How Your Immune System Works & How to Improve It | Dr. Max Krummel
In a Nutshell
The immune system functions as a complex, tunable sensory network that continuously monitors the body rather than simply defending against foreign invaders. Aging creates challenges through accumulated cellular mutations and thymic involution, which reduces new T-cell production and makes it harder to distinguish self from non-self. Sleep, stress management, and foundational health practices directly impact immune function through mechanisms like immune cell migration and brain-immune connections, while autoimmune conditions represent misplaced immune responses that may offer trade-offs like enhanced infection resistance.
These notes were generated by AI and may contain inaccuracies.
A famous immunologist in the 1970s drew a parallel to wartime submarine operations. In World War II, submarines had two sets of books. One contained sound profiles of all US submarines, allowing them to identify friendly vessels by engine sounds and avoid firing. The other book contained engine sounds of known German submarines, which they would fire upon. This represents a self versus non-self discrimination problem, exactly like the immune system faces.
As people age and become more complex, their bodies create more permutations of every biomolecule. This makes it harder for the immune system to distinguish viruses, which may no longer have anything uniquely foreign about them.
Dr. Max Krummel is a professor and leading expert in immunology and cancer biology at the University of California, San Francisco. He discusses how the immune system works, what it needs to function optimally, and how factors like aging, vaccines, sleep, and even thoughts and emotions shape immune function.
There is a specific set of cells that need to migrate in a particular way during sleep, explaining why sleep deprivation makes people more prone to illness. Certain brain states and memories can be associated with immune system status from when those memories formed, and recalling those memories can activate the immune system in the same way.
Dr. Krummel has a zero-cost Substack called "The Immune Beyond" at theimmunebeyond.substack.com.
When Dr. Krummel started studying immunology 30 years ago, rotating in labs at Berkeley, a transcription factor biologist mentor questioned why he wanted to work in immunology, stating it wasn't really a field. At the time, everything was about DNA cloning and molecular biology.
The immune system was understood as something that activated against viruses or foreign elements and otherwise remained quiet. Cancer immunotherapy changed this perspective by demonstrating that the system could be tuned - raising the threshold of T-cell activation to allow cells to attack tumors that were previously being ignored.
Tumors are neither exactly self nor foreign - they're cells that have evolved from the original self. This shifted the view from a simple foreign-versus-self framework to understanding the immune system as a tunable system.
The immune system has roles beyond fighting foreign invaders. In the nervous system, microglia perform various functions including cleaning up debris. In the gut, it allows microbes to live while titrating their quantities. In the liver, a collection of cells regulates metabolism. In the heart, immune cells help remove byproducts from cardiomyocyte function.
The immune system measures everything about the body constantly and exists to help people be who they are. In chronic disease, it can perpetuate problems by applying the wrong program to the wrong situation.
Dr. Krummel entered immunology in 1989, at the peak of the AIDS epidemic. HIV infects CD4 T cells, a subset of T cells. The body normally contains approximately 10 to the 11th T cells. When HIV depletes CD4 T cells, people develop opportunistic infections from soil bacteria that healthy individuals fight off without issue.
People with AIDS also developed Kaposi's sarcoma and other opportunistic viruses, along with dementias. This revealed the immune system's importance across many different systems and fueled discoveries about previously unknown functions.
Every single T cell in the body functions like a free agent and part of a sensory system. Each T cell can measure the concentration of a set of biomolecules and proteins, forming peptides. Each one can determine whether something is out of range or in range. With approximately 10 to the 11th sensors throughout the body, the system constantly curates and monitors whether everything is functioning correctly.
When humans are young, they get sick more frequently because their immune system isn't fully developed. However, children tend to recover from illness quickly. As people age into the last quarter of life, they tend to get sick more frequently.
The question of where the body ends and the outside world begins reveals that humans are covered with microbes on all surfaces and throughout the gut. Without gut bacteria, humans cannot digest animal fats - the bacteria make key components of bile acids that enable this digestion.
Humans have only 20,000 genes in their genome, limiting what can be accomplished with those genes alone. By absorbing other species, humans gain access to their genomes. For example, eating sushi introduces bacteria that help absorb seaweed nutrients.
For the first six months of life, the immune system is relatively poor at being trained on new things. This is presumably because the body develops so rapidly that an active immune system might attack developing self-tissues that express new genes. This is why some childhood vaccinations aren't given until six months or older.
Until approximately age 10, children get sick frequently because they haven't encountered many pathogens before. Their immune systems have no prior exposure to flu or other viruses. When pathogens hit, they elicit illness, though the immune system typically reacts and eliminates them.
Certain viruses like mumps, measles, and rubella are lethal in children, which is why vaccination is important. These are diseases where the immune system cannot handle high pathogen loads.
The immune system must reach a detente with microbes - firing back against harmful ones while allowing beneficial ones to live. This process occurs throughout the first years of life. Children's guts develop diverse microbiomes as they allow various beneficial organisms to establish themselves.
As people age, immune cells become less functional and fewer cells are produced. One hypothesis suggests this occurs because humans were never evolutionarily selected to live as long as they currently do. Selective pressure for passing on genes ends around age 16 when reproduction becomes possible.
Psychologists propose a "grandfather effect" where genes may be selected for social behaviors in elderly people that benefit grandchildren's fitness. However, this remains difficult to prove experimentally.
Every person starts with 23 chromosomes from each parent, and at birth every cell is a clone with identical information. However, DNA replication isn't perfect. Skin cells may accumulate 10 to 30,000 mutations per cell per day from sun exposure alone. UV radiation causes these mutations, which is why sunscreen is recommended.
Over years, every cell becomes different from its neighbors due to accumulated mutations. This creates a mosaic of cellular identities throughout the body. Some mutations make certain cells more fit, allowing them to fill voids when tissue damage occurs, while other mutated cells may not survive.
Neurons in the central nervous system are largely the same cells present from birth, though their DNA is still subject to ongoing mutation. Hair cells in the ear also retain the same protein molecules and atoms from birth.
Immune stem cells reside in bone marrow within long bones. The bone cavity protects these cells from solar radiation and chemical mutagens in the environment. Similarly, neurons inside the skull and spinal cord are protected from environmental mutagens.
The immune system is not simply about defending against outsiders. All the bacteria that live on us bring benefits and contribute to our overall function, creating a more robust person than we would be without them.
During World War II, submarines would use two sets of books to determine friend from foe. One book contained the sound profiles of all US submarines, allowing them to identify friendly vessels by their engine sounds. The second book contained the engine sounds of known German submarines, prompting immediate action if detected. This mirrors the immune system's self versus non-self discrimination problem.
As we age, our bodies become more complex with every possible permutation of biomolecules potentially being made. This creates a problem where a virus may not have anything unique about it since it also makes proteins. The immune system can recognize viral proteins as new and mount a T-cell response. However, with aging, the self becomes so complex that the system designed to sense self has significant background noise, which may explain increased cancer prevalence in later life.
Cancer becomes more prevalent in later life for two reasons: accumulated mutations in cells that could become cancerous, and the immune system having seen all various accumulations over the years to the point where the unusual no longer appears that unusual.
The immune system continuously prunes cells throughout life. White spots that appear on skin around age 40-50 represent places where the immune system has eliminated precancerous or early cancerous cell collections. Melanoma originates in melanin-producing cells, and white areas indicate where melanocytes have been wiped out by immune surveillance.
Wound healing in young people is remarkably faster and more efficient than in adults. If you want cells that quickly replicate to fill gaps from scratches, mutations that allow faster cell division are selected for. However, cancer is defined as cells that divide faster. Events throughout life where certain cells win by filling spaces left by dying cells select for cells that get slightly out of range with growth.
Immunity was once viewed like a fuel gauge - low for self, high against viruses. Original cancer immunotherapy approaches aimed to make the immune system generally hotter. However, between the immune system not caring about something and releasing all its fury, there are many other responses possible. The immune system can quarantine bacteria without killing them, produce substances that either clear them from circulation or maintain their presence, and is consistently present in organs like the heart, continuously measuring the complex self.
Every virus leaves evidence of itself in the body. The immune system aims to quarantine rather than kill every infected cell. Herpes virus infection of nerves can cause nerve pain during emergence, and much of this damage comes from the immune system reacting to the virus rather than the virus itself. This is called immunopathology - the immune system causing as much damage as the virus.
If the goal is to reach reproductive age, the immune system may tolerate certain infections like early liver HCV or HPV infections rather than mounting massive responses that could destroy the liver. The immune system can kill any cell it wants, so the space between complete tolerance and aggressive response contains specialized roles that are not always about elimination at all costs.
The immune system may assess how many cells throughout the body have similar mutations or differences, rather than attacking individual mutated cells. If the number of mutated cells exceeds a certain threshold, the immune system could decide to fight. This resembles neuronal accommodation, where constant exposure to a stimulus like the smell of a particular cheese leads to tuning it out.
For danger, the immune system looks for signals over time. A virus creates a spike of appearance followed by replication, then returns to nothing if eliminated. Self signals are different: either present throughout life at consistent levels like insulin, or things that rise slowly. Cancer's problem is that it grows slowly and nefariously over time, and the body is designed to absorb slow change. If something is not causing illness yesterday and a little more of it is not causing illness today, it is probably a developmental change.
Immune cells crawl around the body surveying tissues. They can form synapses like neurons and exchange information, forming clusters that function like mini-brains in tissue. The slow burn of gradual change does not trigger this communication network, while sudden spikes and damage do.
T-cells were originally named thymus cells. The thymus is an organ near the heart that produces all T-cells. In the past, when children had heart surgeries, doctors would remove what appeared to be an overgrown white organ near the heart. These children then became susceptible to opportunistic infections, revealing the thymus's critical immune function.
Jo Miller, a 97-year-old researcher in Australia, removed the thymus from newborn mice, which then grew up but succumbed to bacterial infections. Some also developed tumors. The thymus receives stem cells from bone marrow that travel through blood to become T-cells. The thymus presents all genes in the genome to developing T-cells, ensuring they only allow cells with correctly tuned sensors to emerge, maintaining tolerance.
The thymus is large in children because the developing immune system needs to create a collection of immune cells that can react against environmental bacteria and viruses while maintaining low-level self-reactivity. The thymus involutes and becomes tiny in aged people, stopping the production of new T-cells. This aging effect may make older individuals more susceptible to diseases.
Interest in thymus peptides and approaches to revitalize the thymus stems from the potential to generate new T-cells with specificity for tumors that have taught existing immune cells to see them as normal. While engineering cells externally is one approach, allowing the thymus to produce more T-cells represents a more natural route to generating anti-tumor immunity.
Humans have evolved to prioritize reproduction and raising offspring to reproductive age. Early humans who survived to age 30 and reproduced were evolutionary winners. The selective pressure historically favored genes that ensured survival to reproduction and successful child-rearing rather than extended post-reproductive lifespan.
The period of raising children creates additional evolutionary pressure for humans to remain healthy longer than other species. Unlike giraffes, human infants are born relatively helpless and require extended parental care. This extended dependency period may have shaped human biology to favor longer healthspans.
Some immune system characteristics that provide advantages early in life may become problematic later. The immune system's high reactivity, which is beneficial early on, may create compensatory problems when faced with the reality of a 50 or 70-year-old body.
Genetic mosaics represent a significant challenge to immune function. As people age, their cells accumulate mutations, creating mosaics of genetically different cells within the same body. This creates something that is quite hard for the immune system to defend against.
Understanding aging and immune system deficiencies requires basic research, where approximately 90% of experiments are dead ends. Science involves hundreds of disappointments for every discovery made. A single control experiment can invalidate an entire project.
The best experiments are called "killer experiments" - experiments designed to disprove hypotheses rather than confirm them. This approach is necessary because intuition about how systems should work often doesn't match how they actually work.
The central nervous system was historically considered an immune-privileged organ with no immune cells present. Research by Carla Shatz on major histocompatibility complex and work by Ben Barres, along with their scientific offspring including Beth Stevens and Shala Ergloo, demonstrated that the immune system is active throughout the CNS lifespan and serves critical roles.
Missing one or two nights of sleep significantly reduces immune system effectiveness against infections. The mechanistic understanding includes several components:
- At night, many immune cells return to the bone marrow
- Tissues become populated with neutrophils from bone marrow that deposit collagen
- Sleep appears to serve reparative functions for the immune system
The data showing immune cells migrating to bone marrow at night is considered solid, though the full implications and mechanisms remain under investigation.
Sleep deprivation causes visible effects including bags under the eyes and glassy appearance, both resulting from lymphatic fluid accumulation. The lymphatic system functions as plumbing that works better during sleep.
One night of poor sleep can make someone susceptible to infections from someone coughing across the room, while being well-rested provides noticeable immune robustness.
Macrophages in the eye continuously clear the lens. These cleanup processes work best when the body isn't simultaneously producing more waste products. Sleep provides a period when the body can address accumulated damage without generating additional byproducts from daily activities.
Sleep appears necessary to reset and clean up byproducts of the body's energetic processes that cause cellular damage.
The thymus produces T-cells critical for immune surveillance. Banking thymic cells for potential future use raises questions about practicality and invasiveness of thymus removal.
Umbilical cord banking stores bone marrow stem cells that could be used for bone marrow transplantation if needed, such as after radiation treatment for bone marrow tumors. While companies offer this service, it's unclear whether any individuals have successfully used their banked cord blood for treatment.
Induced pluripotent stem cells (iPSCs) created from skin fibroblasts using Yamanaka factors may carry mutations accumulated during aging, making them potentially unsuitable for research or therapeutic applications.
The California Institute for Regenerative Medicine was established with the expectation of developing stem cell therapies within 7-8 years, but this timeline proved unrealistic. While stem cell therapies will eventually be developed, the timeline for practical applications remains uncertain.
Interest in extreme longevity (living to 120) is less compelling than maintaining vitality, health, mobility, sensory function, and cognitive ability during one's existing lifespan.
Thymus removal for banking would require invasive surgery, and it's unclear whether the thymus itself or its cellular contents would be most valuable for potential longevity interventions.
CAR-T cell therapy has been considered promising for 10-15 years but has faced significant challenges in clinical application, demonstrating that scientific progress often takes longer than initially anticipated.
Scientific progress often involves steady pressure building over decades with many failures before sudden breakthroughs emerge. Fields experience consistent incremental work that rarely transfers directly to applications, yet this groundwork appears necessary for major leaps. CRISPR technology exemplifies this pattern, evolving from basic bacterial defense studies into a powerful gene-editing tool that enabled sickle cell anemia treatments, despite earlier questionable applications in human embryos in China.
The GLP-1 agonist drugs for obesity followed a similar trajectory. Originally developed as diabetes medications at lower doses, these compounds were later found effective at higher doses for weight loss, representing what appears to be a substantial therapeutic advance despite side effects including muscle wasting and potential apathy.
Fundamental discoveries frequently originate from curiosity-driven research rather than targeted problem-solving. CRISPR emerged from studying how bacteria defend themselves against viral invasion, not from efforts to engineer human genomes. Similarly, the Gila monster's ability to survive extended periods without eating led researchers to investigate the underlying mechanisms, eventually contributing to metabolic drug development.
Cancer immunotherapy originated from basic T-cell research rather than cancer-focused investigations. The initial experiments involved blocking molecules on T-cells to enhance their activation, with tumor treatment emerging as an unexpected application after the foundational immunology work was established.
Major advances often come from unexpected directions rather than direct problem-solving approaches. X-ray technology developed from physics research before finding medical applications. The principle suggests that restricting research to immediately applicable goals would limit discovery of novel tools and approaches.
This pattern indicates that fostering curiosity-driven research remains essential for generating new knowledge, as opposed to focusing exclusively on known applications or commercial development.
Scientific experiments typically have low success rates, with approximately 10% chance of yielding interesting results, requiring researchers to conduct numerous experiments to achieve meaningful outcomes. This creates an asymmetric reward structure where most efforts produce no immediate value, but occasional breakthroughs generate substantial knowledge gains.
The training process of pursuing long-term projects with uncertain outcomes develops valuable skills for managing extended efforts without immediate feedback, which proves relevant beyond academic research.
Historical medical observations suggested that placing severed limbs or tissues in the abdominal cavity could preserve viability, possibly due to warmth, immune factors, or reduced infection risk. Modern research confirms that certain tissues can function when transplanted to non-native locations if they receive adequate blood supply and growth factors.
Pancreatic cells can survive under the kidney capsule, which provides suitable vascularization. However, autoimmune conditions like type 1 diabetes create additional challenges, as the immune system may attack transplanted pancreatic tissue just as it destroyed the original cells.
The immune system exhibits both migratory and resident cell populations. While many immune cells circulate through blood and lymphatic systems, certain T-cells become tissue-resident, remaining in specific locations to provide localized protection without further migration.
Lymph nodes serve as organized structures along lymphatic drainage pathways, facilitating immune cell interactions and responses to tissue-derived signals.
The insular cortex appears to link cognitive processes with immune function. Research demonstrates that neurons activated during gut inflammation can later trigger similar immune responses when artificially stimulated, even after the original inflammatory condition resolved.
This suggests contextual learning extends to immune states, where environmental or cognitive cues associated with immune challenges may later reproduce corresponding immune responses. The mechanism potentially operates bidirectionally, with thoughts and memories influencing peripheral immune function.
Acute stress appears to enhance immune function, contrasting with the well-documented immunosuppressive effects of chronic stress. The relationship between nervous system activity and immune responses suggests potential mechanisms through which practices like meditation might influence immune states.
Meditation's effects on the autonomic nervous system, particularly through breath control, may provide pathways for modulating immune function through established brain-body connections rather than representing purely subjective experiences.
There's an intuitive element to the idea that certain sensations can reset tissue and reduce stress. Some people claim they never get sick, while others seem to get sick repeatedly in a given environment. This may relate to a reinforced mindset where the immune system responds to brain states and triggers rather than language or thoughts directly. Immune cells listen to biological triggers associated with feeling states, not word content.
Spatial biology demonstrates that context matters for the immune system and all biological systems. In wound healing studies, cells one layer back from a wound perform different functions than cells further away, creating a gradient similar to neural patterns. Development happens through these gradients, and the challenge lies in understanding when something is good for a process versus when it's only effective at the right dose at the right time.
Transplanting healthy cells to novel environments could theoretically work, as tumors thrive when placed under mouse skin in cancer studies. However, tissue engineering faces challenges when introducing new genes through viral vectors or plasmids, as this creates new cellular identity that the immune system may recognize as foreign.
There's a rise in people experimenting on themselves with peptides and other substances obtained from the internet. The problem is that these experiments don't generate captured data, leading to anecdotes being treated as data. While reading books represents a form of self-improvement, physical experiments carry different risks when safety profiles are uncertain.
Vaccine hesitancy often stems from questions about timing and combinations rather than outright opposition. Many parents ask whether spacing out vaccine delivery might be preferable to administering multiple vaccines simultaneously to a young immune system. The protocol for immunotherapy of cancer was largely based on mouse work, and while mice and humans differ, protocols exist because statistics provide a sense of safety.
When conventional cancer treatments aren't working, people become interested in tumor-specific vaccines containing proteins and peptides unique to the tumor. The context of having cancer versus preventing disease dramatically changes people's willingness to try vaccines.
Protocols designed from single studies may not represent the only effective approach. Mouse experiments show that vaccinating on slightly different schedules can still achieve protection outcomes. However, convenience for doctors, hospitals, and patients drives adherence to standard protocols, similar to how brushing teeth twice daily at consistent times ensures the behavior happens.
Some parents have delayed vaccines by a month when children weren't feeling well. The shingles vaccine provides an example of one that can knock people out completely, raising questions about whether studies examined optimal dosing regimens.
The frustration around pharmaceutical companies often relates to feeling dictated to about timing and requirements rather than having choice in medical decisions. Parents whose children appeared fine before vaccination and then developed symptoms experience understandable anger and guilt, particularly when they made the choice based on what they believed was best for their child.
The legitimacy of pharmaceutical companies has declined partly because people are advertised products where side effects may outweigh symptoms being treated. This contributes to the pioneering spirit of wanting to choose one's own best interests rather than relying on experts whose interests may not align with individual needs.
The discussion addresses how pharmaceutical companies face perverse incentives when developing diagnostic tests for their therapies. With checkpoint blockade drugs for melanoma, only 50% of patients respond, yet 100% of the market takes the drug because responders cannot be identified beforehand. Companies have no financial incentive to develop tests that would identify non-responders, as this would cut their market in half. This creates situations where the best interest of corporations may not align with individual patient interests.
The conversation emphasizes that 99.9% of scientists work diligently to discover important knowledge for humanity, but issues arise when communication breaks down. Rather than distrusting science entirely, the solution involves making knowledge freer and better communicated while watching for situations with perverse incentives. The pandemic demonstrated that the "fire hose" approach of commanding behavior changes without nuance failed to convince the public.
The panel format with multiple experts providing nuanced information would have been preferable to single-individual messaging during the pandemic. The path forward requires educated individuals who understand complex systems like the immune system to acknowledge why people have questions and propose actual experiments rather than polarized positions.
The historical reality of diseases like smallpox and measles provides important context for vaccination discussions. Smallpox was a dreadful disease, and measles can cause massive inflammation and brain inflammation. The risk of these diseases remains real even if they haven't been seen recently, similar to how parents teach children to cross streets safely despite not witnessing accidents daily.
An important experiment demonstrates that injecting bacterial infection into pregnant mice induces autism-like symptoms in offspring, showing that immune challenges can affect neuronal development. This establishes that immune insults can influence neural development, though it remains unclear whether this relates to vaccines or if mothers had infections during pregnancy. The timing of vaccines at 2 years of age coincides with when autism typically appears, creating correlation questions that require data.
Research shows that injecting gamma interferon (an immune molecule produced during infection) into healthy mice causes social isolation behavior without any actual infection. The brain has receptors for immune molecules, demonstrating that the brain can sense infection and alter behavior even in mature organisms. This work continues in laboratories studying autism origins.
The COVID-19 situation was characterized as data-sparse, where decisions had to be made without sufficient information about transmission, safety protocols, and appropriate responses. This led to confusion about masking, touching surfaces, and other protective measures. Society struggles with synthesizing knowledge under data-sparse circumstances to make informed decisions.
Thousands of parents contact experts asking whether to delay certain vaccines, not as extremists but because they love their children and question financial incentives in the system. The data cannot be as polarized as presented in media, where sensational stories like plane crashes drive engagement while routine safety information receives less attention.
Scientists face motivation to make results appear extensible beyond what the data shows, seeking orthogonal applications for discoveries. However, some findings are not extensible - a mechanism that works in one context might disrupt entire systems if applied broadly. Human bodies demonstrate remarkable resilience across temperature ranges and fasting periods, suggesting biological systems can withstand significant variation.
Most biological systems are wired in complex ways rather than responding to single interventions. While checkpoint blockade represents a successful "one-and-done" drug approach for 50% of melanoma patients, most diseases require understanding multiple interconnected mechanisms. The immune system operates more like a fuel gauge requiring movement between states rather than simple on/off switches.
Machine learning can analyze gene expression data from patient tumors to build network models showing how cells are wired together and predict consequences of targeting specific molecules. However, this differs from AI large language models that work within existing knowledge corpora. Discovery requires experiments beyond statistical relationships, and human judgment remains essential for selecting which expensive experiments to pursue.
Rather than seeking single interventions, effective disease treatment may require sequential nudges to shift biological systems between states. This involves first removing conditions that prevent immune recognition (making tumors not appear as healing wounds) before teaching the immune system to attack. This mirrors how tissues organize into archetypes - complex configurations of immune cells, fibroblasts, and epithelial cells that require understanding developmental sequences to transition between states.
The collection of behaviors, foods eaten, sleep obtained, and all these things create the broader context for health. Loves of your life, friends you have, they're all part of this picture. A physician friend in the Bay Area says better living through chemistry still requires better living, meaning you should never abandon the foundational stuff of sleep, exercise, nutrition, circadian rhythm, light, social connection, and stress mitigation.
Many people are curious about autoimmune issues. Chronic fatigue is considered an autoimmune issue by most, and a lot of people seem to have it. There was debate about whether it really exists, but for someone who believes they have it, it absolutely exists. People with chronic fatigue are tired and should be believed. Myalgia and psoriasis are also known autoimmune conditions, as is asthma. These are interesting conditions, not all of them life-threatening, but some cause a lot of discomfort.
Fundamentally, the immune system has playbooks like a football team that it can run, putting players in particular configurations called archetypes. The immune system is trying to do a certain kind of thing, genetically and through history wired to work with cells in certain ways. Autoimmunities represent a misplaced immune system that either thinks it's under attack or thinks it's meant to be doing something it really isn't. The origins of some autoimmune conditions are genetic for sure.
Lupus has a familial mutation in a receptor on a B cell that normally helps turn off the immune system, and when defective, those people are susceptible to getting what are called autoantibodies. B cells make antibodies and can be overactive, genetically overactive. One wonders why we'd ever have such genes and why they would be propagated, except that maybe in some circumstances you need it when there's a big pandemic, people might have a particularly good response.
Asthma was historically called an allergy and still is an allergy, where you have inciting things like grass pollen, but in a lot of these settings the concept that it's coming in part and parcel with the immune system recognizing self is a thing. Ten years ago you might have taken a lung of an asthmatic patient who died, cut it, looked at it in a microscope and said you can really see thickening of the airways and that's why they couldn't breathe, but now we can go into those and look at every single cell and ask how those are wired together.
Is there only one form of asthma? No. There are actually seven or eight different forms, which is why some people can take inhalers and it works and other people can't. Some people are very chlorine sensitive and go to a pool and it initiates symptoms, others are cold sensitive. There are variations on what sets up that inflammatory focus, called an archetype. Some have lots of cells called eosinophils, other ones have lots of cells called neutrophils. Asthma isn't just one disease, it's one symptom failure, difficulty breathing, but it has many different configurations.
There's a study looking across a bunch of autoimmunities to figure out whether they have things in common with each other. Psoriasis is one where you start to see variations, lupus for sure, and inflammatory bowel disease. In the clinic with inflammatory bowel disease, you ask about drugs because it's a good case where there are a couple different drugs that for some patients work really well. TNF therapy blocks a cytokine, and for some people with IBDs it manifests as really bad diarrhea that's very painful. There start to be classes of patients that have responses to these things.
Those drugs are exciting because they say you can modulate this, but like the checkpoint drugs we don't really understand why one works in one patient and one doesn't. Inflammatory bowel disease and autoimmunity is pretty tricky because people will respond to a drug for a while and then they'll stop, and then doctors have to do this whack-a-mole thing where they try one and it doesn't work, they try the next thing and it doesn't work.
This sounds like psychiatry, where drugs will work for a while then they don't work, side effects crop up that never existed before. It's a tough one. Autoimmunity is a real thing, similar to cancer where we're just starting to understand the fact that it comes in these different immune flavors. The drugs you try to use, it's clear the immune system can do a lot of good work for us, but what you need to do to it in these different archetypal immune systems is going to be different. You just got a different football team out there playing or they're running a different play.
If somebody has a kind of mild autoimmune condition like mild psoriasis, that might confer them with a bit better viral and bacterial infection resistance. There's a trade-off there, so scalp cells are sloughing off, and the treatment involves interleukin 17, some good shampoos for this or anti-inflammatories, but that individual is maybe better at fighting other infections. So you could see how it's adaptive in the modern context, and yet you're more resistant to infection. Severe psoriasis can be very disruptive for people, but this is sort of an individual point for why autoimmunity could actually be useful. It's not always the case that it's there to give us asthma or flaky scalp.
There are a lot of disease states, and the argument for why we would ever have a sickle cell gene, the one that causes people to have hemophilia, and it's a lot of sub-Saharan African gene, people from that origin have this, is that it's actually defensive against malaria. It seems to be the case that having that, this is true of a lot of these situations where the diversity of the human population over time, by having some of these things that make some people hypersensitive to maybe bacterial viral infection at the cost of having things like psoriasis pop up or various other autoimmunities, is the only way that a billion strong population has to move forward.
If you take a flask of bacteria and put them in glucose, which is like sugar like you put in your coffee, maybe sucrose either one, you put them in a simple sugar and you watch the colony grow, you'll get these cells that grow really fast, the bacteria becomes billions, trillions of individual cells, but there's almost always some just losers that are dividing slowly. It's for whatever reason the system always springs us off. Why would you do that? Why wouldn't just the winners win? But if you take a little bit of that culture and put it into galactose, which is a milk sugar, often the ones that were winners don't win anymore, and it's from the loser pool that the new ones emerge. This is a case of crowd fitness that comes from diversity of genes.
Some of these things that make some of us susceptible to disease are also, in other situations, going to be quite good for you. That seems unfair at the time that you have these kind of bad genes, but a different day you would have been happy. The differences in our vitamin requirements is going to be quite profound because the metabolic enzymes we have for the vitamins that we might take in are going to be different between us. FDA limits, these numbers are averages. Some people may need five times that amount of vitamin X and other people may need a fifth. The supplement world is kind of like scattershot.
There's a rational grounding in all of it. Some peptides are beneficial, some are still experimental. The preference is for more data collected the right ways and communicated the right ways, the same way with vaccines and all the rest.
The inspiration to get into public education about science and health started about 10 years ago when a group was hanging around after a conference talking about some of the issues with science in society. The capacity for everyone else to think as a scientist is important, to ask yourself why don't people agree with this data that you show and take the action that seems logical, but then you present it in such a way that they can't.
Two things are important: if you present the information in a format that isn't familiar, you're not going to be able to teach anybody anything about what's important. If you say you're a scientist, it's not a neutral statement. Science has a history and history is stronger than science actually. There's hesitancy among African-Americans to take drugs because of the history of Tuskegee, which is like 80 years ago or 60 years ago. It's not in their lifetime in many of these people.
Part of what scientists should be doing is figuring out how we relate to other humans. If we want to relate, if we want to have impact of the work you do, if you want it to be relevant, at some point the science field needs to make sure that it doesn't ostracize itself from people. One of the issues is this concept that we speak in our vocabulary that gets very precise and we forget that if you hear a foreign language and you hear one word that you don't recognize, it throws you off for a few sentences and next thing you know you don't know what people are talking about.
Bringing it down a level and giving analogy strikes as really important to the impact that you can have with your science and that science can have in terms of teaching people what we could do better. But if you end up thinking that science is a distrusted weird collection of people that have different motivations and designs, then you've lost the potential for it to do good.
The Substack came about because there was a need to write as a person a little bit more and tell about the time spent on this and why it matters and what it's like to do this work, and in some respects also what it's like to lose in this, which happens way more often than the glory story. The best bestselling books about science are the wins, but it might be more relatable at some point to get all of it. The immune system is also just so relevant and so important and it's got all these different facets and these archetypes and these sorts of things that it's doing.
People will really learn from the Substack, and that's essential especially in this day and age. Even not in this day and age, science is just really cool. With all the meaningless drivel out there, it's nice to go to a place like the Substack and learn, be inspired by certain things. At some point somebody's going to contact you that they decided to study the immune system or they learned something or they explored a novel treatment with their physician in a given unfortunate or maybe even fortunate situation that bettered their lives. Substacks and conversations like this can really do that.
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