SPEAKER_01 0:00

Welcome to this deep dive. Today we are looking at a genuinely, well, a really mind-bending article.

SPEAKER_00 0:06

Trevor Burrus, Jr.: Oh, it is absolutely fascinating.

SPEAKER_01 0:08

Yeah. It's by William Ayrd, and it's titled Evolution of Von Willebrand Disease: Observation to Molecule. And normally, you know, when we talk about a medical diagnosis, there's this expectation of precision, like, I don't know, like engineering.

SPEAKER_00 0:23

Trevor Burrus, Jr.: Right, exactly. You want a clear answer.

SPEAKER_01 0:25

Trevor Burrus, Jr.: Yeah. You break your arm, the x-ray shows that jagged white line, and the doctor just points and says, Well, there it is.

SPEAKER_00 0:30

Aaron Powell It creates a sense of comfort, doesn't it? Like this idea that biology is binary. It's either broken or it's functional. We just really crave that clean categorization.

SPEAKER_01 0:39

Aaron Ross Powell We totally do. But then you look at the history of medicine and specifically the history of how we define what a disease even is, and suddenly that x-ray machine is just broken.

SPEAKER_00 0:48

Aaron Powell Yeah, the lines get very blurry.

SPEAKER_01 0:50

Trevor Burrus, Jr. Exactly. We're looking at a diagnostic landscape that is honestly incredibly murky. So our mission today isn't just to give you a biology lesson on a bleeding disorder. We are exploring a historical mystery here.

SPEAKER_00 1:02

Aaron Ross Powell The really profound one, too.

SPEAKER_01 1:04

Aaron Ross Powell Right. This is a story about how the tools we invent fundamentally change the way we understand reality. We are going to see how a disease didn't just become, you know, better understood over the course of a century. It became differently understood.

SPEAKER_00 1:19

Aaron Powell That is such an important distinction.

SPEAKER_01 1:21

Aaron Powell It really is. And to help synthesize this wild medical evolution, I have the absolute perfect guide sitting right across from me.

SPEAKER_00 1:28

Well, thank you. I am so thrilled to dig into this material with you because this story, it forces us to question the very labels we confidently stamp onto patients today. It just completely upends how we think about health and diagnosis.

SPEAKER_01 1:42

Okay, let's unpack this. We have to start at the beginning, right? Like long before anyone was looking at DNA or running complex molecular assays.

SPEAKER_00 1:49

Way before all that.

SPEAKER_01 1:50

Yeah. We are going back to the 1920s to a clinician named Eric Adolf von Willebrand and a young girl named Hiordis.

SPEAKER_00 1:58

Right. So to set the scene a bit, Hjordis lived in the Oland Islands, which is this remote archipelago nestled between Sweden and Finland. And her family was marked by this absolute tragedy that they just couldn't explain. Several of her relatives had these severe, unyielding bleeding symptoms.

SPEAKER_01 2:15

Like life-threatening stuff.

SPEAKER_00 2:16

Oh, entirely. Three of her siblings had actually already died from hemorrhage. And Hiordis herself, I mean, she suffered from constant nosebleeds, bleeding gums, severe bruising from the absolute slightest touch.

SPEAKER_01 2:28

Oh, wow, that is awful.

SPEAKER_00 2:30

It is. And devastatingly, she eventually passed away at just 14 years old from uncontrolled bleeding.

SPEAKER_01 2:37

It's just heartbreaking. But medically speaking, it was also a massive puzzle for Von Willebrand. Because, you know, back then the medical establishment actually knew about bleeding disorders.

SPEAKER_00 2:48

They did, yeah. They knew about classic haemophilia.

SPEAKER_01 2:50

Right. But this tragedy on the All In Islands, it just didn't fit the established script at all. Trevor Burrus, Jr.

SPEAKER_00 2:55

No, it broke every single rule they had. I mean, classic haemophilia provided the dominant template for the medical world at the time.

SPEAKER_01 3:02

And that was a pretty rigid template, right?

SPEAKER_00 3:04

Incredibly rigid. It almost exclusively affected males. It was passed down in a very specific X-link genetic pattern. And the physical symptoms were really distinct. Hemophilia caused deep muscular and joint bleeding. Deep internal bleeding, got it. Exactly. But Jurdis's family presented an entirely different pattern. First of all, the bleeding was heavily affecting women.

SPEAKER_01 3:25

Which already breaks the hemophilia rule.

SPEAKER_00 3:28

Right. And the locations of the bleeds were what we call mucocutaneous.

SPEAKER_01 3:31

Meaning what exactly?

SPEAKER_00 3:32

Meaning the mucous membranes and the skin. So nosebleeds, gums, surface level bruising. Furthermore, the severity varied wildly, even within the same family line.

SPEAKER_01 3:44

Aaron Powell It's like trying to solve a jigsaw puzzle where you suddenly realize the pieces you have uh they belong to a completely different picture than the one printed on the box.

SPEAKER_00 3:52

That's a great way to put it.

SPEAKER_01 3:53

But von Willebrand didn't have the biochemical pieces. He didn't have gene sequencers or advanced hematology labs. So how could he possibly guess what the actual problem was without any modern tools?

SPEAKER_00 4:05

Well, he had to rely entirely on bedside observation and the you know the very blunt instruments of the 1920s. And the logic he applied is nothing short of brilliant.

SPEAKER_01 4:15

What did he do?

SPEAKER_00 4:16

He started by measuring their bleeding time, which literally involved making a small standardized cut on the earlobe or forearm and just using a stopwatch to see how long it took to stop bleeding.

SPEAKER_01 4:26

Just a stopwatch. Wow.

SPEAKER_00 4:28

Yeah. And in these patients, the bleeding time was dangerously prolonged. But here's the catch. Okay. When he looked at their blood under a microscope, their platelet count was completely normal.

SPEAKER_01 4:40

Wait, really?

SPEAKER_00 4:41

Yes. And when he took a vial of their blood to see if it would clot in a glass tube, testing the overall plasma coagulation, it clotted normally. The clot even retracted and solidified exactly the way it was supposed to.

SPEAKER_01 4:54

So the individual building blocks seemed to be there, but the wall still wouldn't hold when it actually mattered in the body.

SPEAKER_00 5:00

That is the perfect way to frame it.

SPEAKER_01 5:01

Yeah.

SPEAKER_00 5:02

Based purely on those rudimentary tests, he deduced that this was a defect in what we call primary hemostasis.

SPEAKER_01 5:08

The body's first responder system, right?

SPEAKER_00 5:10

Exactly. When you get a cut, your blood vessels constrict and platelets rush in to form a temporary plug. Secondary hemostasis is what comes later. The plasma proteins that build a reinforced concrete web of fibrin to like hold the plug in place.

SPEAKER_01 5:25

So he thought the concrete was fine, but the first responders were failing.

SPEAKER_00 5:29

Yes. He guessed there was a disturbance in how the platelets functioned, combined with some physical abnormality in the capillary walls themselves. I mean he didn't know the molecule, no one did. But using just his eyes and a stopwatch, he identified the exact mechanism of the failure.

SPEAKER_01 5:46

That is amazing. He found the shadow of the disease, but he couldn't see the object casting it. And because he couldn't point to a specific tangible molecule, his brilliant observation kind of got sidelined, didn't it?

SPEAKER_00 5:58

It really did. As the decades passed and medicine became totally obsessed with plasma and blood chemistry, this condition got shoved into a really awkward identity crisis.

SPEAKER_01 6:06

Aaron Powell Yeah, I read that by the 1950s the medical establishment had started calling it hereditary pseudohemophilia. Trevor Burrus, Jr.

SPEAKER_00 6:12

Which is just such a terrible name.

SPEAKER_01 6:14

Pseudo. Like it's a fake disease. That word just drips with this assumption that classic hemophilia is the, you know, the real biological event. And this condition on the Olin Islands is just some cheap, confusing imitation. Trevor Burrus, Jr.

SPEAKER_00 6:29

It really reveals a profound bias in medical history. The term named the resemblance, but completely failed to explain the difference. And the difference is where the actual biology lives.

SPEAKER_01 6:38

Right.

SPEAKER_00 6:38

The medical community was stuck in this rigid mindset, constantly asking, is this a playlid problem, a blood vessel problem, or a plasma coagulation problem? Because in their mental models, those were completely separate isolated systems that did not overlap at all.

SPEAKER_01 6:53

Which brings us to a massive paradigm shift in 1957. A researcher named Inga Marie Nilsson goes back and revisits this exact same Olin family, runs some new updated tests, and finds a paradox that just shatters the whole isolated systems model.

SPEAKER_00 7:07

She discovered something deeply confusing. She found that these patients who had a disease that clinically looked entirely like a platelet and blood vessel issue, you know, the primary hemostasis failure, they actually had severely reduced levels of antihemophilic factor in their plasma.

SPEAKER_01 7:25

And that's the plasma factor.

SPEAKER_00 7:26

Yes. That is the exact protein missing in classic hemophilia, which we now call factor eight.

SPEAKER_01 7:32

Wait, I have to push back here. If Von Willebrand was right that this was a primary hemostasis issue, like a problem with the platelets and the vessel wall forming that initial plug, why on earth is a plasma coagulation factor suddenly showing up as the culprit?

SPEAKER_00 7:46

Right. It seems entirely contradictory.

SPEAKER_01 7:48

Yeah. Factor eight builds the reinforced concrete later on. That makes zero sense based on the surface level symptoms like the nosebleeds and skin bruising.

SPEAKER_00 7:56

What's fascinating here is that the disease was forcing doctors to realize that the body systems aren't isolated silos. The missing molecule, which we now call von Willebrand factor or VWF, occupies what the author specifically calls an interface position.

SPEAKER_01 8:10

An interface, meaning it lives between two different worlds.

SPEAKER_00 8:14

Precisely. VWF is one massive molecule that connects two entirely distinct hemostatic systems. On one hand, it acts like a molecular glue.

SPEAKER_01 8:23

Okay, glue.

SPEAKER_00 8:24

Yeah, when a blood vessel is damaged, VWF sticks to the exposed tissue and provides a gripping surface for platelets to adhere to. That explains the primary hemostasis failure.

SPEAKER_01 8:34

Ah. So without the glue, platelets can't stick, resulting in the nosebleeds and the bruising.

SPEAKER_00 8:39

Exactly. But simultaneously, VWF acts as a specialized carrier protein for factor eights in the plasma.

SPEAKER_01 8:45

Carrier protein.

SPEAKER_00 8:46

Yes, because factor eight is incredibly fragile on its own. If it flows freely in the bloodstream, enzymes will destroy it in a matter of hours. So VWF acts as its molecular bodyguard, carrying it around and stabilizing it until it's actually needed.

SPEAKER_01 8:58

Oh wow. So the low factor eight wasn't the root cause of the disease at all. It was just a secondary casualty. Yes. The factor eight was low simply because its transport vehicle, its bodyguard, was missing.

SPEAKER_00 9:09

You've hit on the exact mechanism that stumped them for so long. Once researchers saw that dual role, the clinical paradox just vanished. One molecule was doing two completely different jobs in two different systems.

SPEAKER_01 9:21

Conceptually, that is a beautiful explanation. But you know, to actually prove that in a hospital, to diagnose a patient, doctors needed a way to measure it. They needed a tool to see this invisible glue.

SPEAKER_00 9:32

They absolutely did.

SPEAKER_01 9:33

And the breakthrough tool they used didn't come from some targeted, genius laboratory quest. It came entirely by accident.

SPEAKER_00 9:39

Aaron Powell, it is one of the great accidents in medical history. Fast forward to 1971, a major turning point occurs. First, a researcher named Zimmerman develops an anticerum that could finally identify the VWF antigen.

SPEAKER_01 9:54

Okay, let's translate that for a second. An anticerum and an antigen, is that essentially like um using a molecular bloodhound to sniff out a very specific protein sent in the blood?

SPEAKER_00 10:04

That is a great way to visualize it. An antigen is just a unique protein fingerprint, and the anticerum acts like a lock and key mechanism that binds only to that specific fingerprint.

SPEAKER_01 10:14

Okay, that makes sense.

SPEAKER_00 10:15

So for the first time, scientists could take a sample of blood and actually count how many VWF molecules were floating around. They could measure the absolute quantity of the protein.

SPEAKER_01 10:25

But simply knowing how much protein is in the blood doesn't tell you if that protein is actually doing its job, right?

SPEAKER_00 10:30

Exactly.

SPEAKER_01 10:31

Right? I mean, I could have a driveway full of cars, but that doesn't mean any of them have working engines.

SPEAKER_00 10:35

Which brings us to the real magic. The work by researchers Howard and Frucken with a drug called ristacetin.

SPEAKER_01 10:42

Ristacetin.

SPEAKER_00 10:43

Yes. Now ristacetin was originally developed as an antibiotic, but it was a catastrophic failure in clinical trials.

SPEAKER_01 10:51

Wait, really? An antibiotic?

SPEAKER_00 10:53

Yeah. They had to severely limit its use because it had this highly toxic side effect. It caused the patient's platelets to dangerously clump together in their bloodstream, causing severe complications.

SPEAKER_01 11:04

It's like trying to invent a toaster, but it keeps short circuiting and shooting out a blinding beam of light. So you say, well, it's a terrible toaster, but it's a brilliant flashlight.

SPEAKER_00 11:14

That is exactly what happened.

SPEAKER_01 11:15

They took a drug's flaw and used it as a diagnostic probe. But how did this failed antibiotic actually test the engine of the protein?

SPEAKER_00 11:24

By using it in a controlled test tube environment, they realized that ristocetin induced this clumping by fundamentally altering the electrical charge and shape of the VWF molecule.

SPEAKER_01 11:35

Oh, interesting.

SPEAKER_00 11:36

It basically tricked the VWF into thinking there was a vessel injury, forcing it to unfold and expose its sticky binding sites to the platelets. So suddenly they had a functional assay.

SPEAKER_01 11:46

They could actually see it work.

SPEAKER_00 11:48

Right. They could take a patient's plasma, drop in some ristocetin, and just watch. If the platelets clumped together, it meant the VWF protein was functionally capable of binding. If nothing happened, the engine was broken.

SPEAKER_01 12:00

That is wildly clever. But you know, as with all new tools in medicine, the moment it illuminated the room, it also cast new shadows. It created a massive new gray zone, didn't it?

SPEAKER_00 12:09

It absolutely did. Once they started testing function, the results were chaotic. They found patients where the VWF was present in normal quantities, but it bound way too weakly to the platelets when provoked.

SPEAKER_01 12:20

Okay, so a weak engine.

SPEAKER_00 12:21

Right. Then they found other patients, which we now classify as type 2B VWD, where the protein bound too avidly, acting hyperactive and literally depleting the blood of platelets.

unknown 12:34

Wow.

SPEAKER_00 12:34

They even discovered cases where the VWF protein was totally fine, but the receptor on the platelet itself was structurally broken.

SPEAKER_01 12:42

So ristocetin proved whether the protein was broken, but it completely failed to explain why it was malfunctioning in such wildly contradictory ways. Exactly. To figure that out, they realized they couldn't just look at the total amount of protein anymore. They had to look at its literal shape, which forced the medical world to invent a whole new way of visualizing blood.

SPEAKER_00 13:00

Bringing us right into the 1980s, the multi-commer era. Researchers like Rugery and Zimmermann demonstrated that von Wildebrand factor isn't just a simple uniform little protein floating in the blood.

SPEAKER_01 13:12

What is it then?

SPEAKER_00 13:12

It is a massive, complex adhesive protein built out of what we call multiquimers, essentially differently sized building blocks stacked together in long chains.

SPEAKER_01 13:22

So it's less like a uniform Lego block and more like, I don't know, a massive chain link anchor. Some of the proteins are just a few links long, but others are these massive unspooled chains dragging through the bloodstream.

SPEAKER_00 13:35

Yes, the chain link anchor is a phenomenal analogy because the size of that chain matters immensely.

SPEAKER_01 13:41

Yeah.

SPEAKER_00 13:42

The author explains that those really large, heavy multi-promes are absolutely crucial for catching and holding onto platelets under conditions of high shear stress.

SPEAKER_01 13:52

Let's decode high shear stress for a moment. Are we talking about when blood is rushing really fast through a narrow or damaged vessel, creating a strong current?

SPEAKER_00 14:00

That's exactly it. Imagine trying to stop a boat in a rushing river. A tiny pebble on a string won't do anything. Right. You need a massive, heavy chain to drag against the riverbed, the vessel wall, and catch the platelets flowing by. The Russian blood literally pulls the coiled VWF string tight, exposing all the sticky hooks.

SPEAKER_01 14:18

That makes perfect physical sense.

SPEAKER_00 14:20

So if your body fails to manufacture the largest chains, you cannot form a clot in those fast-flowing vessels.

SPEAKER_01 14:26

So the entire classification of the disease shifted again. It wasn't just a quantity issue anymore, which is what we call type one, or the severe total absence, which is type three. It became a structural architecture issue.

SPEAKER_00 14:39

Yes, exactly.

SPEAKER_01 14:40

This became type two disease, which got subdivided into all these granular specific categories, 2A, 2B, 2M, 2N, depending on the exact architectural failure. Like, did the protein lose its large chains? Did it lose its ability to bind to factor eight? The labels finally reflected the actual physical mechanism of failure.

SPEAKER_00 15:00

They finally had a map of the architecture.

SPEAKER_01 15:02

Okay, here's where it gets really interesting. If we now have this perfect architectural map of the protein, and we can look at a lab result and say, ah, you have the exact structural defect of type 2a, does that mean we finally have a 100% predictable disease? Do we know exactly how that patient is going to bleed?

SPEAKER_00 15:19

Aaron Powell You would naturally assume the answer is yes, but the reality is a resounding no.

SPEAKER_01 15:23

Why not? I mean, if we know the exact mechanical flaw, shouldn't the symptom be perfectly predictable?

SPEAKER_00 15:28

Aaron Powell Because a lab test is a static blueprint, but the human body is a deeply dynamic, constantly changing system. Understanding the structure explains the severity of the disease much better than the old models did, but it doesn't eliminate the need for human clinical judgment.

SPEAKER_01 15:43

Really?

SPEAKER_00 15:44

Yeah, you can have two patients with the exact same laboratory pattern, missing the exact same heavy molten border, and their actual real-world bleeding symptoms will be completely different.

SPEAKER_01 15:54

So if the laboratory maps are just static blueprints, how did doctors figure out the dynamic part? How did they measure the living system?

SPEAKER_00 16:01

Ironically, they discovered it through a treatment, not a diagnostic test. In 1977, a researcher named Minucci introduced a drug called DGAVP. Now, prior to this, treating a severe bleed was incredibly dangerous. You had to give patients plasma or cryoprecipitate.

SPEAKER_01 16:18

And cryoprecipitate is essentially taking donor plasma, freezing it, and thawing it slowly to scrape off the concentrated clotting proteins, right? Which carries huge risks, especially in the 1970s and 80s with viral contamination like HIV and hepatitis.

SPEAKER_00 16:31

It was incredibly risky. But DDAVP bypassed that entirely. It is a synthetic analog of the hormone vasopressin.

SPEAKER_01 16:39

Okay.

SPEAKER_00 16:40

It didn't replace the missing VWF from the outside. Instead, it sent a chemical signal directly to the patient's own endothelial cells, the cells lining their blood vessels.

SPEAKER_01 16:50

To do what?

SPEAKER_00 16:51

Well, these cells contain little storage units called Wibel Pollade bodies, which are packed with VWF. DDAVP commanded the cells to dump their stored up VWF directly into the bloodstream.

SPEAKER_01 17:02

It essentially squeezed the body's own natural spon.

SPEAKER_00 17:06

It did. And because of that specific biological mechanism, this therapy inadvertently became a real-time diagnostic test right at the bedside.

SPEAKER_01 17:14

How so?

SPEAKER_00 17:15

A doctor could administer DDAVP and simply watch how the patient's biology reacted. The response revealed the patient's hidden endogenous reserve, meaning how much emergency VWF did their body actually have tucked away.

SPEAKER_01 17:27

That's so smart.

SPEAKER_00 17:28

Right. And it also showed their clearance rate. Once the protein was released, how fast did their body's biological garbage disposal chew it up and clear it out? It turned static endothelial biology into an observable dynamic experiment.

SPEAKER_01 17:40

Which is incredible. We're finally seeing the whole moving picture. But even with that dynamic view, the article shows that we still hit another wall. By 1985, scientists finally sequence and clone the VWF gene. You'd think, boom, we have the foundational DNA. The mystery is solved forever. But it wasn't, was it?

SPEAKER_00 17:59

If we connect this to the bigger picture, the gene cloning created what the author calls the boundary problem. Yes, mapping the genetic code beautifully clarified the severe cases, the total absence in type 3, the specific architectural flaws in the type 2s. But it left mild type 1 disease, which accounts for the vast majority of cases in this deeply confusing genomic gray zone.

SPEAKER_01 18:22

Because with mild cases, the genotype, the actual DNA sequence, doesn't always match the phenotype, the actual physical bleeding symptoms the person experiences.

SPEAKER_00 18:30

That is the core of the problem. And this raises an incredibly important question for modern medicine. Does this person actually have a genetic bleeding disorder, or are we just looking at normal physiologic variation? Because VWF levels in humans are not a binary switch. They exist on a vast continuous spectrum. Your specific levels are modified by your age, your stress levels, pregnancy, inflammation, and most surprisingly, your ABO blood group.

SPEAKER_01 18:55

Wait, blood type. If I have typo blood, how does that affect a completely different clotting protein?

SPEAKER_00 19:00

It comes down to a process called glycosylation. The VWF protein is covered in sugar chains that act as a shield, protecting it from being cleared out by the body. People with typo blood naturally lack certain sugar molecules on their VWF.

SPEAKER_01 19:14

Oh, I see.

SPEAKER_00 19:15

Because that shield is weaker, their body's garbage disposal recognizes the protein and clears it out of the bloodstream much faster. As a result, the natural healthy baseline of VWF in a typo individual is 25 to 30% lower than someone with type A blood.

SPEAKER_01 19:30

Wait a second. So if I have typo blood, I could go to the doctor tomorrow, take a standard BWF test, and be labeled with a chronic disease, even though that lower number is just my natural healthy baseline.

SPEAKER_00 19:40

You've nailed the problem. When a lab prints out a reference range and says normal is above 50 and disease is between 30 and 50, that range is essentially a historical residue. It is the result of modern medicine trying to force a messy, continuous human trait into a rigid, categorical box built on averages.

SPEAKER_01 20:01

That is wild.

SPEAKER_00 20:02

For some patients in that 30 to 50 range, the label of von Willebrand disease is life-saving. It validates their lifelong bleeding, and it ensures they get preventative treatment before a major surgery. But for others who have never had a severe nosebleed in their life, that exact same lab value might just be their biological normal.

SPEAKER_01 20:21

So a label could actually cause harm.

SPEAKER_00 20:23

Exactly. Slapping a disease label on them just gives them unnecessary anxiety, higher insurance premiums, and medicalization they don't even need.

SPEAKER_01 20:31

So what does this all mean for you, the person listening right now? Because we see this exact boundary problem everywhere today with the absolute explosion of health data.

SPEAKER_00 20:40

Oh, everywhere.

SPEAKER_01 20:41

We have fitness trackers on our wrists, smartwatches tracking our sleep, direct-to-consumer blood tests arriving in the mail. We get an alert on our phone that a specific metric, our deep sleep percentage, our resting heart rate, our vitamin D levels has dipped into the red zone. And we instantly think, I have a disease, I am broken, I need to fix this.

SPEAKER_00 21:01

Yep, the immediate panic.

SPEAKER_01 21:02

But what the 100-year history of von Willebrand disease brilliantly illustrates is that a number without the context of the living, breathing human being is largely meaningless. The diagnostic label is not the patient.

SPEAKER_00 21:17

That is the ultimate synthesis of Ayard's article. Von Willebrand disease didn't move from a state of complete ignorance to a state of absolute molecular certainty. It moved from one useful model to another useful model. Right. From von Willebrand's bedside observation and stopwatch to the realization of plasma factors to understanding multimere chain architecture under sheer stress, and finally to genomics and clearance rates. And the very best clinicians, the doctors you actually want treating you, they inherit all of those historical models.

SPEAKER_01 21:46

They don't just rely on one test.

SPEAKER_00 21:48

No, they respect the DNA sequencing, they respect the advanced lab assays, but they never worship any single one of those data points at the expense of looking at the actual patient sitting in front of them.

SPEAKER_01 22:00

It's profound, and it brings us right back to that x-ray machine we talked about at the very start of this deep dive. We love the clean white line on the black background. We want the easy answer, but biology is rarely a clean break. It really makes you wonder if the very definition of this disease was completely rewritten every single time we invented a new way of looking at it, from drawing family trees to mixing test tubes to visualizing protein chains to sequencing DNA. What diseases or absolute medical facts in our world today are going to completely change their meaning when we invent the next generation of diagnostic tools? Are we currently treating the shadow of a disease, just waiting for someone to invent the right flashlight? Thank you so much for joining us on this deep dive. We'll catch you next time.