Director, Life Sciences Institute, UBC Professor, Dept of Medical Genetics, UBC
Canada 150 Research Chair in Functional Genetics Professor of Genetics, University of Vienna
Honorary Professor, Chinese Academy of Medical Sciences and Qingdao University Guest Professor, Medical University of Vienna
Adjunct Professor, Dept of Immunology, University of Toronto
Josef Martin Penninger, born in Gurten, Austria, is a world-renowned geneticist and the Canada 150 Research Chair in Functional Genetics. Dr. Penninger is currently the Director of the Life Sciences Institute (LSI) at the University of British Columbia. He studied medicine at the University of Innsbruck in Austria. From 1990 to 1994 he worked as post-doctoral fellow at the Ontario Cancer Institute, thereafter until 2002 at the Department of Immunology and Medical Biophysics at the University of Toronto. As Principal Investigator of Amgen, his independent lab contributed to the development of the antibody Denosumab for bone loss and also found the first connection for RANKL to mammary gland development in pregnancy and breast cancer. In 2002, he moved to Vienna, Austria to start and develop the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), which has become one of the prime research centers in the world. Dr. Penninger envisions to recreate this environment at the LSI to nurture and train the best and brightest young minds of UBC scholars. His major accomplishments include pioneering insights into the molecular basis of osteoporosis and breast cancer, and demonstrating a critical role for ACE2 as the cellular receptor for the SARS Coronavirus infections and linking ACE2 to lung failure in such infections. He has published extensively in several multidisciplinary scientific journals, with over 60 publications in Cell, Nature, and Science. Josef has received numerous awards including the Wittgenstein Prize of the Austrian Federal Government, the Descartes Prize for Research, the Ernst Jung Prize for Medical Excellence, the Innovator Award of the US Department of Defense, and the Austrian Cross of Honor for Science and Art First Class.
Transcription summary.
Professor Josef Penninger was introduced by Peter Scott
Professor Penninger, joined us from his hotel room in Barcelona to talk about his 24-year journey to finding a universal therapy for the coronavirus. He describes himself as a genetic engineer. His work has contributed to understanding how immune cells recognize cancer and he was also one of the first people to genetically modify animals. After achieving great success in Europe, Professor Penninger came to UBC with the goal pushing some of his team’s philosophies and infrastructure to help shape the future. He is passionate about using today’s new technologies to understand nature and human physiology on a fundamental level and using this knowledge to anticipate the future. He applies this through all scales of his work from basic research to starting and financing new companies.
Professor Penninger is involved with many life-changing projects, but the one keeping him in the spotlight right now started back in 1998 when he was just a young researcher in Toronto studying fruit flies. In particular, he was interested in the genes that were responsible for regulating the development of a fruit fly’s heart. This is when he found the Angiotensin-converting enzyme 2 (ACE2) gene. ACE2 is an enzyme that is expressed on the membranes of cells, a critical component of the renon-angiotensis biochemical pathway, an ancient evolutionary system which could be the solution to the pandemic. ACE, a previously discovered gene, makes the peptide Angiotensin II which is critical in regulating blood pressure and inflammation. Too much of the peptide leads to heart failure, kidney disease, and diabetic changes in the kidneys and the liver. Through some fancy molecular footwork, Professor Penninger found that the function of ACE2 was actually to get rid of Angiotensin II. Simply put, ACE and ACE2 in balance lead to healthy blood pressure and heart and kidney function. In 2002, Penninger’s team found that the ACE2 gene was also expressed heavily in the lungs. At the time, this didn’t make much sense. To better understand why this heart-regulating gene was showing up in the lungs, they built an intensive care unit for mice. This care unit would allow them to dissect the molecular mechanisms for lung failure in a stable, standardized, reproducible, and disposable environment. They genetically engineered ACE2 out of the mice which quickly led to leaky blood vessels and ultimately lung failure. Therefore, ACE2 was shown to protect against acute lung injury.
Around this time, the 2003 SARS virus was spreading through the world. Through their research, they found that the SARS virus used ACE2 as an integral entry gate to infect humans. The virus’s spike protein binds with ACE2 which in turn, downregulates ACE2 causing the loss of the cell’s surface and therefore results in injury and inflammation in the lungs, making the SARS virus so deadly.
Earning him the nickname Mr. ACE2, Professor Penninger theorized that supplementing a soluble decoy version, ACE2 should help fight against lung failure. The decoy ACE2 would make it so that the virus could not find the ACE2 receptor. However, since the SARS virus was contained after just ten months, he was told that this research was no longer relevant. However, lung failure is the end stage for many diseases like
anthrax, the Spanish Flu, small pox and of course now, COVID-19. ACE2 is now at the heart of the pandemic. Every vaccine and almost every medicine used to treat COVID-19 is based on the molecular principle of using antibodies to block the virus’ ability to bind to ACE2. Penninger’s team also ran tests on genetically engineered mice to confirm that there was no secondary entryway for the virus.
Penninger and others have mapped ACE2 to the gut, the epithelium of the nose, the brain, and as previously mentioned in the heart and the kidneys. They also found differences in ACE2’s expression between males and females, different ages, and those who are diabetic, smoke, or are obese. This is why COVID-19 is a multi-organ disease which can cause diarrhea, blood clots, long COVID, and increased levels of heart disease. Because the virus affects so many different tissues and organs, the disease needs to be treated early and simply. Penninger’s solution to this is a soluble and inhalable version of the decoy ACE2. Their treatment has been almost 100% effective to all of the existing variants in animals and is now in clinical trials for approval.
Since we started vaccinating during the pandemic, humanity is now in an evolutionary ping pong game with the virus, creating different variants. The coronavirus is now endemic like the flu and so, vaccines, testing, treatments, and public health regulations are all still very important. But with all that we know, it is possible to develop a universal strategy to treat any future variants through ACE2.
Finally, Professor Penninger acknowledges all of the other researchers working on managing this virus, and of course the patients, nurses, and frontline workers seeing the effects of this virus first-hand and who are integral to the fight against the coronavirus.
Qs & As transcription:
Question from Chris Finch: Can the receptors on the cell membrane be blocked safely in view of the organ with receptors?
Answer: Yes, it can, because mutant animals are totally healthy. So, what we see is, if you don’t have ACE2, the animals are fine. And they also see this in clinical studies, in terms of side effect profiles. However, if there’s a disease, kidney failure, heart failure, diabetes, etc, then it gets worse. And every time we bring back ACE2, it actually gets better. So, beyond COVID, we actually would like to develop this as a therapeutic for chronic diseases like kidney disease and so on.
Question from Michael Jacobson: If ACE2 in the body increases COVID, how does administering ACE2 prevent the virus?
Answer: Because what we administer is a soluble version of ACE2. So, ACE2 sits on the on the surface of the cell, the virus comes, docks on, and this is the signal that allows the virus to get inside the cell. So, we give a soluble version which floats around and basically makes it so the virus can’t find the real receptor. It cannot find the cells to infect in our animal experiments and experiments from many other groups. And of course, the vaccination strategies show that this is working because the vaccine, the antibody is more or less a soluble version of ACE2, blocking infection. So, why would we like to develop ACE2? You know, you could say there are vaccines already. We do this because the virus mutates and can escape this signal recognition. It cannot escape from ACE2 binding.
Question from Bill Hooker: What do you see as the scale of preventative efforts required at the public level? And at what cost globally?
Answer: Oh my god. I mean there are different ways to deal with this. You know, one of my collaborators was actually here in Barcelona. Olivia Biermann from Sweden. The Swedes never imposed a lockdown. So, initially, they had higher death rates, but they never shut down the schools, no restaurant was ever shut down, nothing. And at the end, they got similar numbers of infections as Canada and many other places in the world. So, I think what we learn from this, and also the chance of variants, is one really needs to protect with public health measures the vulnerable population, older people, old age homes, people with comorbidities, with diabetes and obesity, people on the frontlines, doctors, nurses who can be exposed on the frontlines, and maybe leave most of the others alone.
Having said this, even Omicron is not harmless. So there have been many cases in Europe of children in intensive care units because of Omicron. So, this is also about how people communicate. It’s not this harmless virus and that we shouldn’t worry about. I just read a paper on the restrictions of travel. Essentially, all the travel restrictions came too late. So, it’s a tricky question to answer. I am a firm believer of testing. I believe that we should really test everybody, because if you test everybody, and there are cheap ways which are feasible, then we all know. So, if you’re meeting in person, everybody gets tested a day before so we kind of know what’s happening. If you don’t test, we don’t know. I’m also saying this because a friend of mine is actually the head of the Salzburg Music Festival, and last year, they reopened. Each attendee had to provide a negative COVID test in addition to other measures. With the 250,000 people going to the operas and concerts, they only found two cases after which could be allocated to the music festival. So one can take measures to control this. So again, I was actually surprised how BC handled this. They did not do well.
Question from Bill Hooker: Do ACE inhibitors and ARB’s we use for hypertension/CCF have any effects on the ACE2 receptors in Covid-19?
Answer: ARB’s are the blockers of the 81 receptors of angiotensin-2. They bind to a receptor, which then communicates a signal. They actually do. It’s not just binding. ACE2 is an enzyme with a function which we see also in animal experiments. This is important. Therefore, there are some studies which actually show that these inhibitors have beneficial effects. And actually, just yesterday, a paper came out in Nature Genetics showing that variants of ACE2 which allow more or less ACE2 expression in different people, correlates with more or less severe COVID-19. So yes, this isn’t just the entry gate, there’s also an enzyme attached to it with enzymatic functions attached to it.
Question from Tim Sehmer: Are there any risks associated with “flooding” the body with “decoy” ACE2? Didn’t you say that the balance between the number of ACE and ACE2 molecules is important for regulating things like blood pressure?
Answer: Yes, it keeps the balance. But it’s the good guy. So, if anything, actually anticipate beneficial effects. Of course, this needs to be tested carefully in clinical trials that we have already been doing. More than 250 people have received it for longer periods of time. So, we have some experience. We’re not just not just guessing that it’s safe. We have some data, because one can never know this, if you don’t do trials with 1000s of people. Beyond COVID, we would like to develop ACE2 for chronic diseases like chronic kidney failure, because the enzyme function protects these tissues. So, it has this beneficial effect on top of it protecting tissues. This is not just something that we are working on. This is published in literally hundreds of papers, from many, many research groups all over the globe, showing this protective effect.
Question from Douglas Filipenko: Why are there so many asymptomatic SARS-Cov2 infections?
Answer: I have no idea. I think this is a really critical question. Can we predict who might get more sick and who will be asymptomatic? Because this is of course critical for our healthcare system to know which people one has to follow closely and who are the people we should just leave us alone because they’ll never get a serious disease. So that’s a very critical question. Blood group systems come into play. Blood Group O for instance is more protective than the Blood Group A. But there are many, many other factors which correlate. So, one thing we are doing for instance, is we can now test on human nasal organoids, human nasal tissue. What we do is, we take a swab from the nose so, not even a biopsy just a swab, you know like we have been doing for PCR tests or antigen tests, and actually infect the stem cells to get an idea of which people might be less likely to be symptomatic. We can do this with bats too which is important because as we know the virus jumped from bats into humans. Bats live with many Coronaviruses but don’t really get sick. There’s actually an island in northern Germany which is totally off limits doing some of this testing too.