Genetics, Cellular Mechanisms & Immune Disorders - The Lucas Lab at Yale School of Medicine

Transcript

• 00:06Inborn errors of immunity is an umbrella term we think about
• 00:08for these primarily pediatric immune disorders
• 00:11and the way I like to think about it is these are genetic diseases.
• 00:14If you think about all humans on Earth
• 00:16as being sort of part of a bell curve, right,
• 00:18in terms of your immune responsiveness.
• 00:20We like to study the extremes.
• 00:22So the kids who have really low immune function
• 00:24and therefore get a lot of infections,
• 00:27and also the kids on the other side of the bell curve
• 00:28who have a really high immune response
• 00:30and rather than infection,
• 00:31they suffer from immune-mediated damage to their tissues.
• 00:40So my lab is really excited to learn fundamental immunology
• 00:44and really how the immune system works as a system,
• 00:46starting first with patients
• 00:48and these are primarily pediatric patients who have severe immune diseases.
• 00:52But we test the hypothesis these kids could be sick from a single gene mutation
• 00:56and then we used models to dissect mechanisms and come up with precision therapies.
• 01:04We do genomics.
• 01:05So this is where we sequenced the whole genome
• 01:07to find that sort of needle in the haystack.
• 01:09So if we're right that the hypothesis is true
• 01:12that this kid is sick from a single gene mutation,
• 01:14we can identify that using genomics.
• 01:17And then we also use models.
• 01:19So we'll use Crispr to engineer versions of the human mutation
• 01:22and then can do all kinds of immunology assays.
• 01:26So it allows us to do in vitro work.
• 01:28In addition, we do experiments to understand why
• 01:31this gene mutation could make their immune cells function abnormally
• 01:35and then we also test therapies and things in models
• 01:38that our goal then is to translate back into the patients
• 01:42and, importantly, it's not just the patients with the rare disease.
• 01:45Also, we think that by studying these extremes on the sort of bell curve,
• 01:49we're learning fundamental immunobiology that applies to more common diseases
• 01:53as well, but maybe in less severe form.
• 02:00Precision therapy,
• 02:01understanding the gene mutation,
• 02:03makes you realize what kind of treatment is best for them.
• 02:06So this is where it leads.
• 02:07It leads to precision therapy for rare disease.
• 02:09But in addition, because we're learning fundamental immunology
• 02:13directly from patients, it builds foundational knowledge
• 02:16that allows us to spin off new knowledge in ways one can't predict.
• 02:19So it can lead to, we think, more well-defined foundations
• 02:23about how the human immune system works and how we might manipulate it.
• 02:27It's an amazing time to be in medicine and in science,
• 02:30where we've got so many different potential therapies on the shelves, right?
• 02:35And there are ways we can modulate the immune system in ways that have really, really advanced
• 02:39and it's partly matchmaking, trying to understand
• 02:42why is this person sick so we can choose the right therapy
• 02:45and also innovating around new therapies because as our knowledge expands,
• 02:49we can think about how we could rewire these these circuits.