Logan Thrasher Collins: The Trojan Horse That Could Fix Gene Therapy | Frameshifts Episode #14

On this show, we’ve talked a lot about gene editors. These are little molecular machines derived from or inspired by the Nobel-prize winning CRISPR system that put gene editing on the radar of the general public.Once these editors get into a cell, they can cut out DNA, change the DNA sequence, insert entire copies of genes or delete faulty genes that cause illness. Think of them as tools to cut, paste, backspace and overwrite the code of life.But the primary challenge with these gene editors, besides off-target edits and low-but-steadily-improving editing efficiencies, is that they need to get into the cell to be able to do anything. Getting gene editors into cells is an entire field of biomedical engineering called gene delivery. And in comparison to the rapidly flourishing field of gene editor tech dev, the field of gene delivery is both under-appreciated and relatively stagnant.And that’s a massive problem.Because without effective delivery vectors, gene editors are limited to a very small number of conditions for which our delivery vectors happen to be okay at. Current clinical successes are concentrated in situations where delivery is unusually favorable:* Liver diseases, where lipid nanoparticles can efficiently deliver cargo to hepatocytes after IV injection* Blood disorders and some hematological cancers, where cells can be removed from the patient, genetically modified ex vivo using lentiviruses and then re-injected into the patient (e.g. HSC therapy for sickle cell anemia or CAR-T therapy for leukemia)* Diseases that only require a very small percentage of cells to be edited in order to be functionally cured* A limited number of tissues, such as the retina or CNS where viral vectors can achieve therapeutically meaningful gene transferThat's the ceiling today. But if we crack delivery, the potential of this field is disgustingly profound.Gene Delivery Vector + Gene Editor = Gene TherapyIf humanity can solve both sides of this equation, we can, literally, cure anything. You have a genetic disease? Here’s an injection that gives all of your cells the healthy copy of the corrupted gene you inherited from your parents.You’re prone to cardiovascular disease? Here’s an injection that gives you new human-designed molecular machines that clear out your clogged arteries.You have a family history of cancer? Here’s an injection that replaces your genome maintenance and DNA machinery with engineered supernatural versions that can protect your cells from cancer-causing mutations for at least 1000 years.Worried about keeping up in a world of artificial superintelligence? Here's an injection that carries the morphological instructions for a population of your cortical neurons to rewire themselves for compatibility with high-bandwidth brain-machine interfaces, connecting you directly into Dario or Sam’s frontier models.Now, I know a lot has to go right for humanity to achieve mastery over the code of life and transcend the limits imposed by “fit enough to have offspring” evolutionary biology.So I’ll get my head out of the clouds for a moment.Currently, the most clinically successful delivery vehicle in the emerging field of gene therapy is a family of viral variants that we call Adeno-Associated Viruses, or AAVs.AAVs are DNA viruses that scientists have hijacked to make little viral couriers that carry a working gene into your cells. Within this group are many serotypes and engineered capsid variants, each with tropism for specific organs and tissue types. Significantly oversimplifying: AAV9 can penetrate the brain, AAV8 is strongly liver-tropic and other capsids are tuned for tissues like skeletal muscle or retina.But somewhere between a third and two-thirds of people already have antibodies against AAVs, left over from ordinary childhood infections with the wild versions. If you’re one of them, a gene therapy that could save your life may simply not be available to you, because your immune system will neutralize the courier before it arrives. And even if you’re in the clear, most AAV therapies work exactly once. The first dose teaches your body to recognize the vector, so a second one gets destroyed the moment it touches your immune system. For a whole field built on delivering genes into people, the delivery itself is one of the deepest unsolved problems there is.Logan Thrasher Collins has spent his career on that problem. As a PhD student in biomedical engineering at Washington University in St. Louis, he invented a new gene-delivery modality called vaultAAV, which does something a bit strange: it hides the AAV inside a protein vault. Wow. Incredible.But what the hell is a protein vault?Vaults are odd, barrel-shaped organelles our own cells churn out in huge numbers, and <a target="_blank" h