Dr. ELLIOT BOTVINICK PhD
Professor of Biomedical Engineering and Surgery
Beckman Laser Institute
Associate Director of the Edwards Lifesciences Center for Advanced Cardiovascular Technology
UC IRVINE: July 2020
We sat down to talk with Elliot Botvinick PhD, who is super smart, full of interesting ideas and open to collaboration with other scientists. In short, someone who we at TSS define as the “perfect” scientist.
TSS: Can we talk a little about CACTUS?
E: CACTUS is not related to Type 1 diabetes(T1D). It started with conversations I had with an ENT surgeon here at UC Irvine [Dr. Hamid Djalilian]. He explained that half of ear infection diagnoses are wrong. I had an idea that diffuse light could be used for a better diagnosis – it is an area of specialization at the Beckman Laser Institute. I contacted my former PhD student Samir [Shreim] and convinced him to found CACTUS. Nine months later we had clinical data.
We met with so many investors. Those with children responded positively to our invention, they were emotive, they wanted in. But then when we explain how small the market is for pediatrics, investors lose interest. We ended up funding it ourselves to a large extent. This challenge of raising funds for pediatric devices is a major problem and I am going to focus the rest of my career on determining how to monetize devices for children because nobody else will – particularly when the market is small. It is very expensive to get a device FDA cleared, but that quest is part of the “fun” I guess.
TSS: Type 1 diabetes is also a smaller market. The community is filled with really intelligent people.
E: True, even Dexcom is not yet very profitable (May 2020). Commercial glucose sensors are amazing and getting close to their limit in functionality. I think the microneedle array will be the end-all. In particular, I am a big fan of Sumita Pennathur and her technology.
TSS: Agreed, she is amazing.
Can you explain your lactic acid approach?
E: My interest in sensing started in grad school at UCSD. I was taking a physiology course in bioengineering. We were talking about the idea of a closed-loop controller for blood glucose [in the mid 1990s]. I then joined Professor David Gough’s laboratory, he is also the founder of GlySense (implantable CGMs).
David asked me “How come these sensors are failing in the skin?”, which led me down a path of microscopy and away from glucose sensors. However, I never stopped discussing glucose sensing with my dear friend Troy Bremer who I met in graduate school. He has a loved one living with T1D. During our daily commute, for over 5 years, all we talked about was how to make a continuous glucose monitor work under the skin.
One day he asked me: How would you design a cell culture system to measure how much oxygen is being consumed by cells?
I “brain farted”: Well, just put some Hemoglobin [Hb] down and look at oxygen saturation changes. We both looked at each other and were like… that’s it!
We soon after set up a little lab in my garage. We realized that we can use Hb to bring far more oxygen to a reaction as compared to glucose. This is important when using glucose oxidase to measure glucose concentration – as is commonly done. We founded a company called Metronome Health — Troy is running it — to commercialize our CGM.
Several years later my laboratory and the Beckman Laser Institute were visited by the former head of the Army Combat Casualty Care Research Program, Col. Dr. Dallas Hack. He explained that a number of deaths on the battlefield could have been prevented if they could measure blood lactate to improved triage decisions. Soldiers are very fit and can compensate BP and vital signs until they die, even though they are bleeding internally. He asked the room, can you give us a CLM (continuous lactate monitor)? I was sitting in the back of the room with my grad student John Wideling, who is now a Senior Scientist in my laboratory. We told each other, we’re going to do it. We’re going to make this thing! And 9 months later we had it working in rabbits.
Next, my collaborator Jonathan Lakey introduced me to the JDRF. At the time I was helping Jon with materials characterization for islet transplantation. Word got around that I was working on a lactate monitor. I soon met JDRF Scientist Vincent Crabtree who is now at Dexcom. Vincent asked if we can add more analytes onto our lactate monitor? Can you also measure glucose?
I said “probably” and asked why it was important to measure both analytes. Vincent explained that most people with diabetes know exercise makes blood glucose unpredictable hours after stopping. And that there was a need to predict blood sugar during exercise and rest. I felt confident we could make such a dual analyte sensor and to my great fortune the project was jointly funded by JDRF and the Helmsley Charitable Trust. The funded project includes a first in human study.
Soon after our initial conversation, Vincent put me in contact with the world’s experts on exercise and glucose control in type 1 diabetes, David O’Neal (Univ Melbourne) and Michael Riddell (York University, Toronto). David shared some of his data showing a relationship between exercise intensity, lactate and glucose trends, and Michael pointed me to his comprehensive paper on exercise management in T1D (slide shared publicly for stem cell center at UCIrvine). Under the guidance of David and Michael, we devised a 12-subject study at UC Irvine for continuous lactate and glucose sensing with our technology. We will determine if continuous lactate signals in combination with continuous glucose signals can be processed for glucose predictions long after exercise. The study has been put on hold due to the COVID-19 pandemic.
My sensing technology replaces electrodes with optrodes. I’m not a big fan of electrochemical sensing. In my hands it’s fussy. But for me, optics are relatively easy.
Our optical lactate (plus) sensor includes a 6-8 mm long insert, sort of like a dexcom unit. The insert is a thin flexible circuit housing several light emitting diodes. The insert is inserted into the skin by a custom made needle and injection system. Currently we are simultaneously measuring: glucose, lactate and oxygen.
TSS: Are you inspired to do more in T1D research?
E: Yes, one of our projects is with Professor Ali Mohraz who is in the department of Chemical and Biomolecular engineering at UC Irvine. We have a grant together funded by the JDRF and Helmsley Charitable Trust. The aim of our project is to develop an infusion set that allows for blood vessels to grow into the cannula. Commercial infusion sets rely on absorption of the insulin solution by the local tissue vasculature. This fluid must flow through and out of the cannula where it may also generate a “pressurized bubble” that blocks insulin absorption into the capillaries. In our design, this insulin solution is taken up by the vasculature before it can leave the cannula. We also include some special materials developed by Ali to promote vascularization and calm down the foreign body response. Our goal is to extend the infusion set lifespan to 14 days.
I am also collaborating with Professor Gregory Weiss who is in the Department of Chemistry at UC Irvine. He and I are developing a continuous insulin monitor, a project also funded by the JDRF and Helmsley Charitable Trust. The project is super difficult but Greg is brilliant and success is near at hand. My lab aims to combine our glucose and lactate sensing with insulin monitoring onto one device. Further, we are currently inventing technology (and applying for grants) to add sensing of beta hydroxybutyrate, which is the ketone body that is associated with DKA.
TSS: You have a lot of collaborations which is amazing, and we hope it becomes more and more prevalent in the T1D scientific population at large. We have had input that some scientists who are funded or backed by pharma or constrained by academic IP agreements might be reticent to talk freely on our website. Our response is that we want to introduce scientists, how they collaborate from there is their business.
E: It’s a many armed octopus. If you can’t commercialize a technology then you can’t get it to the patients. If you give away the secret sauce, the idea is dead. If there was a non-profit mechanism for making devices for T1D then it might be a safer space. In my lab, we keep trade secrets close but we also share and collaborate extensively.
TSS: You have a lot of very wise input!
E: One last thing. Just to frame what we are doing in my world. I was recently asked “What does it mean to be a scientist?”
I answered: A scientist spends 90% of their time, effort and thoughts trying to prove their ideas WRONG!”
When you come across people promoting ideas as if they are right, but without facts, ask yourself, “How much time did they spend trying to prove themselves wrong?”
TSS: We Love that philosophy! In fact, we provide space on our site where Negative Data can be shared, because Negative Data has a huge place in constructing new hypotheses and looking at questions from a 360 degree view. It could be negative data in some hands and not others. It will be in a forum setting so that people can weigh in and share methodology
Thank you so very much for taking time out of your day to speak with us, and thank you for being a CHAMPION for Type 1 Diabetes research! We can’t wait to see what you will do next!