ted talk lecture
Overview
Proteins are the most amazing machines in biology, carrying out essentially all important functions in our bodies.
Functions include digestion of food, muscle contraction, neural signaling, and powering the immune system.
Almost all biological processes happen because of proteins.
Proteins are linear chains built from building blocks called amino acids.
Nature uses an alphabet of 20 amino acids.
In a cell, proteins fold into unique three-dimensional structures, guided by chemical forces between amino acids.
Folding is extremely precise and happens very quickly — the process takes a fraction of a second and yields a characteristic shape for each protein.
The shapes of proteins enable their remarkable functions.
Example: Hemoglobin has a lung-friendly shape that binds oxygen; when it moves to muscle, its shape changes slightly and oxygen is released.
Proteins’ shapes and functions are completely specified by the amino acid sequence.
In diagrams, each letter on top represents an amino acid in the sequence.
From gene to protein: the protein folding problem
Genes in the genome specify the amino acid sequences of proteins.
Each gene encodes the amino acid sequence of a single protein.
The translation from amino acid sequence to structure and function is known as the protein folding problem.
It is a very hard problem because so many different shapes are possible for a given sequence, and predicting which shape will form is complex.
Building on nature, then engineering new proteins
Historically, humans have mostly altered natural proteins with small changes to amino acid sequences instead of creating entirely new ones.
This is akin to early tool-making with sticks and stones; it’s incremental, not revolutionary like a bird’s wings, which came from aerodynamic principles rather than random bird modification.
Engineers studied the principles of aerodynamics to design flying machines, illustrating how foundational science leads to new capabilities.
In protein science, researchers sought fundamental principles of protein folding and encoding those principles in software.
A computer program called Rosetta was developed to capture those principles.
Breakthrough: designing new proteins from scratch on the computer
The field has made a breakthrough: it’s now possible to design completely new proteins from scratch entirely on the computer.
Once a new protein sequence is designed, its amino acid sequence is encoded in a synthetic gene.
A synthetic gene is necessary because the designed protein is new and does not exist in nature.
Advances in understanding protein folding and design, plus cheaper gene synthesis and the growth of computing power (Moore’s Law), enable designing tens of thousands of new proteins with new shapes and functions on a computer and encoding each as a synthetic gene.
After designing, the synthetic genes are inserted into bacteria to produce the brand-new proteins.
The produced proteins are then tested to determine whether they function as designed and whether they’re safe.
This is exciting because nature’s diversity represents only a small fraction of the total space of possible proteins.
Exploring an astronomical design space
Nature uses 20 amino acids; a typical protein is about 100 amino acids long.
The total number of possible sequences for a 100-amino-acid protein is 20^{100} \approx 10^{130}.
This is unimaginably larger than the number of proteins that have existed on Earth, illustrating the vast space now accessible through computational design.
In contrast to natural evolution, which solved problems with existing proteins (e.g., replicating the genome), computational design can proactively create solutions for modern challenges.
Why this matters now: addressing modern challenges faster
We face new challenges today: longer lifespans bring new diseases; climate change and pollution introduce ecological stressors.
If we waited for natural evolution for millions of years, new proteins might emerge to solve these problems, but we don’t have that luxury.
Computational protein design enables creating new proteins to address these challenges today.
The overarching goal is to entrepeneurially “bring biology out of the stone age” through a technological revolution in protein design.
Early successes and applications
Vaccines: designed protein particles can display pathogen proteins (e.g., from RSV) to provoke a stronger immune response, improving vaccine efficacy.
RSV (respiratory syncytial virus): a major cause of infant mortality worldwide; improved vaccine candidates are particularly impactful.
Gluten digestion for celiac disease: new enzymes designed to break down gluten in the stomach.
Cancer immunotherapy: proteins designed to stimulate the immune system to fight cancer.
These advances mark the beginning of the protein design revolution.
Inspiration from the digital revolution: Bell Labs example
The team draws inspiration from the digital revolution, particularly Bell Laboratories, which fostered openness and collaboration.
Bell Labs produced a string of innovations: transistor, laser, satellite communication, and the foundations of the Internet.
The goal is to build the Bell Labs of protein design: an open, collaborative, world-spanning institute to accelerate progress.
The institute seeks talented, diverse scientists from around the world at all career stages to join the effort.
Five grand challenges for the protein design revolution
First challenge: universal flu vaccine
Take proteins from around the world and display them on top of designed protein particles to create a universal flu vaccine.
Objective: one shot of protection that lasts for a lifetime.
Rationale: designable vaccines on the computer can respond to natural epidemics and, importantly, mitigate bioterrorism threats.
Second challenge: expand the amino acid alphabet
Move beyond nature’s 20 amino acids to thousands, enabling new therapeutic candidates for conditions like chronic pain.
Third challenge: advanced delivery vehicles
Create delivery systems that target existing medications precisely where they are needed (e.g., delivering chemotherapy to tumors or gene therapies to the tissue needing repair).
Fourth challenge: smart therapeutics with in-body computation
Design therapeutics that can perform calculations inside the body to distinguish specific immune cell subsets (e.g., targeting a small subset involved in autoimmune disorders while sparing healthy cells).
Fifth challenge: design protein-based materials inspired by natural materials
Draw on materials like silk, abalone shell, and tooth to create new protein-based materials addressing energy and ecological challenges.
How to participate and contribute
The institute invites participation from around the world to join the protein design revolution.
Public involvement options:
Fold It: an online folding and design game that lets people contribute to protein design problems.
Rosetta @ Home: a distributed computing project that people can run on their laptops or Android devices to help with protein design calculations.
Ethical, safety, and societal implications
Advances in design enable rapid vaccine development and new therapeutics, with significant positive potential for public health.
There is also a risk dimension: enabling design of new biological agents or delivery systems could be misused in bioterrorism or harmful applications.
The emphasis on safe testing and rigorous evaluation is essential as capabilities expand.
The broader goal is to “make the world a better place” by aligning protein design with societal needs while maintaining ethical and safety standards.
Closing perspective
The presenter emphasizes excitement about these possibilities and invites others to join the journey.
The work is framed as a continuation of iconic technological revolutions, now translated into the realm of biology and medicine.
Final note: the potential impact spans vaccines, therapies, targeted delivery, smart diagnostics, and novel materials, all enabled by computational design and synthetic biology.