Understanding cancer: A new paradigm shift
Cancer is humanity's one true archnemesis. In 1970, President Nixon declared the war on cancer, but for the next 30 years, the rate of people dying of cancer had maintained a steady increase, while the death by heart disease was gradually decreasing. What is the deal with cancer?. Despite the insane amount of funding that was being poured into the field of cancer research, we were nonetheless losing the war. Cancer was, for the most part, a disease of aging. So the 50% decrease we'd achieved in children's cancer( 3% of total cases) didn't tip the balance in our favour. We were still losing. A doctor emerged in the meanwhile ,in an attempt to reveal the error in our ways; We were applying the same patterns of fighting. During that period, The FDA was approving drugs based on what they called "successful partial tumor response" which pretty much meant nothing for cancer as it is known for it's infamous for metastasizing.
A new dawn emerges. It is the year 1990, and for the first time since declaring the war, cancer death rates were finally showing an auspicious decline, thanks to anti-smoking campaigns.
There are three paradigm shifts in understanding cancer: excessive growth paradigm(1.0); but why? Genetic mutation accumulation paradigm(2.0); but why accumulate? Third(newest) paradigm: why do our own cells turn against us and turn into alien cells?
A very short history of cancer
Cancer has been with us since the dawn of humanity( there are accounts of people dying of cancer that dates back as far as 2000B.C). Cancer is first detected as tumours. Benign tumours are rarely fatal. Malignant tumours, however are seriously fatal because of the cells' ability to metastasize(hang on to new neighbouring soft tissues and thereby building colonies in all stations in the body( liver, pancreas, lungs, and brain..). People from ancient times came up with The humourist theory to explain the cause of cancer, thinking that it is the result of an imbalance between blood,, yellow bile, black bile, and phlegm. Next came the lymph theory: Cancer travel along lymph nodes. Our first successful understanding of cancer was finding out that it is an excessive growth of cells. The war on cancer is a war against ourselves( cancer is not an invader). So what do we do to cells that grow beyond the usual? we eliminate it. Enter the age of gruesome surgeries. Surgeries practiced before modern medicine are what you'd see in American horror story, season 10. Just picture the simplest of surgeries done without antisepsis and no anaesthesia. Surgeries were the last resort back then. You were more likely to die of surgery than of the cancer. I shudder to think of the "breast guillotine". When caught early, localized surgery is effective, and with tech like CT scans and X-rays, we can demarcate the extent to which surgery is needed. We can sometimes, eliminate cancer without opening the hood: Radiation. An effective way to kill localized cancer cells. Precision has increased over the years, and fractioned radiotherapy remains the most widely used on patients. This method is performed periodically in order to expose cancer cells (which are more sensitive to x-rays than normal cells radiation) and leave the overlying surface intact, while killing the cancer underneath. Local treatment is fine but what if cancer had metastasized? Introducing Chemotherapy. Chemotherapy is a systemic solution that was accidentally discovered. Germany was using poison to slowly kill opponents. This poison known as nitrogen mustard was later combined with Target, and other drugs( folic acid inhibiting drugs) to kill fast growing cancer cells. Okay, cancer is a systemic problem, but what is it?
Paradigm 1.0
Lumper splitter effect lumps all cancers together and give them 8 hallmarks:
Grows, sustains proliferative signaling, evades growth suppressors, resists cell death, enables replicative immortality, and uses the Warburg effect( aneorobic growth environment with the need for more glucose to grow), dregulates cellular energetics, and induces angeogenesis( creates new blood vessels that bring in a supply of oxygen and nutrients.
The cellular energy needed for the cells to perform their daily tasks is stored in a molecule called adenosine triphosphate( ATP) . Glucose is metabolized for energy either with oxygen( aerobic respiration) or without oxygen( aneorobic..) energy is extracted through most efficient process called oxidative phosphorylation( OxPhos) which burns glucose and oxygen and generates 36 ATP molecules+waste and that process occurs in the Mitochondria. The least efficient process( no oxygen available) is called glycolisis( generates only 2 ATP and lactic acid for waste) warburg effect is cancer cells using glycolic instead of oxphos
Genetic mutation of cells( how it becomes a cancer) are the mechanism, not the cause of the disease(why?).
Chemicals causing cancer ( carcinogens) were first discovered during the famous London chimneys' sweep where orphan children were employed in the hundreds to clean it up. It was discovered that the benzopyrene( main component of soot) is a carcinogen responsible for the scrotal cancers that were prevalent in these kids. The agency for research on cancer defines four groups of chemicals( definitely carcinogens, probably carcinogens, unclassifiable, and probably not carcinogens( the caprolactam used in nylon fibre and plastic for example)
Asbestos had a big role in the industrial revolution; it was used in clothes and building materials, thanks to its excellent insulation properties. But it was found that it causes a rare type of cancer( mytheliomia) and accumulate in the lungs over years. It took a lot of time to deliver the death blow to asbestos because of big companies persistently lobbying against discarding it.
Radiation or some chemo drugs( cyclophospamide) can cause cancer.
Marie curie( Nobel prize physics and chemistry) with her husband discovered polonium( pretty radioactive) and radium( most radioactive element on earth). Radium girls, they were called. These girls were licking watches as they finished lacing radium to it, which, to their detriment, were revealed to have a literal jaw dropping effect. Ionizing radiation carries enough energy to disrupt molecular bonds and break them apart into ions damaging cells. Surviving cells are left with unstable chromosomes that are prone to mutations when the cell replicates. Non ionizing radiation is less intense; it can be dissipated without lasting tissue damage. Chronic vs intense radiation( the Hiroshima survivors study concluded that the long-term effect of the radiation the survivors were exposed to was insignificant). Constant Ionizing radiation from space. Cells self protect through antioxidant defences and radiation induced apoptosis( damaged cell is removed).
What if Cancer is caused by a virus?!?!
There are cases where contracting certain viruses can lead to cancer such as the Epstein-Burr virus that once spread in African countries and struck people with malaria, which stimulated overproduction of B lymphocytes( malignant cells in lymphoma) which in turn got infected with EBV. EBV causes different cancers in different regions( nasopahrygeanal cancer NPC in Hong Kong, Taiwan, and Alaska) Asian immigrants to the US have less NPC. The preponderance of this type of cancer in Asia might be chalked up to bad methods of preserving salt in china( putrefaction leads to development of N-nitro putrefecation, a carcinogen) but it is pretty rare.
Between 1964 and 1980, The Special virus cancer program(SVCP) was recieving a lot of funding but with no results. Turns out infections and viruses had little to do with cancer.
Hepatitis A, B, and C are liver disease caused by liver inflammation that appeared due to the use of infected needles, blood transfusion, and transmission by other means. Human papillomavurus( HPV) was found to cause cervical cancer( especially subtype 16 and 18) . H pylori, a bacteria that survives the acidic environment of the stomach was the cause behind stomach ulcers and cancers. Stomach cancer used to be the most lethal in the 1930s but when we found out that HPylori is the culprit, we started fighting it with antibiotics and it worked. Stomach cancers have been assigned to the lower ranks of cancer deaths due to better sanitation n housing conditions and antibiotics. Against viruses, Vaccines were pretty effective.
Paradigm 2.0: cancer as a genetic disease
There are two types of genes when it comes to cancer: Growth promoting cells( oncogenes) and tumour suppressor genes. P53 is the most mutated, cancer causing gene. Cell growth could be accelerated by repeated mutation of oncogenes(growth promoting) and supressor genes( somatic mutation theory SMT). Somatic cells represent all body cells save for the reproductive( sperm and egg cells). Inherited mutations( 5% of cases) like Hippel-Lindau supressor gene increased risk of kidney cancer. SMT: multiple random genetic mutations( intrisnic+extrinsic), all derived(were cloned) from one cell.
The Cancer genome atlas TGGA(2005) was a project to map not one single human genome but thousands of cancer patients. In 2018, Pan cancer atlas was declared complete and the genetic codes for every cancer were mapped. The results complicated things further. It was found that Cancers may have too many genetic mutations or none at all!. Mutations were classified according to driver mutations( important) and passenger mutations( not important). The two mutations exhibit differences across people, even for the same type of cancer and even in the same body between the metastasis and the original. Different mutations can occur in the same tumor. Also the denominator problem: same genetic mutations in cancer patients can be found in cancer free people. Do cells with genetic mutations always develop into cancer? The answer is No.
Between outcome and the root cause there are a lot of proximate causes: in lung cancer, certain genetic mutations are proximate causes but smoking is the root cause. To understand how random genetic mutation(proximate cause) lead to cancer, we need to figure out what make random genetic mutations develop into powerful cancers that have the same hallmarks/superpowers: growth, movement,immortality, and the warburg effect. Preposterous reductionism is what the SMT theory had been doing for a lot of time; trying to catalogue genetic mutations in order to figure out why brakes( tumor supressors) and oncogenes( accelerators) become defunct. It is time we zoomed out and saw the forest. Cancer is developing on purpose. So much for bad luck causing cells to mutate. The seed is important, true, but what's more important is the soil( environment: infections, radiation, and Diet).
Precision cancer treatments that identified genetic mutation and targeted it with drugs had shown miniscule success rates. Imagining was pretty effective but Drug companies, to maximize profits, started making copycat drugs( changing some molecules in a far away for patent control). The benefits were non-existent. Surrogate outcomes are outcomes that doesn't really benefit the overall survival of the patients. Drugs were approved by the FDA but were not effective. The hype made it look like as if things are working and meanwhile, big pharma were cashing in. Exorbitant prices with low effectiveness.
Cancer is older than humanity. It does not develop by accident. It is organized and can survive all attacks of modern medicine. It is no longer sensible to look at only SMT as the cause. Medicine progresses very slowly because of the tendency to hold on to the consensus and reject old ideas whereas physics progresses in leaps and bounds because every new explanation and theory changes things. What if we brought people from other fields to investigate the Cancer dilemma.
Origin of life. Eukryotic cells transform into multicellular cells and energy production separates into glycolysis( anerobic process) and oxphos( aerobic) generated by mitochondria .Multicellularity favors the good for the organism( society) over the individual( sacrifice) so when an individual cell had replicated enough and their telomeres get short enough, they got replaced by apoptosis. But unicellularity has 4 characteristics: a single cell organism grow, is immortal, moves, and use glycolysis( warburg effect) to produce energy. Exactly the behavior of cancer cells!!
There are 3 stages of energy production: anerobic photosynthesis( increased oxygen in atmosphere), and oxphos( breaks glucose into 36 ATP as opposed to 2). Multicellularity means division of labor. When cells Shift toward less specialization and more primitive forms, this is where the cancer develops. Multicellular cells follow strict rules regulations while single cells are autonomous.Cancer cells( unicellular) invade other environments, compete for resources, and mutate haphazardly. The Origin of cancer lies in the origin of life itself. Reversion to unicellarity. The seed is in every cell. That until one cell in the multicellular organism decides to go rogue and stop following rules favoring its own survival over the survival of the organism. It competes instead of cooperate.
Evolution. Selective pressure( soil) and genetic diversity( seed) decide the nature of the evolution( gene mutation). Artificla selection( man-made) or natural selection. Could cancer follow the same principle?
Intratimoral heterogeneity the genetic diversity inherent in a single cancer cell. Metastasis sites( subclones) might evolve different genetic mutation than the origin's
Branched-chain evolution: evolving like tree branches. Static treatment( attacking branches) is futile which is why combination of drugs get used. You have to attack trunk but how do these cell develop resistance?
Different CANCERs evolve various different genetic mutations over their life span that ends up killing host and own life when resources are depleted. However all cancers have same characteristics, grow, immortal, move, and warburg effect. How did they end up so similar( even at a microscopic level) is it convergent evolution? Where different selective pressures lead different species to adopt similar evolution?
Atavism( ancestry): going back. Cancer is multicellular life going back to its ancestral roots( unicellularity). Every cell within the multicellular organism has the genetic blue print to develop into cancer but these tendencies are suppressed by an overlying programs that regulates its behavior within the confines of the useful. Cancer happens at the intersection between unicellularity and multicellularity( 500 m years ago) and focus more on disabling existing cell function( tumor supression) than enabling new abilities( oncogenes). Cancer evolvev defense mechanism against therapies( speciation) and turn into new species. Chronic carcingogeneis( sublethal factors) gives the time necessary for cancer to evolve under many selective pressure. One high dose of radiation is far less damaging than chronic low doses, same for all carcinogens. Radiation and chemotherapy are carcinogens.
Paradigm. Cancer is an excessive growth disease but why? Paradigm 2 : cancer is caused by a " chance" accumulation of genetic mutation? Paradigm 3 cancer develops as a response to a sublethal chronic injury. Dust off the restrictions imposed by multicellularity and revert back to survival mode( unicellularity) despecializing and dedifferetiating. Cancer is common because every cell in the body has the blue print necessary to go rogue. What makes cancer flourish? The soil!
Surprsing fact: stomach environment is acidic Lining cell of the stomach is designed but when acid goes up to the esophagus it causes burn and the cell Lining of the esophagus adapts making unauspicious diseases develop: cancer.
Two pathways to generate energy oxidative phosphorylation oxphos( most efficient) in the presence of oxygen turns glucose to 36 ATP and lots of co2 that get exhaled. But cancer chooses the less efficient pathway: glycolysis that generates only 2 adenosine phosphates ATP but expel only little carbon leaving the majority inside which provide the necessary building blocks for life amino acids. With a lot of glucose, it is also a faster way of generating ATP.
Cancer uses thevless efic8tnet energy oridyctuon pathways( warburg effect) because it provides protective lactic acid that helps cells invade tissues and güve them a Unique survival advantage over normal cells that play it nice.
Cancer start metastasized from the very beginning. Micrometastases bunch of small cells that hide from the immune system for a while. Bloodstream is a hosting environment for cancer cells. Cancer cells evolve the ability to survive.
Cancer cells can return to the primary site after they have evolved better survival mechanism having survived being exposed to the bloodstream.
Mammography produced more harm than benefit. Cancer it was found out, started metastasis at a very earlyvstage by spew8ng a slow of cancer cells into the blood. Reasons like ocerdiagnosis, and unecessary harmful treatmetnst like chemotherapy radiation and surferies to a unlikely to grow cnacers( false positives bc sophistication of breast tissues for women aged 40-49)
PSA prostate specific antigen tests good for nothing.
Some screenings succed when the cancer follows an orderly evolution small to big tumor to metastasis but when some early cancers are contained by the immune system and need not be treated. Removing them won't cure late stage progressions. Hence overdiognosis.
Proiotics containing live cultures( yogurt) promote the growth of good bacteria in the gut.
Mainstay of treatment is to reduce growth factors like insulin and insulin emissions
Chemoprvention, fasting, low insulin diet,
Coleys toxins: induce fever in the body that cause immune system to ramup up defenses and kill cancer.
Bacillus calmette Guerin BCG vaccines to treat initual
bladder cancers
T-cells with kill and active switch. 2 kill switches(PD-1/CTLA-4)were found. Cancer cells disguise as kill switch or clock themselves with a kill switch like a normal cell. Discover the kill switch and unleash the war on hidden cancer. Or extract T-CELLS AND attach a chimeric antigen receptor(CAR-T) switch to it and then release i t back into the body
Immunotherapy is a systemic solution to a systemic problem. It evolves with cancer and remembers it years later.
Abscopal effect( far from target): produced by combining Immunotherapy with older treatments radiation( fractioned, low doses to avoid activation of TREX1 enzymes that cleans up the mess and deactivate immune system in the process)
Adaptive trtment:: containing the disease making it hard for her to resist rather than trying to eradicate it which cause selective pressures for survivalists and resistance to future treatment. Slightly above than average dosage instead highest dosage
Cancer and diet
Focus on soil( environmental factors) instead of seed( genetics)
Nutrition n cancer: western diet with lots of grains and few fibers was the culprit.. Eating more fibers which improved bowel movements was believed to prevent cancer but studies show that a high fiber diet( lfruits n vegatables) was inconsequential in the prevention of colorectal cancer.
Between 1960-1990s saturated fats was pointed as the culprit for all maladies. Turns out it was wrongly accused.
Vitamins:
Supplements don't work
Beat carotene.VA precurosor The component that gives carrots its color has been found to promote cancer growth. Cancer cells need nutrients.
Folic acide( vitamin B 12 ) FOLate supplements have also promoted cancer cells growth and resulted in anti-folate chemotherapy drugs in the 1940s
Vitamin C? Sane
Since sun is significant provider of vitamin D it was bieved that low exposure could increase the onse of diseases but VitaminD n onega-3 fatty acids supplements? No effect
Vitamin E supplements cause cancer
Cancer is: not a vitamin deficiency disease
Nor by Diateray fat
Nor by lack of dietary fiber
Diet plays a huge role
Obesity is actually what's making cancer likely to develop in younger n younger generations. BMI kg/m 2 can indicate the likelihood of developing cancer. The slimming effect of smoking obscures the culprit. Keeping a BMI within the normal is key to lower the risk significantly. Calorie restriction!
Type 2 diabetes and obesity have been found to increase risk of cancer. The cause of these diseases is hyperinsulinemia, an excess of insulin in the blood. Insulin is a nutrient sensor that signals the presence of carbohydrate n proteins to the restaurant only yhe body hormone released through the pancreas in response to food.
Before the import of western diet the inuit n eksimo had zero cases of cancer n diabetes.
Numerous studies have now shown that high insulin levels increase risk of cancer to a significant degree, regardless of weight!( could be non diabetic, BMI<25 KG/m2 n still have high insulin)
Insulin,playing a huge role in glucose metabolism increases with food. It is a growth factor.
Insulin is a growth factor, which promote the lipid molecule P13K which give the green light for cells to grow. But excessive growth for adults is not good. It increases risk of cancer. Cell surface insulin receptor are similar to insulin nutrients and theere is an additional mediation which allow glucose to enter the cell promoting MTOR promoting growth when there is a food intake. Laron dwarves have zero incidence of cancer and the reason is that the nutrient sensing hormone( Igf) is
Nutrient sensors like, AMPK( high energy in cell ATP converted to MTP. , MTOR( was given to transplant student, suppressing immune system and decrease cancer risk as opposed to previous drugs that promote cancer) was accidentally discovered. Ramapmaycin the drug inhibit MtOR which supress cell growth.
Main nutrient sensors( insulin, MTOR, AMPK) with short, medium, and long term responses respond to macronutrients( carbohydrates n proteins) amd overall cellular energy. When food is scarce , they use body fat for energy and decrease cell growth.
Insulin/IG3F signals growth for the cell.. positive( lack of oxygen) and negative stimuli( default path) starts apoptosis( cleaning up dead cells). Cells marked for dead should die n be replaced by new cells. If an unbalance happens and the tilt is toward proliferation( fertil soil for cancer growth) because of high insulin/ Igf, cancer happens. Mitochondria is responsible to keeping apotheosis running properly.
Mitochondria must be regenerated through a process called mitophagy. Healthy mitochondira= healthy netabolism. Autgophagy happens when there is low growth which is triggered by the nutrient sensors( growth factors).
Cdc report that there are no state with less than 20% obesity n that happened only in the last 31 years( onr generation). In medicine it's hard to voice opinions against what's being practiced but to solve problems we have to. Caloric counting ( 500-1000 less calorie) will more you lose weight is not e ought. Obesity is a hormonal imbalance not caloric one.
1 in 10 Americans have type 2 diabetes which is considered a chronic disease among practitcioners and treated with medications like insulin to diminish blood glucose levels but no one admits that the problem is not going away and there are other solution like losing weight.
Philadelphia chromosmoe: CML, genetic rare cancer whose protein we were able to target with a very effective non toxic drug.
Antibodies are produced by the immune system to fight invaders.
Only bad guys killers targeting specific genetic mutations was an upgrade. Cancer develops mostly due to environmental factors not genetic ones.
Traditional cancers vs lifestyle associated cancers
Immigration from Asia to the US changes cancer risk# SMT:carcinogens causing genetic mutations.
The interaction of Seed(genetics, 30%) soil( environmental, 70%) is what determines risk of cancer
Except for rare cases when the seed( genetics) are the root of cancer, it is generally the combination of soil( environmental factors) and seed. We should focus on the soil.