surgery. My first job actually was at 3M company. So I’ve been in industry all my life, really, except for a few years.

And there, 3M was starting to develop medical devices in all specialties. And so again, I had great mentors. Engineers would usually design something with the help of a champion physician surgeon. And then we would work on animal models and surgical techniques to put these devices in. And then they would go back to their practice, and I got to do all the surgery. So again, it was a dream come true. There were no financial hindrances. I could build and buy whatever I wanted to. And it was quite amazing for about 18 years. But then, 3M decided to get out of medical devices for a couple of reasons. Mostly Post-it Notes and silicone breast lawsuits. Post-it Notes generated a little over $100 million a year in profit, not just in revenue at the time. Medical, because silicone, interestingly, never went through the biocompatibility testing; it was just grandfathered in. You know, that’s when you used to build total hips in somebody’s garage and then. 

Ken:  You’re implying that after all, the metal-on-metal stuff changed problems. 

Vince:  And so, they were getting $100 million a year in lawsuits for silicone breast leakages. And because there was no background to say that silicone was not the cause of these autoimmune diseases, because it had never been tested. So, they decided to get out of medical devices. They’re probably not going to get a whole lot of lawsuits from not selling Post-it Notes. So I think it greatly decreased the amount of work they were doing. But they did support implants for about five years. Like most companies, for about five years, I traveled the world, actually went to 48 countries, and assisted physicians in putting in implants that I would help develop in animals and assisting them in how to put them into humans. So for about five years, I assisted and sometimes was the primary human surgeon. I could do that outside of the States because it wasn’t quite as litigious there. 

Ken:  Right. 

Vince:  And that only goes on for about five years. Plus, it really got to be bad because I would be gone for periods of like 6 to 8 weeks and then home for a week, and then gone for 6 to 8 weeks. And so I began to just really start to get burned out. And that’s how I got into the CRO industry because 3M said, “Well, I guess we don’t need you anymore”. And so they gave me a very nice severance package. 

And I had started to make friends with Steve Niemi, who was running Genzyme Transgenics. And he, we made contact and I went out there and did some things, but not necessarily surgically related. And they had just amazing laboratories at the time. And Worcester, the company, was trying to transfer from doing just mouse and rat toxicology to contract toxicology. And so they needed an attending veterinarian. And I just happened to be at the right place at the wrong time, because I was not really built to be an attending veterinarian, but they hired me anyway. 

And shortly after, and that was in Worcester, a study came up that needed a lumbar laminectomy. And so everybody was worried about where they were going to find somebody that could do that. And I said, “Well, I can do that”. I’ve done it hundreds of thousands of times. The client was the boss at that time. And he said, “Really?” Well. And so, yeah, we did our first continuous infusion intrathecal study in dogs back in about 1993 or ‘94. And then we were able to turn because I had his support, and, you know, very important supportive management. Then and then, well, I had the rooms there that you have now, but they were not in as good a shape as they are now. We built them and then brought all kinds of instruments and things for studies that we didn’t know we would get or not. But we did, and we turned the place around from just mouse and rat toxicology of about what it was, about 25 or 30 people, to over 107 people and $26 million or more a year in revenue. I look at Mike Lyons CV and he points that out quite well. So that’s how I got into the CRO business heavily. And it mostly started with pharmacokinetics and toxicology. So vascular access ports.

Prior to that time, we were using cutaneous catheters which had all their big issues with infection primarily. We were able to change that over to vascular access ports, which is a huge device, in comparison to the size of the animal. But at that time, the Worcester facility had all species. It was mostly monkeys at the time, but they shifted to doing everything up to cows. In fact, we did our first total hard work on cows there. And lots and lots of sheep and pigs. And we got into the interventional stuff, especially with pigs. And so it really built up great. And then the interventional people came in, and with pig coronary artery stents, that was extremely profitable for a number of years. You know, you could do it quickly, and once you learned how, you could do 10 or 15 pigs a day with coronary stents at $5,000 each. But it was a big pain. I could catheterize coronaries eventually. Sometimes it would take five minutes, and sometimes I’d give up after a few hours. I just stuck with incisional surgery. While all the guys in the front, the interventionists, were getting all the platitudes and everything, I was in the back just maintaining things and taking the X-rays.  

But also mostly, the surgery I was doing still then was colony telemetry and pharmacokinetics, mostly under the direction of Peter Markham, who became the sort of the god of decay. And it built up so much that we had colony animals. At one time we had 30 people devoted only to colony surgery. So we were doing colony surgery every day. Our motto was, “Tell us where you want the tip of the catheter and we’ll put it there”. We did bile ducts, portal veins, hepatic arteries, and a lot of intrathecal. You wanted it wherever you wanted it.

And then the telemetry took off as well. That whole back room on the third floor was nothing but telemetry. We worked with their site quite a bit in developing some of their new stuff. It was so good, in fact, that we moved, we moved, the second location to Southbridge, and then it was mostly nothing but pigs out there. Pigs and occasional sheep and goats, but still mostly those stayed in Worcester. And the company, really, at the time, changed the name to Primerica from Genzyme Transgenics and got to be really noticed. So Charles River acquired it. But not until we built that facility out at Shrewsbury, which, if you look at the design, was completely surgically oriented. The surgery rooms, the two huge rooms, and everything else was in the center of the building, and all the animal stuff radiated out from there. 

Ken:  Yeah, that’s perfect. 

Vince:  Charles River wanted to stick mostly to toxicology work. And so, the surgery business sort of went away.  So did I, because that’s what I did. That was my short little intervention time in university. I created a job at Wake Forest University primarily for personal reasons to move to Winston-Salem, North Carolina. And I ended up mostly helping physician residents with the surgical portion of their NIH grant. But that was not very satisfying, and so I became a full-time consultant back in 2015. 

And I’ve been doing the same thing now. And I used to do that for quite a number of clients, other than just one CRO. So that was a long way to go to answer a question.

Ken:   I know that was great. I mean, in the CRO business, would you recommend this path to a graduating vet if they’re into research?

Vince:  You don’t have near the financial restrictions that you do as a practicing vet. You probably know the suicide rate in veterinarians is right up there with everybody else. In fact, for a while, it was number one. And one of the primary reasons for that is that in vet school, we’re taught how to do all these things that physicians are not. You know, very complicated stuff with CTs and MRIs and transplants and so forth and so on. But it’s only in a few geographical areas that people will pay for their animals’ insurance. Companies for animals usually don’t cover very much beyond the necessities. And so we know how to fix the condition, but all we end up doing is charging $30 for adults. And this is so, and after a while, that gets to you.

In research, you can treat the animals much better, actually, than they’re treated in the clinic, at least for the time that they’re there. But they’re making a contribution, and you make their lives as painless and as happy as they can be, especially the lucky animals when you can get them outside. So, no, it has lots of advantages. The disadvantages, of course, is that the lifespan of the animal is dictated. When you’re in the business for a while, you begin to think that there are financial restrictions, but it’s nothing like practice. So, yeah, I would highly recommend it. What do you know? Yeah, that’s not good, but I remember I’m only stuck in surgery. Lab animal vets, in my opinion, don’t have near the exciting time that I do.  But lab animal vets are able to create the environment that the animals that are under their care are very, very well cared for. And that makes a difference.

Ken:  Yeah, definitely. You and I have obviously done some cases together. It was amazing to rely on your knowledge, your veterinary knowledge, especially when things go south. 

Vince:  You know, we had a couple of cases I can’t really talk about. But it was fun to watch you jump into action. I do a lot of training and teaching now because I’m theoretically supposed to be thinking about retiring. And so I’m teaching a lot of people like I was trying to teach you what you already know what to do. So, yeah, but you got to turn the student loose. And depending upon how management looks at it, when you say the student can certainly do the surgery, you got to remember that what makes you a surgeon is not the technical part of doing the procedure but knowing what to do when something goes wrong. Because something nearly always will start to go wrong. And all that comes about from is from experience. And so if you have an unexpected death rate or complication rate in what you’re doing, the last thing you want to do is to stop doing it. It’s like riding a bike. If you fall off the bike, you’re never going to learn how to ride a bike if you don’t get back on it. And you’re never going to learn how to do surgery unless you keep doing it and trying to evaluate why there were complications or what you did wrong or weren’t expecting, and different animal anatomy and physiology because everyone is a little bit different.

Ken:  That takes me to a good point. I wanted to ask you, what do you feel about sponsors providing some sort of data on, for example, intrathecal catheterization? 

Vince:  I’ve come to find that, you know, it’s difficult to get feedback because as a CRO, we never actually have our hands on the data. 

Ken:  That’s true.

Vince:  You know, coming from research for me, it’s like I want to do the surgery and then I want to see the results. Okay, how did I do? Is this right? 

Ken:  Good. And do you ever see sponsors doing that or saying, “Hey, we recommend that you change this”? Do the sponsors share the data? I mean, especially if you’re doing the whole study in-house and you’re the data collector, will you share the data with the sponsor? 

Vince:  Right. But a lot of the testing, you know, especially in CSF, we ship it out and then it gets tested. 

Ken:  Exactly. And also with the new biologics and genes and all that sort of thing. 

Vince:  Yeah, the sponsor usually does all that evaluation. But yeah, you need to know the results. That’s how it came about with the intrathecal method that we do, actually, because I insisted. You know, before we were just doing lumbar punctures like everybody else did, and you’d have CSF dripping out of your needle, not thinking that the other end of the bevel might be epidural. And so you go ahead and dose, and you’ve got CSF dripping out. So you must be in the right spot, right? Well, it turns out that maybe over half of the test material was epidural or subdural and didn’t come to the critical spot. Whereas in humans, of course, they usually do the lumbar puncture in the L5-S1 or L4-5 space, which is quite deep. It’s on the order of 4 to 5 mm or more deep. And the bevels of the needles are a millimeter or more. Our intrathecal space, especially in monkeys, is less than a millimeter. All you have to do is look at it. And so, it’s very tight. And you don’t have the large cauda equina to help you out. And so sponsors were actually honest with me and said, “You know, these results are all over the map, but some places we really like .” “In some places they’re not. So what are you doing that they should be so different”? And that’s when I started really looking into it. They weren’t really criticizing me. They were telling me that maybe something was a little wrong. And so when you start looking into it, the best way to do it is to know.

 At least, even in sheep, the intrathecal space is really small. And you can get a better stick at the L7-S1 or L6-S1 space in a large animal than you can in a monkey. But certainly not all the time. 

Ken:  Right. 

Vince:  And so that’s how we came up with the current technique of the, you know. Well, then the dirty marks needle was actually first intended for humans for basically the same reason. But it’s because then that’s why it’s so short, and it comes off the side. But even that is way too long for a blind stick in most animals. That’s why we do the small little dinky laminectomy so you can see it and watch the bevel disappear under the intrathecal space. I even stopped doing that.

I’m on to a direct stick. I’ll do the surgical cut down, and I’ll put the catheter in, and then I’ll do a dural sealant, and then I’ll dose and I’ll take the catheter out for that exact reason that I want to make sure we are certainly intrathecal. Okay. And we have fluoroscopy now, too, so that helps. I only put catheters in if I’m going to leave them in, but generally, but that’s a good idea to use the neuro sealant. 

Ken:  At least you’re still exposing us, right? 

Vince:  See, that’s how it has evolved. You know, I first started doing intrathecal work back in the 90s. It was if we wanted to collect CSF many different times, we would go ahead and put in the catheter. If we were going to do just a dose, the conventional wisdom, even in clinical veterinary medicine, is just to do a puncture. But once you look at your results, as you say, and what also makes you a good surgeon too, is to constantly criticize what you’re doing and never get lackadaisical and laissez-faire. And I presented that at ASR, have you ever heard of or listened to or read any of Atul Gawande’s work? 

Ken:  No. 

Vince:  He’s an Indian neurosurgeon that’s quite well known, not as well known as Deepak Chopra. 

Ken:  Yeah, sure. 

Vince:  But Atul Gawande’s famous on Ted Talks, especially. 

Ken:  Yeah.

Vince:  And it just recently had one that compared the profession of surgery to sports, to playing basketball or football. And so you get to be a really good football or basketball player, you know, like LeBron James, I guess. But you teach and teach and teach. And the sports person never in his entire career, even though maybe. Sure. Never goes anywhere without a coach, whereas a surgeon goes to school, learns a bunch of stuff, starts doing stuff, and nobody ever talks to him or her again about it. And so he decided he would have one of his mentors that had since retired come in and watch his surgery. He was now like 20 years into doing their surgery. And he thought it was kind of ridiculous, but maybe it would be fun anyway. And the Ted Talk is amazing. You should look it up on YouTube. I didn’t expect my mentor of 20 years ago to have any comments at all except platitudes and accolades about how wonderful I was. Instead, he had several pages of notes of little things I was doing wrong. You know, like when I was, in certain ways, that I didn’t even notice if the lights were still on the incision or not. 

Ken:  Right. 

Vince:  A headlight still. And other little things. And so he started paying attention and inviting people to criticize his surgery from then on. And he noticed that all of a sudden, when he paid attention to these other people, that his complication rate was decreasing quite a bit. And, of course, you hate to say that in a public forum that a surgeon even has a complication rate. And so that’s what I mean. I just learned from you. So there you go.

Ken:  Yeah, I think that’s where The Checklist Manifesto developed. 

Vince:  Could be, yes. 

Ken:  Yeah, you’re right in getting everyone on board and letting people speak up. I think there’s a big, you know, nobody wants to contradict the surgeon, but many times you have to.

Vince:  I’ve never operated in that environment. I was taught that by my mentor way back when. You’ve got to have a flat hierarchy because the surgeon will learn more from the techs than from another surgeon.

Ken:  Right. 

Vince:  But that’s a bit by case. 

Ken:  Yeah, you know, if you want a successful career, surround yourself with competence. It’s definitely right to be open for suggestions.

Vince:  Yeah, definitely. 

Ken:  So, Vince, what do you think is the next area, the next frontier of preclinical research? One last question, and then I’ll let you go. 

Vince:  Well, you know, I think you’ve noticed, you may have noticed, since you’ve had the job that you have right now. It was finally verbalized to me that there’s a big shift in NIH funding, and therefore, research interest is now away from cardiovascular and under neuro. And that’s why, you know, when I first started to think about retiring, when I stopped doing cardiovascular work, I thought I would end up with half the amount of work or more that I had, and all of a sudden it just doubled. And it turns out that NIH is now funding neuro in preference to cardio. And I think a lot of that is, of course, Alzheimer’s and other disease-related things. But the ranking and the CSF importance that the CSF is playing, that’s why you’re getting so many interesting studies here. As the lymphatic system of the central nervous system, nobody had really realized that until not too long ago. And how important sleep is in that as well, because the CSF only acts as a lymphatic system when you’re asleep. There’s rhythmic contractions. A lot of the research now on neuron diseases, and especially Alzheimer’s, and not so much for the eyes because that’s more the cardiovascular thing, but Parkinson’s, Huntington’s, and all these other things, seems to be due to insufficient attention to things related to the cerebrospinal fluid. And so I think that’s at least our next frontier is the more wonderful things we can do there. And, you know, still nobody knows what the circulation of CSF is. We all assume that’s the ventricles to the tail. 

Ken:  Right? 

Vince: It does not. 

Ken: That’s fascinating. 

Vince:  Yeah. That’s one of the things too.

You dose into the ventricle as an attempt to treat something locally. But then the more cells that are lining the ventricular system are secretory; very little of them are absorptive. The absorptives are down in the arachnoid villi in the intrathecal space, which could be just as more important over the brain than it is over the spinal cord. And thirdly, you do get some absorption of drugs administered in that general area, but it’s more a mass osmosis issue than it is an actual absorptive issue. So, we’re just beginning to learn things like that. So in other words, if you did a lumbar puncture and a CSF tap from the system to magna and then one minute after each other, you would find that most of your drug that you gave lumbar is already equal in the intrathecal space because it’s a sac. That’s what they call it, stands for, from the Greek. Right. So that’s where I’d say most research is going to be directed, at least in the next 5 or 10 years, is more neuro-based than cardiovascular. 

Ken: Right. And all a, b vectors and CRISPR-type gene editing? 

Vince:  Oh yeah. Yeah. From a test article standpoint, yeah. Gene editing. I don’t understand genetics at all, but you know the alphabet soup with names this long. But more power to them. But the more technical assistance can help the molecular biologists and the data sets understand more what’s going on, the better it is. You know, nobody does anything by themselves. It has to be a total team effort. 

Ken:  All right, Vince, thanks for talking with us.