Infinite Loops – Parmita Mishra: How to Think About Biology (EP.244)

Podcast: Infinite Loops
Host: Jim O'Shaughnessy
Guest: Parmita Mishra (Founder, PreciGenetics)
Date: November 28, 2024

Episode Overview

This episode delves into the complexities of biology, genetics, and epigenetics through the lens of innovation and first-principle thinking. Parmita Mishra, a computational biologist and founder of PreciGenetics, explores how biology is far from a static science, the perils of relying on outdated measurement tools, and why dynamic, non-invasive, and individualized approaches will define the next era of biomedicine. The discussion ranges from foundational definitions to the future of medical technology, regulatory obstacles, the challenges of communicating complex science, and the personal journeys that shape scientific ambition.

Key Discussion Topics & Insights

1. Defining Genetics vs. Epigenetics (03:47–10:49)

• Genetics: Your core DNA sequence, mostly identical in all somatic (body) cells, encoding "recipes" for proteins.
• Epigenetics: "Epi means on top of… you have your genetics and then you have things sitting on top of your genetics, literally as well as metaphorically." (Parmita, 04:29)
  • Concerns how, when, and where genes are expressed—explaining how identical DNA leads to drastically different cell types (e.g., cheek vs. eye cells).
  • Epigenetic markers (like methyl groups) can turn genes on/off, affecting protein production and cell behavior.
  • Epigenetic changes are reversible—potential for targeted therapies.

Notable Quote:
"Every single cell in your body...roughly have the same genes... but your cheek cell is very different from your eye cell. The reason for that is the way in which your genes are expressed."
— Parmita Mishra (05:27)

• Analogy: Genetics is the switchboard; epigenetics is which switches are flipped on or off at any time.
• For laypeople, one's broader environment and life choices can affect gene expression, but traits like intelligence are polygenic and complex—no single "IQ gene."

2. Complexity in Trait Inheritance, CRISPR, and Pop-Science Gaps (10:49–18:48)

• Many sought-after traits (e.g., intelligence, height, male pattern baldness) are polygenic, involving many genes with unknown interactions.
• Sickle cell anemia = single-gene disease (easy to engineer), male pattern baldness = highly polygenic and poorly understood, possibly influenced by epigenetics and environment.
• The media often misrepresents genetic discoveries with oversimplified or sensational headlines.

Notable Quote:
"If there's anything in the world that we should be, or at least capitalism should be trying to solve, it is male pattern baldness. But why is it not solved?...There's no baldness gene. I can say that with near certainty."
— Parmita Mishra (15:37)

3. How to Think About Biology: First Principles & Communication (18:48–27:15)

• First-Principle Thinking: Start from basic definitions—cells, metabolism, information transfer—not from trivia or memorized facts.
• Parmita advocates for learning through foundational frameworks, not rote memorization or clickbait news.
• Physics and computation offer powerful ways to abstract and model biological complexity, citing Schrödinger's "What Is Life?"

"A physicist can do the best job at expressing biology… a biologist is more of a person who is looking at statistics…a physicist is someone who is incredible at looking at something very complex and abstracting away and simplifying it."
— Parmita Mishra (21:14)

• Dangers of clickbait/pop-science headlines: Biology is rarely binary or deterministic, so any overly definitive claim is suspect.
• Tools like LLMs (large language models) can help make dense papers more accessible; helpful educational resources include physicists’ interpretations of biology.

4. Limitations of Current Biological Measurement & the Need for 'Movies' Not 'Snapshots' (27:15–37:35)

• Most of biology relies on "cellular autopsies" (killing the cell)—one-time snapshots, not dynamic views.
• Life is a dynamic process ("the dance is actual life"), and our current methods may miss the true picture.
• Technological progress (e.g., the camera, microscope) often revolutionizes what we see in biology and how we see it.

“We’re looking at cellular autopsies every single day and calling it life science. And it just feels like there’s something fundamental missing there.”
— Parmita Mishra (29:10)

5. PreciGenetics' Vision: Continuous, Non-Invasive Measurement (33:23–42:10)

• Parmita’s company aims to create a "very, very good camera" for biology—a device that, using first principles and machine learning, allows for dynamic, chemical-specific, non-invasive measurement.
• Comparison to continuous glucose monitors—imagine this level of feedback for broader bodily processes.
• Expanding the metaphor: New measurement techniques could catalyze a leap in understanding, just as expansion of the EM spectrum or better microscopes did.

6. Frontiers & Barriers: AI, Regulation, and Data Collection (42:10–51:51)

• AI in Biology: LLMs are powerful because code/information is easily accessible. In biology, measurement and data collection are bottlenecks.
• The Data Problem: "You have to kill the sample to measure it." No continuous or dynamic datasets exist for most biological processes.
• Regulatory Hurdles: FDA and similar bodies focus on safety and efficacy, not on mechanisms of action; approval processes are statistics-based, not biology-based.
• Many of our drugs (SSRIs, Tylenol, minoxidil) act via poorly-understood mechanisms.

"FDA is only interested in efficacy and safety. The problem is that safety and efficacy tell you nothing about mechanisms of action. It's all statistical."
— Parmita Mishra (48:09)

7. Innovation Wish List & Technical Challenges (53:12–57:43)

• The biggest unsolved challenge: non-invasively/dynamically measuring the brain (the skull is a barrier).
• Need for new tools and platforms—“an Illumina equivalent”—for dynamic, non-invasive, universal biological measurement.
• Emphasizes equitable tech: methods must work for all skin tones and types, not just the median sample.

8. Building a Science-Based Startup: Learnings & Mindset (57:43–72:14)

• Parmita's personal journey: Encouraged by Gary Tan, found fulfillment and mission in building PreciGenetics.
• Surprised by how receptive some investors are to science-driven, speculative ideas, while others shy away due to regulatory complexity.
• Advocates for “adventure capital” and learning from every experiment, even if the outcome is not as expected or desired.

"Failure is a ladder. It is the only way that you can climb and see further and see further and see further."
— Jim O'Shaughnessy (65:59)

9. Philosophy, Motivation, and the Value of Obsession (72:14–76:26)

• Disease viewed as an engineering problem; personal family history in medicine shapes Parmita’s drive.
• The quest for answers isn't about a binary succeed/fail, but about pursuing knowledge and "being blinded by your mission."
• Obsession and agility—ability to pivot and learn—are defining traits of successful founders.

10. Personal Journey: Moving from India to the U.S. (80:02–84:50)

• America's unique environment: Open to failure, places ultimate value on mission and building.
• Science and technology act as “great equalizers”—background matters less than contribution and ideas.
• The U.S. “privilege of undistracted creation”: An environment ripe for those with big, audacious goals.

"The most beautiful part about [intellectual fields] is that people forget who they are talking to, who they are themselves, because you're talking about something a little higher." — Parmita Mishra (81:26)

Notable Quotes & Memorable Moments

• On epigenetic free will:
  "The most fascinating part about epigenetics is that first of all it gives this level of free will... you can really control some things, or at least you have some control that you don't see."
  – Parmita Mishra (08:32)

• On facing the unknown:
  "That's what I enjoy and that's what frustrates a lot of people" (on the unknowability, complexity, and open questions in biology).
  – Parmita Mishra (23:49)

• On American culture and innovation:
  "If you fail in America, then that is part of being American or that's part of being in America. And that's a unique thing about America is that as a country it's so open to failure because that's how the greatest stories are written."
  – Parmita Mishra (83:06)

Timestamps by Topic

• Intro & Background: 00:02–03:47
• Genetics vs. Epigenetics: 03:47–10:49
• Trait Complexity & Media Misconceptions: 10:49–18:48
• How to Learn Biology: 18:48–27:15
• Measurement Problems in Biology: 27:15–37:35
• PreciGenetics' Approach: 33:23–42:10
• AI, Data & Regulatory Bottlenecks: 42:10–51:51
• Non-Invasive Innovation Wish List: 53:12–57:43
• Startup Journey: 57:43–72:14
• Philosophy, Obsession, Motivation: 72:14–76:26
• Immigration & American Science Culture: 80:02–84:50
• Closing & 'Empress of the World' Question: 86:16–90:05

Closing: The Empress of the World Advice (86:39–88:51)

Parmita’s two world-changing messages:

1. Self-Belief and Intentionality:
   Connect with your heart, believe your idea can come true, act on it. "Intentionality, even from a logical perspective, is a big thing."

2. Empathy for ‘the Other’ in Conflict:
   In any war, remember the children on the other side of the border.

"The kids did not ever make an aggression towards the other side." — Parmita Mishra (88:45)

Follow Parmita and PreciGenetics

• Twitter: @parmita_mishra
• Company: PreciGenetics (Website in development, updates via Twitter)
• Upcoming: Video from the World Biotech Congress, Singapore

Summary by Infinite Loops Podcast Summarizer – for listeners and the curious alike.