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

Hello, hello, welcome back to the show. My name is Sam and I'm the footnote writer for this episode. And 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.

Yes, the current drugs are doing amazing things, but I think we're equally excited about the pipeline, more to come.

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.

Obviously antibiotics have been one of The great innovations for mankind.

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Okay, welcome to The Tech Optimist, uh, the 3 Breakthroughs Show, where we get together, um, and talk about what we think are the most important, powerful technology breakthroughs of the last week or two. And, uh, I'm Mike Collins. I'm 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.

Hey, Mike. Good to see you.

Good. So I think I get to 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. I think, you know, obviously this is something that affects most Americans directly or indirectly. I think it's something that I think all of us personally worry about affecting our loved ones, ourselves. And, there has been not 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, I think is a whole different conversation.

A lot of money is actually spent having drugs with the not-so-great name.

And, picking the right color so it can imprint during the CBS Nightly news on their core audience, but it's Kesunla, which is dabonumab, I believe. I probably butchered those names, but this seems to be very promising. And, it got recommended pretty broadly, pretty quickly. Clearly, there are some costs associated with it that, again, I think are concerning to all of us. It's $30,000, $35,000 a year, 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 and 84% in 18 months. So, this is obviously one of the things that goes on with the disease is the development of these plaques. And, Objective scales that people were— this was greatly reducing the progression of this disease, the reduction in these plaques is material. In fact, I think there even was some conversation about people being able to go off of this drug. Interesting. So, we shall see. Again, I don't think this is a cure. I don't think this was clearly getting Better results for people that have early-stage symptoms. Again, I think we're talking about, you know, we're talking about brain damage ultimately here. So reversibility is not something I think that's on the near-term horizon, but I think very promising. And again, I do think that there is an emerging pipeline We've talked about some other drugs, GLP-1s, where yes, the current drugs are doing amazing things, but I think we're equally excited about the pipeline. More to come. More to come. And I think there's likely to be an arsenal of treatments for these diseases, for different conditions, different manifestations, different stages. You try one thing, Or, you rotate off of them like we've seen in AIDS treatment, for example. So, yeah, for me, this was big news.

Yeah, it's a big breakthrough and, yeah, super exciting. And, yeah, I think we're going to see this, we are seeing this trend towards more personalized medicine. So, I think there'll be some segment of the population that this is a great step forward for as part of that arsenal that's coming. I know there is a lot in You know, pipelines of large pharma and also biotechs trying to help address this.

I've said it once and I will say it many more times. I am not a doctor. I am not a neurosurgeon. I am not a biomedical engineer. But I am this podcast editor and I do a lot of research for this podcast. So this first footnote of this podcast deserves a bit more context as to what exactly we're talking about here. So right after this, I'm going to sort of talk about the drug that might That Mike mentioned and how it works. But first, I think we all need to be on the same page about Alzheimer's and how it literally affects the brain. So in my research, I found a really awesome video by Seeker on their YouTube channel, which is called What Does Alzheimer's Do to the Human Brain? So I'm gonna provide the video here for you to listen to. So then when we hop into the footnote right after where we talk a little bit more about the drug and how it actually works, It's a bit more clear on you know how it works, and all the terminology is out on the table for everyone to understand. So enjoy this video, and then I will see you right after and get into the specifics on the drug.

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 How to prevent this disease has been a puzzle that has eluded the medical community. Now, we may be closer than ever to solving it.

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

Alzheimer's disease is a progressive condition, typically starting in the part of the brain associated with memory. 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 ages 85 or above have it. And 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.

There are 2 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 which builds up inside of neurons. Both of these proteins are toxic, and ultimately they lead to dysfunction and death of neurons.

As these proteins accumulate and neurons start to die, the brain's immune system kicks into gear.

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.

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.

Although it starts typically in areas that affect our memory, ultimately Eventually it starts affecting areas that control our movements, that control our swallowing and our breathing. And in the terminal stages of this condition, our patients with Alzheimer's disease lose their ability to move and they become bedbound. And at the end, our patients unfortunately succumb to pneumonia, malnutrition, generalized sepsis of the body, and this is all All because of Alzheimer's disease and what it does in the brain.

And while all this sounds dire, decades of studies on patients show that there may be a window of opportunity to prevent the condition advancing before you would see any symptoms.

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, in the brain, or in blood. So biomarkers are quantifiable measures that can help us detect disease or an aspect of the disease. So for example, we can think of glucose levels, blood glucose levels, as being a biomarker for diabetes. We can think about blood pressure measurements as being a biomarker for high blood pressure. In the same vein, we have developed and continue to develop biomarkers for Alzheimer's disease.

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.

Those risk factors that are bad for your heart are generally bad for your brain. So diabetes, hypertension, smoking, and obesity On the flip side, what we recommend to our patients and even the general public is that they stay engaged, both cognitively, physically, and socially.

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

We are also at an amazing time in research and clinical studies. We are able to combine clinical information with very complex genetic and other molecular information. And this helps us try and identify the very complex molecular perturbations that can lead to this condition.

The drug that Mike is talking about is called donanemab with the brand name Kizuna, and it is a monoclonal antibody, which is a type of immunotherapy drug. So how it works, it targets and binds to a protein called an amyloid, which builds up in the brain during the early stages of Alzheimer's disease. By binding to the 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 through an IV about once a month, and 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 confirmed elevated beta amyloid in their brain. So just like Mike had mentioned a little bit earlier, a bit more on effectiveness here. So the clinical trials showed that donanemab slowed the decline in memory and thinking skills by more than 20% compared to placebo. And it also reduced the decline in ability to carry out daily activities by 40%. So overall, a pretty pretty good change. And nearly half of the people taking the drug had no decline in memory and thinking skills after about 1 year. So what makes this new drug so revolutionary? The treatment can be stopped once these amyloid plaques, which Mike briefly talked about earlier, are cleared from the brain. So in trials, almost half of the participants were able to stop taking the drug within a year, which is pretty exciting. This is also super imperative to, you know, the Alzheimer's disease space, um, that this drug represents a significant advancement in the treatment for Alzheimer's, as it is one of the first drugs shown to slow the progression of the disease itself. Now, it's not a cure. We want to keep that very clear on this podcast and about, you know, what Mikey's bringing to the table here. This is not a cure, but it's important to note that this can help sort of Slow the fast and rapid progression of Alzheimer's disease and the damage that it does to the person afflicted with it. More on this right after this short break. Don't go anywhere.

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And we've talked too about this idea of, you know, clearly we all count on the FDA and our regulatory agencies to keep us safe. But, I think there's always a place for the healthy debate about risk-reward in that you're looking at some devastating diseases where people's certain outcome is very, very poor where maybe there may be opportunities to allow some riskier treatments in those kinds of cases. And I think, again, some of the recent court decisions, which we do talk about and we've talked about on this show, perhaps challenging where the regulatory agency has drawn the line. You know, I don't think anybody with common sense is looking to make an argument we don't need the FDA and protect people's safety and drug safety, airline safety. Nobody wants to go crazy with that stuff, but I think it's always good to have a healthy debate so we can get even more of these drugs to people sooner.

Yeah, yeah. No, great.

What's yours?

Okay. So, yeah, I came across an article in the scientific journal Nature and the title was Last Year's Summer Was the Warmest Mm-hmm. So these researchers did a lot of work collecting climate data from many different sources, and they reconstructed temperature trends going back 2,000 years. 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, underscoring, you know, the severity of what we're experiencing with climate change. with climate change. And, I think most people probably have experienced it personally. We had exceptionally high temperatures across North America, Europe. I mean, really most places or many places in the world.

And, Vegas, I think last week set a record at 121 or something. Well,

we'll see what the data comes back for for this summer once it's over. So, Yeah, and the article highlighted what I think we know, but it's important maybe to just put a little more emphasis on it. Heat waves are one of the deadliest natural disasters that we have. Right. Obviously, you've got increased mortality amongst humans, but there's a lot of stress on the ecosystem, reduced harvests of crops, obviously high temperatures, extreme temperatures associated with wildfires. So there's all these negative outcomes associated with temperature. And these wildfires actually release carbon dioxide into the atmosphere, creating further warming. And the scientists highlight in this article atmospheric CO2 levels, which if you look at the data, just continually go up and to the right. We're now well over 400 parts per million, and we've known that this is an issue for a long time, and that curve is not— Yeah. So you're seeing many climate researchers kind of sound the alarm on this, that we're going into uncharted territory. We may hit some of these tipping points that may put us into even worse scenarios than we're in right now. So when you kind of look at the information that's out there, these specialists are saying we need to lower CO2 emissions to get to, to near zero by 2050, and then actually start pulling CO2 out of the atmosphere. So we're removing more CO2 than we emit. Um, that's creating some really interesting trends, and this is the Tech Optimist podcast. Yeah. Um, so we, we invest behind a lot of these trends related to climate change. Um, so I thought I'd just kind of quickly talk about 2 examples of some of the exciting opportunities that we're seeing related to climate change. The first is a really direct one talking about the CO2 in the atmosphere issue. There are technologies that are called direct air capture, or DAC, where companies are actually capturing these carbon dioxide molecules out of the air, and then they're able to put them underground and sequester them permanently. So just one example, we've invested in several, but it's a company called AirMine. Mm-hmm. So they're building this very efficient system to, to remove CO2 from the atmosphere, really with a focus on industrial scale.

Mm-hmm.

And what we really liked about this company was the founding team. So these were 2 veteran engineers from Honeywell and BASF who have just a very practical, scalable engineering approach to get after this. So we're excited about Direct Air Capture. The other big trend that we're seeing is transitioning the power grid to much more renewable sources of energy, solar and wind being big ones. Obviously, those power sources come and go depending on the conditions, time of day. Mm-hmm. So it's created this opportunity for technologies that can efficiently store and distribute energy, produce energy with a low carbon footprint efficiently. So one example there is a company called Mainspring Energy. We backed them, a team out of Stanford that has built this highly efficient— they call it a linear generator. So it allows them to produce onsite electricity as people need it, as solar at night, if you don't have the solar power coming in, you can produce energy efficiently. So just 2 examples of many we've seen that we're excited about to help address this.

Yeah, I mean, I think, you know, just to build on that too, Matt, is, you know, you look at the energy needs of some of the technologies that we're big believers in— AI, for example, we're big believers in distributed ledger blockchain stuff. These things have You know, energy bottlenecks as well. So

that's what we're hearing a lot about in AI after the chip bottlenecks. It's energy is the bottleneck. Energy demands are massive. Yeah.

And so again, as you know, these are opportunities as well, right? So it's like, you know, as we all try to pull carbon out of the system, that's a business opportunity. Energy is an opportunity. Some of this stuff is glamorous and some of it is kind of the blocking and tackling of infrastructure. And again, like you mentioned with that team, how can you scale it? There's one thing to do it in a lab, it's another thing to do it in kind of meaningful numbers at scale.

So, this is all about massive scale. If the technologies can't scale, Yeah, no impact.

Yeah. No, I mean, if you look at how much carbon is being put into the system, you know, you have to think at enormous scale to pull it out. And I think that's— I think that's coming. And again, I think, you know, you mentioned 2. I think we probably have a dozen to 2 dozen investments in that related space because it is— it is going to happen.

We are going to take a quick break and then we will hop into the last footnote for this episode. We'll be right back.

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All right, here we are. So Matt has some really interesting innovations to bring to the table about, you know, sort of helping this global issue of climate change. And I figured that there's got to be a bunch of other innovations out there. Not that the ones that Matt shared weren't amazing, but I'm wondering if there were more. So I found more. And I wanted to share them. So one of the biggest ones, Matt also talked about scale, right? And how a lot of these solutions need to be large scale so that they'll actually, you know, make some headway and make a dent in the insane climate change crisis that we're dealing with right now on this planet. So I found an innovation called solar geoengineering, and it involves reflecting a portion of the sun's energy back into space to cool the planet. So techniques include deploying reflective particles or aerosols in the atmosphere to create a sort of sunshade. There's obviously DAC, which Matt talked about. There also is ocean fertilization. This method involves adding nutrients to the ocean to stimulate the growth of phytoplankton, which can absorb CO2 through photosynthesis. There's also space-based solar power. Uh, this concept involves placing solar panels in space to collect solar energy and transmit it back to Earth via a microwave or laser beams. There's obviously geothermal energy. There's green methanol and biofuels, which we've talked about many times on this podcast. There's advanced geothermal power where startups like Fervo are developing advanced geothermal power generation techniques that harness hot rocks deep underground to produce steam for electricity. That one is pretty cool. There's also some super futuristic options like smart cities, where there's, you know, which utilize technology including AI and smart sensors that are implemented to reduce urban emissions and improve air quality.

Yeah, so my third one, I'm going to go back to healthcare. We've talked a little bit about antibiotics in prior episodes, but again, just a new antibiotic that was just released. Now, one of the issues, again, just to lay the groundwork with the dual edge of technology is obviously antibiotics have been one of the great innovations for mankind. Yeah. And directly have impacted kind of longevity and reduced suffering. Really a miracle, just the whole innovation of antibiotics. One of the unintended negative consequences, as we've learned, is, you know, really kind of— we've talked about resistant strains. Yeah.

Yep.

But we've also, and I don't think we've touched on this, which is the emerging science that it screws up your microbiome, right? And the importance of our gut health to our health period, signaling just associations with our immune system, with autoimmune issues, Yeah. You can go on and on about. And, we, again, are big investors in technologies that are related to the understanding and the improvement of the human gut, if you will, to make it simple. But, one of the things about this new antibiotic, lolamycin, really uses some new technology that has clinicians very excited. This comes out of University of Illinois Urbana, I believe.

Yeah.

And, it's really a next-generation antibiotic has been released. And, one of the things that has people very excited about the mechanism and pathways it uses simplistically are worse for bad bacteria than the good bacteria in your microbiome. Interesting.

Yeah.

So, again, one of the issues potentially related to obesity and autoimmune issues is we are using generously antibiotics with kids from a very early age now. And, One of the things that I know a lot of doctors and people very thoughtful in the space, if they go on an antibiotic, they go on a very rigorous regimen to rebuild their microbiome. And, if we can develop a class of what I'm going to call smart antibiotics that are just not broad-scale but just we can go in and kill what we want to kill and not take out—

Not everything. Yeah, all the beneficial ones.

Take out your whole—

Yeah.

I've heard the microbiome, a healthy one is described as kind of a lush forest with an incredibly diverse environment. And unfortunately, a lot of the antibiotics are like Agent Orange and they just kind of take out everything. Yeah. And so, this is as I've read and have listened to people discuss lolamycin, that this is maybe the first in a new direction that we're going to head with kind of smart antibiotics. So, one that I think is of note and really exciting to the positive.

Yeah. No, that's a great one.

Well, great. Again, another great week in technology, amazing people doing work. You don't read about it, at the front page of the newspaper, but a cause for celebration. And that, you know, we have our challenges, but, you know, a lot of great science being done, a lot of great people doing really hard work and moving us all forward. So thank you, Matt. We'll do it next time.

Yeah, see ya. Have a great rest of your week.

Excellent. Thank you.

Take care.

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