Gene Hunting with o1-pro: Reasoning about Rare Diseases with ChatGPT Pro Grantee Dr. Catherine Brownstein

**Erik Torenberg** (0:02)
Before we dive into today's episode, I want to tell you about a new show from Turpentine called Modern Relationships. On the season ahead, I sit down with power couples in tech and leading relationship thinkers to explore how ambitious people actually make partnerships work. Whether you're dating in a relationship or just curious how technology is reshaping modern love, I think you'd enjoy this on your feed. Our first episode features founders funds Delian Asparuhov and tech researcher Nadya Asparuhov, who take us through their evolution from dating to marriage to parenthood, with absolutely no filter on the challenges and growth along the way. You can find Modern Relationships wherever you get your podcasts. Now, on to today's episode.

**Catherine Brownstein** (0:37)
Rare diseases are quite common, actually. There's more people with rare diseases in the United States than there are natural blondes. We need to sequence the whole world in order to understand what is actually disease-causing and what is just background variation. Logging in to the Harvard Library, getting that paper, skimming the abstracts is not at all what I want. Then going back and being able to ask for a summary, be like, oh yeah, this sounds good, has changed my life. It's all cutting down on this mundane, time-consuming, really tedious part of the job. And getting back to the fun part, which is gene discovery. There's going to be this whole generation of geneticists that aren't going to know how things were done before all this was available, because it's going to be a huge game changer and time saver.

**Nathan Labenz** (1:33)
Hello, and welcome back to The Cognitive Revolution. Today, I'm speaking with Dr. Catherine Brownstein, MPH PhD and Assistant Professor at Boston Children's Hospital and Harvard Medical School, whose research focuses on identifying the genetic causes of previously unexplained rare and orphan diseases, and who was recently awarded a ChatGPT Pro grant from OpenAI. You might be surprised to learn, as I was, that so-called rare diseases are not necessarily all that rare. Any disease affecting fewer than 1 in 2,000 people, or fewer than 200,000 people in the United States, is classified as a rare disease. And often, families spend painfully frustrating years bouncing around the medical system in search of an accurate diagnosis before ultimately reaching Dr. Brownstein's elite team at Boston Children's. Of course, considering the radical cost reduction that we've seen in genetic sequencing in recent years, which with nearly a 10,000x improvement in affordability is one of the very few cost curves ever to rival that of large language models, there's been an ongoing revolution in this space even before the current AI moment. In 2007, a genome sequence cost upwards of $1 million. In that era, it was used only in the most challenging cases and was often a difference maker. Today, it's just a couple hundred dollars and has become commonplace for individual patients. But that creates new challenges for specialists like Catherine, who now have to comb through a vast and still exponentially growing literature to find candidate diagnoses for their most challenging cases. This new wealth of information, which as you'll hear, could be growing even faster still with improved regulations and incentives, makes information processing capacity relatively scarce and valuable. And you can probably guess where this is going, a great target for the latest generation of reasoning models. This conversation then is above all a window into how frontier large language models are starting to become useful in highly specialized fields. Dr. Brownstein is pioneering the application of AI to rare disease research in real time. She's using AI to triage potentially relevant research, and in some cases to connect the dots between subtle clues. She's working directly with OpenAI to develop use cases and provide feedback. And considering that every case represents a real person with a life-altering or even life-threatening condition, she's constantly working to find the right balance between enthusiasm for AI's capabilities and a healthy skepticism for any specific AI output. As you'll hear, she's still figuring out where AI's can be the most valuable, how best to use them, and how much to trust them.
That such an established expert is bringing what amounts to a beginner's mindset to such high-stakes cases may be surprising to some, but really I don't think it should be. Even the most AI-obsessed folks like me have only managed to log a few thousand hours with large language models, and nearly all of that was with earlier and less powerful models. So for the current frontier, we're all still figuring this out together, and there's currently an unprecedented opportunity for people with deep experience in specific niche domains to become the leaders in applying AI to their particular fields. Importantly, if you are listening to this podcast, this is probably something that you can personally do, even if you're still relatively new to the AI tools themselves. If you're inspired to take on that challenge and think I might be able to help, or if you have any feedback or guest or topic suggestions, please don't hesitate to send me a note. One of the very best parts of doing this podcast is hearing from you, the listeners, and I am pretty consistent about reading and responding to every message I get. Of course, we always love it when listeners share the show with friends online or offline, and we very much appreciate the many reviews we've received on Apple Podcasts and Spotify, as well as the increasingly active comment section on YouTube. For now, I hope you enjoy this conversation, which I hope will become the first in a series of episodes with ChatGPT Pro grant winners, on the application of Frontier AIs to High Stakes Medical Research with Dr. Catherine Brownstein. Catherine Brownstein, MPH, PhD, and Assistant Professor at Boston Children's Hospital and Harvard Medical School. You are specializing in the discovery of new genes for rare and orphan diseases, and you've recently been awarded a ChatGPT Pro grant. Welcome to The Cognitive Revolution.