Episode #29: Three Breakthroughs: Exciting News on Alzheimer’s, Warming Globe Problems and Solutions, and Smart Antibiotics

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  Sam:
  Hello, hello. Welcome back to the show. My name is Sam, and I’m the footnote writer for this episode. Today, we’re talking about a treatment for Alzheimer’s, how hot this planet is, and a bad bacteria killer in the form of an antibiotic. Welcome back.

  Mike Collins:
  Yes, the current drugs are doing amazing things, but I think we’re equally excited about the pipeline—more to come.

  Matt Caspari:
  Long story short, what they were able to conclude from all this analysis is that the summer of 2023 was the hottest we’ve ever had.

  Mike Collins:
  Obviously, antibiotics have been one of the great innovations for mankind.

  Sam:
  In a world captivated by criticism, it’s easy to overlook the groundbreaking technologies shaping our future. Let’s shine a light on innovators who are propelling us forward. As the most active venture capital firm in the U.S., we have an exceptional view of tech’s real-world impact. Join us as we explore, celebrate, and contribute to the stories of those creating tomorrow.

  Welcome to the Tech Optimist. As a reminder, the Tech Optimist podcast is for informational purposes only. It’s not personalized advice, and it’s not an offer to buy or sell securities. For additional important details, please see the text description accompanying this episode.

  Mike Collins:
  Okay. Welcome to the Tech Optimist, the three breakthroughs show where we get together and talk about what we think are the most important, powerful technology breakthroughs of the last week or two. I’m Mike Collins, the founder and CEO of Alumni Ventures, and I’m joined by Matt Caspari, one of our managing partners out in our Menlo office. Hello, Matt.

  Matt Caspari:
  Hey, Mike. Good to see you.

  Mike Collins:
  Good. So, I think I will kick it off today. I’ve got a couple of healthcare things that caught my eye, the first being FDA approval of this new Alzheimer’s drug. This is something that affects most Americans directly or indirectly. It’s something we all personally worry about—affecting our loved ones or ourselves.

  There hasn’t been a lot of great news over the last period of time—some dead ends—but this drug, going under the brand name (and who names these drugs is a whole different conversation)…

  Matt Caspari:
  A lot of money is actually spent naming those drugs, with not-so-great results sometimes.

  Mike Collins:
  And picking the right color so it can imprint during the CBS nightly news on their core audience. But it’s Kisunla, which is donanemab, I believe—I probably butchered those names.

  This seems to be very promising, and it got recommended pretty broadly and quickly. Clearly, there are some costs associated with it—$30,000 to $35,000 a year—that are concerning. But the results are compelling.

  With 1,700 participants, it slowed the progression of Alzheimer’s by about 35% over 18 months versus placebo. Importantly, they were doing imaging, and there was an 80% reduction in the amyloid plaques—84% over 18 months.

  This is one of the key disease factors: the development of these plaques. On objective scales, this was greatly reducing the progression of the disease. The reduction in these plaques is material. In fact, there was even some conversation about people being able to go off this drug.

  Matt Caspari:
  Interesting.

  Mike Collins:
  So we shall see.

  Matt Caspari:
  Yeah.

  Mike Collins:
  Again, I don’t think this is a cure. I don’t think this is clearly reversing symptoms. It’s getting better results for people with early-stage symptoms. Ultimately, we’re talking about brain damage here, so reversibility isn’t on the near-term horizon.

  But it’s very promising. And again, I think there’s an emerging pipeline. We’ve talked about other drugs like GLP-1s where, yes, the current drugs are doing amazing things, but we’re equally excited about that pipeline—

  Matt Caspari:
  More to come.

  Mike Collins:
  More to come. And I think there’s likely to be an arsenal of treatments for these diseases—different conditions, different manifestations, different stages. You might try one treatment or rotate off, similar to how AIDS treatments evolved. So, for me, this was big news.

  Matt Caspari:
  Yeah, that’s a big breakthrough and super exciting. I think we’re seeing a trend toward more personalized medicine. There’ll be some segment of the population for which this is a great step forward as part of that arsenal.

  I know large pharma companies and biotechs have a lot in the pipeline trying to address this.

  Sam:
  I’ve said it once, and I’ll say it many more times—I’m not a doctor, I’m not a neurosurgeon, I’m not a biomedical engineer. But I am this podcast’s editor, and I do a lot of research for this podcast.

  So, this first footnote deserves more context about what exactly we’re talking about. Right after this, I’m going to talk more about the drug Mike mentioned and how it works.

  But first, we all need to be on the same page about Alzheimer’s and how it literally affects the brain.

  In my research, I found a really awesome video by Seeker on their YouTube channel called What Does Alzheimer’s Do to the Human Brain? I’m going to provide the video here for you to listen to.

  Then, when we hop into the footnote right after—where we talk more about the drug and how it works—it’ll be clearer because we’ll have all the terminology out on the table for everyone to understand. So, enjoy this video and then I’ll see you right after to get into the specifics on the drug.

  Speaker 4:
  Alzheimer’s disease is the most common cause of dementia in the world. Nearly 50 million people worldwide have it, and every 66 seconds, someone in the United States is diagnosed with it. It’s been called the epidemic of our century, but even after decades of research, finding a way to prevent this disease has been a puzzle that has eluded the medical community. Now, we may be closer than ever to solving it.

  Nilufer Ertekin-Taner:
  I personally have a lot of hope that we will see the first survivors of Alzheimer’s disease in our lifetime. I’m Nilufer Ertekin-Taner. I’m a neurologist and a neuroscientist focused on Alzheimer’s disease and related dementias.

  Speaker 4:
  Alzheimer’s disease is a progressive condition, typically starting in the part of the brain associated with memory. It then spreads, causing trouble with memory, cognitive ability, and eventually loss of bodily functions. It’s a relentlessly progressive condition that leads to death by or with the disease.

  Age is the most common risk factor for Alzheimer’s. In fact, about a third of individuals aged 85 or above have it. While the exact cause of the onset of the disease is not known, what is known is that it is characterized by a buildup of toxic proteins in the brain.

  Nilufer Ertekin-Taner:
  There are two main hallmarks of Alzheimer’s disease in the brain. One of them is amyloid beta, which builds up in plaques outside of neurons, and the other one is tau, which is a fibrillar protein that builds up inside of neurons. Both of these proteins are toxic and ultimately lead to dysfunction and death of neurons.

  Speaker 4:
  As these proteins accumulate and neurons start to die, the brain’s immune system kicks into gear.

  Nilufer Ertekin-Taner:
  The immune cells of the brain, called microglia, try to get rid of these toxic protein substances, and they also try to get rid of the dead neurons.

  Speaker 4:
  Ultimately, this immune response leads to chronic inflammation of the brain. Over a longer period of time, as the disease progresses and neural cell death continues, the affected brain regions begin to shrink, and that’s about when symptoms start to show.

  Nilufer Ertekin-Taner:
  Although it starts typically in areas that affect our memory, ultimately it starts affecting areas that control our movements, swallowing, and breathing. In the terminal stages of this condition, patients with Alzheimer’s disease lose their ability to move, become bedbound, and eventually succumb to pneumonia, malnutrition, or generalized sepsis of the body. This is all because of Alzheimer’s disease and what it does in the brain.

  Speaker 4:
  And while all this sounds dire, decades of studies on patients show that there may be a window of opportunity to prevent the condition from advancing before symptoms would even appear.

  Nilufer Ertekin-Taner:
  We know that 10 or 20 years before the symptoms of Alzheimer’s disease can be observed, there are changes in the brain. We know this from biomarker studies looking at levels of abnormal proteins in the spinal fluid, brain, or blood.

  Biomarkers are quantifiable measures that can help us detect disease or an aspect of the disease. For example, blood glucose levels are a biomarker for diabetes. Blood pressure measurements are a biomarker for high blood pressure. Similarly, we have developed and continue to develop biomarkers for Alzheimer’s disease.

  Speaker 4:
  And while these biomarkers are important to follow the disease’s progression, the research is still ongoing. Right now, knowing a patient’s risk factors can help them make choices to slow the onset of Alzheimer’s.

  Nilufer Ertekin-Taner:
  Those risk factors that are bad for your heart are generally bad for your brain. Diabetes, hypertension, smoking, and obesity are risk factors for Alzheimer’s disease.

  On the flip side, we recommend to our patients and even the general public that they stay engaged cognitively, physically, and socially.

  Speaker 4:
  That can be anything from exercise to maintaining a strong social network. The takeaway seems to be: stay active.

  Nilufer Ertekin-Taner:
  We are also at an amazing time in research and clinical studies. We can now combine clinical information with very complex genetic and other molecular information. This helps us identify the complex molecular perturbations that can lead to this condition.

  Sam:
  The drug that Mike is talking about is called donanemab, with the brand name Kisunla. It is a monoclonal antibody, which is a type of immunotherapy drug.

  How it works: it targets and binds to a protein called amyloid, which builds up in the brain during the early stages of Alzheimer’s disease. By binding to amyloid, donanemab helps the body’s immune system recognize and remove these protein buildups, which are thought to be toxic to brain cells.

  Donanemab is given intravenously through a drip about once a month. It is designed for people in the early stages of Alzheimer’s disease, including those with mild cognitive impairment or mild dementia due to Alzheimer’s, who have confirmed elevated beta amyloid in their brain.

  In terms of effectiveness: clinical trials showed that donanemab slowed the decline in memory and thinking skills by more than 20% compared to placebo. It also reduced the decline in the ability to carry out daily activities by 40%—a substantial improvement.

  Nearly half of the people taking the drug had no decline in memory and thinking skills after about one year.

  What makes this drug revolutionary is that treatment can be stopped once amyloid plaques—mentioned earlier by Mike—are cleared from the brain. In trials, almost half of participants were able to stop taking the drug within a year.

  This is significant in the Alzheimer’s treatment space because donanemab represents one of the first drugs shown to slow the progression of the disease itself.

  It’s not a cure—we want to be clear about that—but it’s important to note that this drug can help slow the rapid progression of Alzheimer’s disease and the damage it causes to those affected.

  More on this right after this short break. Don’t go anywhere.

  Ludwig Schulze:
  Hi. Just a brief interruption to introduce you to the Health Tech Fund from Alumni Ventures. Alumni Ventures is one of the most active and best-performing VCs in the U.S., and we have raised over a billion dollars from more than 10,000 individual investors.

  With our Health Tech Fund, you’ll have the opportunity to invest in a portfolio of around 20 health tech startups—from transformative healthcare services to groundbreaking diagnostics. Our founders are paving the way for a healthier future.

  To learn more, visit us at av.vc/funds/healthtech.

  Mike Collins:
  And we’ve talked about this idea that while we all count on the FDA and our regulatory agencies to keep us safe, there’s always a place for a healthy debate about risk and reward.

  When you’re looking at devastating diseases with very poor outcomes, maybe there’s an opportunity to allow some riskier treatments in those cases.

  Some recent court decisions—which we’ve discussed on this show—have challenged where regulatory agencies have drawn the line. I don’t think anyone with common sense argues against the need for FDA oversight, drug safety, or airline safety. Nobody wants chaos there.

  But I do think it’s good to have a healthy debate so we can get even more of these drugs to people sooner.

  Matt Caspari:
  No, great.

  Mike Collins:
  What’s yours?

  Matt Caspari:
  Okay. So I came across an article in the scientific journal Nature titled “Last Year’s Summer Was the Warmest in 2000 Years.”

  Researchers collected climate data from many different sources and reconstructed temperature trends going back 2000 years. Long story short, they concluded that the summer of 2023 was the hottest we’ve ever had.

  This underscores the severity of what we’re experiencing with climate change. I think most people have experienced it personally. We had exceptionally high temperatures across North America, Europe—really, many places around the world.

  Mike Collins:
  In Vegas, I think last week set a record at 121 or something.

  Matt Caspari:
  Well, we’ll see what the data shows for this summer once it’s over.

  The article highlighted what we already know but is worth emphasizing: heat waves are among the deadliest natural disasters.

  They increase human mortality, stress ecosystems, reduce crop harvests, and are associated with wildfires. Wildfires release carbon dioxide into the atmosphere, creating further warming.

  The scientists highlighted atmospheric CO2 levels, which, if you look at the data, just keep climbing. We’re now well over 400 parts per million. We’ve known this is an issue for a long time, and that curve is not bending.

  Matt Caspari:
  So you’re seeing many climate researchers sound the alarm that we’re going into uncharted territory. We may hit some of these tipping points that could put us into even worse scenarios than we’re in right now. When you look at the information out there, these specialists are saying we need to lower CO2 emissions to get to near zero by 2050 and then actually start pulling CO2 out of the atmosphere, removing more CO2 than we emit.

  That’s creating some really interesting trends. And since this is the Tech Optimist podcast, we invest behind many of these trends related to climate change. I thought I’d quickly talk about two examples of exciting opportunities we’re seeing in this space.

  The first is a very direct one addressing CO2 in the atmosphere. There are technologies called direct air capture, or DAC, where companies capture carbon dioxide molecules from the air and permanently sequester them underground.

  One example: we’ve invested in several of these, but a company called Air Mine is building a very efficient system to remove CO2 from the atmosphere, with a focus on industrial-scale applications. What we liked most about this company was the founding team—two veteran engineers from Honeywell and BASF. They bring a very practical, scalable engineering approach to tackling this problem, and we’re excited about the future of direct air capture.

  The second big trend is transitioning the power grid to much more renewable sources of energy—solar and wind being major contributors. These power sources fluctuate depending on conditions and time of day, creating an opportunity for technologies that can efficiently store and distribute energy, producing power with a low carbon footprint.

  One example there is a company called Mainspring Energy. We backed them—a team out of Stanford that has built a highly efficient “linear generator.” It produces onsite electricity as needed, filling gaps when solar isn’t available, such as at night. It’s another example of innovation enabling a cleaner, more reliable grid.

  Mike Collins:
  Yeah. Just to build on that, Matt—you look at the energy needs of technologies we’re big believers in, like AI and distributed ledger blockchain systems. These have massive energy demands and create bottlenecks.

  Matt Caspari:
  That’s exactly what we’re hearing in AI. After chip bottlenecks, energy becomes the bottleneck.

  Mike Collins:
  Right—energy is the bottleneck.

  Matt Caspari:
  And those energy demands are massive.

  Mike Collins:
  Again, these are opportunities. As we try to pull carbon out of the system, that’s a business opportunity. Energy is an opportunity. Some of it is glamorous, but a lot is just blocking and tackling infrastructure. Like you mentioned with that team, can you scale it? It’s one thing to do it in a lab; it’s another to deploy it meaningfully at scale.

  Matt Caspari:
  This is all about massive scale. If the technologies can’t scale, there’s no impact.

   

  Mike Collins:
  Exactly. When you look at how much carbon is going into the system, you have to think in enormous scale to pull it out.

  Matt Caspari:
  Exactly.

  Mike Collins:
  And I think that’s coming. As you said, we have two examples here, but we probably have a dozen or two dozen investments in this related space because it’s going to happen.

   

  Sam:
  We’re going to take a quick break and then hop into the last footnote for this episode. We’ll be right back.

   

  Speaker 7:
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  Sam:
  All right, here we are. Matt shared some really interesting innovations to help address this global climate crisis. I figured there must be many other innovations out there—not that the ones Matt shared weren’t amazing—but I wanted to find more.

  One of the biggest ideas focuses on scale. Matt talked about how these solutions need to operate on a massive scale to actually make a dent in the climate change crisis we face. I found a technology called solar geoengineering, which involves reflecting a portion of the sun’s energy back into space to cool the planet. Techniques include deploying reflective particles or aerosols in the atmosphere to create a sort of sunshade.

  There’s also DAC, which Matt already mentioned. Another method is ocean fertilization, which involves adding nutrients to the ocean to stimulate the growth of phytoplankton that can absorb CO2 through photosynthesis.

  Other futuristic innovations include space-based solar power, where solar panels in space collect energy and transmit it to Earth via microwaves or laser beams.

  We also have geothermal energy, green methanol, and biofuels, which we’ve discussed in past episodes. Advanced geothermal techniques are being developed by startups like Fervo, harnessing hot rocks deep underground to produce steam for electricity.

  Finally, smart cities are emerging—urban areas that use technology, including AI and smart sensors, to reduce emissions and improve air quality.

   

  Mike Collins:
  For my third breakthrough, I’m going back to healthcare. We’ve talked about antibiotics in prior episodes, but a new antibiotic was just released.

  One of the dual edges of technology is that while antibiotics have been one of humanity’s greatest innovations—directly improving longevity and reducing suffering—they also have unintended consequences.

  We’ve talked about resistant strains of bacteria before, but there’s also emerging science showing that antibiotics can disrupt your microbiome. Our gut health plays a huge role in our overall well-being, impacting immune system signaling and even autoimmune issues.

  We’re big investors in technologies that aim to better understand and improve the human gut.

   

  Mike Collins:
  But one of the things about this new antibiotic, Lolo Mycin, is it really uses some new technology that has clinicians very excited. This comes out of the University of Illinois Urbana, I believe, and it’s really a next-generation antibiotic.

  One of the things that has people very excited about the mechanism and pathways it uses—simplistically—are that they’re worse for bad bacteria than the good bacteria in your microbiome.

  Again, one of the issues potentially related to obesity and autoimmune problems is that we are using antibiotics very generously with kids from a very early age now. And one of the things that I know a lot of doctors and thoughtful people in space do is, if they go on an antibiotic, they also go on a very rigorous regimen to rebuild their microbiome.

  If we can develop a class of what I’m going to call smart antibiotics that aren’t broad scale but instead can just go in and kill what we want to kill—

  Matt Caspari:
  Not everything.

  Mike Collins:
  Right—not take out your entire system. I’ve heard a healthy microbiome described as a lush forest with an incredibly diverse environment. Unfortunately, many of today’s antibiotics are like Agent Orange—they just wipe out everything.

  So, as I’ve read and listened to people discuss Lolo Mycin, it sounds like this might be the first step in a new direction toward smart antibiotics. It’s one that I think is really notable and exciting in a positive way.

  Matt Caspari:
  Yeah, no, that’s a great one.

   

  Mike Collins:
  Well, again, another great week in technology. Amazing people doing work that you don’t read about on the front page of the newspaper, but still a cause for celebration.

  We have our challenges, but there’s a lot of great science being done and a lot of great people doing really hard work and moving us all forward. So thank you, Matt. We’ll do it again next week.

  Matt Caspari:
  Yeah. See you. Have a great rest of your week.

  Mike Collins:
  Excellent. Thank you.

  Matt Caspari:
  Take care.

  Sam:
  Thanks again for tuning into the Tech Optimist. If you enjoyed this episode, we’d really appreciate it if you’d give us a rating on whichever podcast app you’re using, and remember to subscribe to keep up with each episode.

  The Tech Optimist welcomes any questions, comments, or segment suggestions. So please email us at [email protected] with any of those, and be sure to visit our website at av.vc.

  As always, keep building.