Invest Like the Best with Patrick O'Shaughnessy

My guest today is Alex Karnal. Alex is the co-founder and managing partner of Braidwell, a life sciences investment firm he built after spending 15 years at Deerfield Management.

The frame we use throughout the episode is the health stack. Alex talks about how most of the diseases that will claim most of our lives are already addressable with medicines that exist today. We work through the five layers of what a defensive health strategy looks like, why GLP-1 medicines represent the first commercial proof that people are ready to be proactive about their health, and why PCSK9 inhibitors may ultimately be the more important drug class even though they get far less attention.

We also get into the science and business of drug discovery itself — why most of the published literature that AI companies are training on cannot be replicated, what it would mean to have a truly agentic scientific lab running 24 hours a day, and why Alex believes we are now on a deterministic curve toward scientific superintelligence in biology.

For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. 

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Become a Colossus member to get our quarterly print magazine and private audio experience, including exclusive profiles and early access to select episodes. Subscribe at ⁠colossus.com/subscribe⁠.

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⁠Ramp’s⁠ mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠⁠ to sign up for free and get a $250 welcome bonus.

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Trusted by thousands of businesses, ⁠Vanta⁠ continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Visit ⁠vanta.com/invest⁠. 

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⁠WorkOS⁠ is a developer platform that enables SaaS companies to quickly add enterprise features to their applications. Visit⁠⁠ ⁠WorkOS.com⁠⁠⁠ to transform your application into an enterprise-ready solution in minutes, not months.

-----

⁠Rogo⁠ is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest.

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⁠Ridgeline⁠ has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgelineapps.com⁠.

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Editing and post-production work for this episode was provided by The Podcast Consultant (⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://thepodcastconsultant.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠).

Timestamps:

(00:00:00) Welcome to Invest Like the Best
(00:02:29) Intro: Alex Karnal
(00:03:15) State of the Union: GLP1s and Life Sciences
(00:07:01) The Health Stack Framework
(00:12:49) Breaking Down the 5 Defensive Layers
(00:21:18) GLP-1: What's Driving the Inflection
(00:28:28) Diet vs. Drugs: Is Food Enough?
(00:31:15) Barriers to Access: Complexity, Cost & Compliance
(00:35:04) PCSK9: The Closest Thing to a Free Lunch
(00:44:10) Alzheimer's & Neurodegenerative Disease
(00:46:59) Cancer: Early Detection & New Treatments
(00:54:49) Body Imaging & Diagnostic Trade-offs
(00:56:31) How Drugs Are Discovered
(01:02:39) AI in Drug Discovery
(01:10:57) The Automated Lab of the Future
(01:13:05) Peptides & Citizen Pharmacology
(01:16:45) Alex's Background
(01:28:25) Braidwell's Investment Approach
(01:30:39) The Kindest Thing

Scott Nolan spent 12 years at Founders Fund looking for the most important problems that no one else was funding. Then he found a problem so critical, and so ignored, that he couldn't find a company to back. So he started one.

General Matter is rebuilding US uranium enrichment. The United States was the world leader in enrichment through the 1980s and then stopped entirely. Today roughly a quarter of US enriched uranium comes from Russia, a ban on those imports takes full effect in 2028, and the advanced reactors everyone is counting on to power the next wave of data centers have no reliable domestic fuel source. Scott believes enrichment is the single bottleneck to a nuclear future, and that the window to solve it is narrow.

The conversation covers how Peter Thiel influenced him, why being in love with an idea is dangerous for investors but required for founders, and what it actually takes to rebuild an industrial capability the country let atrophy for 40 years.

Please enjoy my conversation with Scott Nolan.

For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. 

-----

Become a Colossus member to get our quarterly print magazine and private audio experience, including exclusive profiles and early access to select episodes. Subscribe at ⁠colossus.com/subscribe⁠.

-----

⁠Ramp’s⁠ mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠⁠ to sign up for free and get a $250 welcome bonus.

-----

Trusted by thousands of businesses, ⁠Vanta⁠ continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Visit ⁠vanta.com/invest⁠. 

-----

⁠WorkOS⁠ is a developer platform that enables SaaS companies to quickly add enterprise features to their applications. Visit⁠⁠ ⁠WorkOS.com⁠⁠⁠ to transform your application into an enterprise-ready solution in minutes, not months.

-----

Rogo is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest.

-----

⁠Ridgeline⁠ has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgelineapps.com⁠.

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Editing and post-production work for this episode was provided by The Podcast Consultant (⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://thepodcastconsultant.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠).

Timestamps:

(00:00:00) Welcome to Invest Like The Best

(00:02:45) Guest Intro: Scott Nolan

(00:03:36) SpaceX, Founders Fund & General Matter

(00:08:04) What Scott learned from Peter Thiel

(00:10:05) The "Avoid Trends" Concept

(00:10:55) Finding Important Problems No One Is Working On

(00:17:32) Gut v. Intuition

(00:18:49) Valuation, Competition & Capital Intensity

(00:20:20) Founders Fund Strategy

(00:21:06) The Steeper the Up Round, the Greater the Undervaluation

(00:21:41) Being in Love with the Problem

(00:26:07) Governments, Technology & History

(00:28:54) Lessons from SpaceX and Elon

(00:29:42) Vertical Integration

(00:33:07) The Role of Energy in Civilization

(00:37:36) State & Direction of US Energy

(00:38:58) Why Nuclear?

(00:42:20) Taxonomy of Advanced Reactors

(00:45:33) The BYOE Concept

(00:46:50) What Could Make Advanced Reactors Fail?

(00:48:04) General Matter: Product, Business & Company

(00:50:12) Enrichment & Weapons-Grade Uranium

(00:56:45) North Star Metric

(01:01:05) Building a Great Enduring Company

(01:04:01) How Scott Runs the Company

(01:06:11) Overcoming Irrational Fears About Nuclear

(01:08:25) Why Aren't There More Founders Funds?

(01:10:03) Operating vs. Investing

(01:11:56) Kindest Thing

My guest today is Alan Waxman, co-founder and CEO of Sixth Street, a $130B global investment firm.

Private credit is one of the most discussed topics in markets right now, and there is a lot to make sense of. The current discourse is almost entirely focused on symptoms. Alan Waxman has spent the time diagnosing the root cause.

Alan thinks about the financial system the way a historian would, studying the incentives, guardrails, and market structure that determine how things play out.

In this conversation, he traces the evolution of American finance from the 1929 crash through Glass-Steagall, the GFC, and Basel III to explain how we arrived at what he calls the factory model, the industrialization of liability-gathering and asset deployment that he believes is the root cause of everything happening in private markets today.

This is my second conversation with Alan, our first one is one of my favorites from last year. 

For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. 

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This episode is brought to you by⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠Ramp⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠. Ramp’s mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠ to sign up for free and get a $250 welcome bonus.

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This episode is brought to you by⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Vanta. Trusted by thousands of businesses, Vanta continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Visit vanta.com/invest. 

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This episode is brought to you by ⁠WorkOS⁠. WorkOS is a developer platform that enables SaaS companies to quickly add enterprise features to their applications. Visit ⁠WorkOS.com⁠ to transform your application into an enterprise-ready solution in minutes, not months.

-----

Rogo is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest.

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This episode is brought to you by⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Ridgeline⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠. Ridgeline has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgelineapps.com.

-----

Editing and post-production work for this episode was provided by The Podcast Consultant (⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://thepodcastconsultant.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠).

Timestamps

(00:00:00) Welcome to Invest Like The Best

(00:02:43) Intro: Alan Waxman

(00:04:35) Financial System Guardrails & Incentives

(00:05:56) System 1: Pre-1933 to 1999

(00:07:39) Glass-Steagall Legislation

(00:10:46) Deregulation & Rise of System 2

(00:12:27) Leverage, GFC, and System 2's Collapse

(00:14:25) Basel III, Dodd-Frank, and System 3

(00:15:32) Why System 3 Could Be the Best Ever

(00:19:04) Behavioral Shifts Starting in 2018

(00:19:52) The Factory Model

(00:24:33) Acceleration of Factory Model

(00:28:25) FRE Multiples and GP Incentives

(00:34:59) Wealth Channel & Asset-Liability Mismatches

(00:36:15) Why This Won’t be the Next GFC

(00:45:31) AI, Creative Destruction & Opportunity 

(00:49:35) Alan’s One-Sheet Brain System

(00:55:01) Lessons by Decade: Hui

(00:59:28) Face the Tiger

My guest today is Sergey Levine, a professor at UC Berkeley and co-founder of Physical Intelligence. The company is building robotic foundation models designed to control any embodied system to do any task in any environment.

Sergey argues that solving robotics at full generality is the right path, and that building systems that learn across many robots, environments, and tasks may be the more scalable approach than building narrow specialists. We discuss how these models can perform new tasks without being trained on them directly, and why everyday human actions remain the hardest problems in the field.

He also reflects on how human trust and acceptance may matter as much as technical breakthroughs in determining when robots become part of daily life.

Please enjoy my conversation with Sergey Levine.

For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. 

-----

Become a Colossus member to get our quarterly print magazine and private audio experience, including exclusive profiles and early access to select episodes. Subscribe at ⁠colossus.com/subscribe⁠.

-----

⁠Ramp’s⁠ mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠⁠ to sign up for free and get a $250 welcome bonus.

-----

Trusted by thousands of businesses, ⁠Vanta⁠ continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Visit ⁠vanta.com/invest⁠. 

-----

⁠WorkOS⁠ is a developer platform that enables SaaS companies to quickly add enterprise features to their applications. Visit⁠⁠ ⁠WorkOS.com⁠⁠⁠ to transform your application into an enterprise-ready solution in minutes, not months.

-----

Rogo is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest.

-----

⁠Ridgeline⁠ has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgelineapps.com⁠.

-----

Editing and post-production work for this episode was provided by The Podcast Consultant (⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://thepodcastconsultant.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠).

Timestamps:

(00:00:00) Welcome to Invest Like the Best

(00:02:43) Intro: Sergey Levine

(00:03:29) Why Bet on Generality Over Specialization

(00:07:24) What if PI succeeds?

(00:09:05) Pros and Cons of Humanoid Robotics

(00:11:02) Timeline of Major Milestones in Robotics

(00:15:47) Sergey's Personal Journey

(00:18:22) Making General Intelligence Happen

(00:19:57) Understanding Robot Data Collection

(00:22:12) Most Surprising Discovery at Physical Intelligence

(00:24:48) The Science of Common Sense

(00:25:36) Long-Range Tasks in Robotics

(00:27:24) Why Wouldn’t We Have A Robot in Our Kitchen by 2050

(00:31:21) Other Interesting Approaches

(00:32:38) Cool vs. Useful in Robotics

(00:36:48) Form Factor Innovation

(00:38:22) Physical Intelligence Analogy

(00:39:30) Economic Transformation from Robotics

(00:40:48) Controversies in the Robotics Community

(00:42:16) Arguments Against End-to-End Learning

(00:42:34) Compositional Learning Explained

(00:43:25) Last Tasks Robots will Conquer

(00:44:30) Dark Parts of the Robotics Brain

(00:47:05) What Makes a Great Researcher

(00:50:15) Manufacturing and Scale Challenges

(00:51:17) How Companies Should Prepare for Robotics

(00:53:38) Boston Dynamics' Demos

(00:55:43) Converging Technologies Enabling Robotics

(00:56:47) How to Stay Up To Date in Robotics

(00:59:51) Near Term Objectives

(01:00:49) Confidence Level Among Researchers

(01:03:31) Google's Experimentation Culture

(01:04:24) The Kindest Thing

My guest today is Mitchell Green. Mitchell Green is the co-founder and managing partner of Lead Edge Capital, a growth equity firm that has spent 15 years building one of the most disciplined investment machines in the business. 

Unlike most firms chasing power law outcomes, Lead Edge is designed to deliver consistent returns by talking to thousands of companies a year, applying a rigorous eight-point criteria to filter down to a handful of investments, and leveraging a uniquely constructed LP base of world-class executives and entrepreneurs. 

In this conversation, Mitchell walks through every component of the machine, from how they source and evaluate companies to how they think about selling, building culture, and staying competitive in a world being reshaped by AI.

For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. 

-----

Become a Colossus member to get our quarterly print magazine and private audio experience, including exclusive profiles and early access to select episodes. Subscribe at ⁠colossus.com/subscribe⁠.

-----

⁠Ramp’s⁠ mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠⁠ to sign up for free and get a $250 welcome bonus.

-----

Trusted by thousands of businesses, ⁠Vanta⁠ continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Visit ⁠vanta.com/invest⁠. 

-----

⁠WorkOS⁠ is a developer platform that enables SaaS companies to quickly add enterprise features to their applications. Visit⁠⁠ ⁠WorkOS.com⁠⁠⁠ to transform your application into an enterprise-ready solution in minutes, not months.

-----

Rogo is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest.

-----

⁠Ridgeline⁠ has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgelineapps.com⁠.

-----

Editing and post-production work for this episode was provided by The Podcast Consultant (⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://thepodcastconsultant.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠).

Timestamps:

(00:00:00) Welcome to Invest Like the Best

(00:00:53) Episode Intro: Mitchell Green

(00:02:01) Cold Calling 10,000 Companies

(00:03:54) Building the Lead Edge Machine

(00:06:15) Lead Edge’s LP Profile

(00:09:22) Hitting Doubles and Triples

(00:11:39) Knowing When to Sell

(00:15:08) Lead Edge’s Eight Buying Criteria

(00:18:12) The Opportunity in Enterprise Software

(00:24:54) Using Criteria for Filtering, Not Prediction

(00:27:11) Building Relationships with Entrepreneurs

(00:29:16) Improving the Investment Machine at Scale

(00:31:59) Lead Edge’s Culture

(00:35:08) Mitchell’s Schedule

(00:36:37) The Mount Rushmore of Investment Machines

(00:38:40) The AI Readiness Score

(00:40:50) Overhyped, Frothy Markets

(00:42:16 When AI Will be a Good Opportunity

(00:44:29) Lessons from Competitive Skiing

(00:47:33) Starting a Fund & Keeping Score

(00:49:15) The Kindest Thing