All the times my daughter has surprised me

 All the times my daughter has surprised me

1-2yr old

The first day of you going to daycare. Although I was relaxed and I knew you'll be fine but your mother was very worried how you'd react. You were mere 15months old. Your mother was convinced you'll cry when you'd see us leaving the daycare and that you'd start to miss us immediately. But we were not only surprised, but slightly annoyed by your reaction. As soon as we signed the attendance sheet, you started walking towards room#5, where Miss Yolande was standing at the door and ready to welcome you in. You didn't even look back at us. Your mother was annoyed! But you just kept walking in, started playing with the toys in the room. We left daycare feeling slightly embarrassed. We came back late afternoon to pick you up and you were perfectly fine the whole day, adjusting seamlessly to the new daycare, new room, new routine all by yourself.

2-3 yrs old

I cooked chicken curry for dinner but it turned out to be little spicy. I was not sure if you'll be able to eat. I even thought to cook something else for your dinner but then thought to try it out first. I did not mention anything about the spiciness and served you on the plate. Not only did you eat the whole serving, you didn't even flinch for one moment. I learned to never underestimate you.

I cooked potato-beans fry one time. Again, I was hesitant because usually kids don't readily eat vegetables like they eat ice-cream. But I thought to serve anyway. Again, you finished the whole plate, and even asked for more. From that moment onwards, I never had issue serving you vegetable dishes. You were even able to handle slightly spicy curries. Totally unlike other kids I came across.

One time when we were eating breakfast together, you took a big spoonful of cereal and put in your mouth. I showed excitement and happiness, even clapped to express my amazement that you can eat such big servings at one go. Then you mumbled "oh, like fippo?". I couldn't figure out what did you mean. I asked multiple times, "what? what?" and you kept repeating "like fippo papa, like a fippo". After few times, I gave up and tried to move away from it, "ok ok, keep eating now, don't stop..". You looked out the window, thought for a sec, then said "papa, like monkey, tiger, mouse.." and suddenly I snapped "oh! you mean you ate like a Hippo there, oh I get it now". You were so happy. I was dumbstruck by your intelligence. You are mere 2-1/2 yr old. You know I keep encouraging you while eating by saying "you eat like a hippo baby girl", and you tried to remind me of the same but because of your lisp (or mouthful of cereal), I couldn't understand what you meant, so you made a correlation that hippo is animal like monkey, tiger etc so you dropped me a hint and voila! that was enough for me to get what you were saying. I'm smart but you proved yourself to be smarter.

3-4yrs old

You have grown surprisingly strong these days. One day we were just play wrestling. You were sitting on my back and for fun I pretended to rise up. You got the hint that we are not playing a new game where you'd try to push me down while I try to power through and rise. I was amazed at the strength through which you tried to keep me down. I was genuinely surprised you can be this string, this early. While I'm down, I count 1...2...3...go and I summon my strength to rise. You are smart enough to get the hint. You start exerting your force from 2 onwards. 

You have started to converse with me in Oriya. Although I would like the frequency to be more but I'm surprised you have picked up the language very early. I have ensured I only speak in Oriya with you and I've to keep prompting you to reply to me in Oriya. Over the past few weeks (you are 3yr 4 months old), you have improved your Oriya skills. It'll not be long before you'd be able to speark with me in Oriya all the time, something that I'll cherish personally, something like a secret thing between you and me, one more special thing binding us.

When you were 3.5 yrs old, my India trip was coming up. I was going to be away for a month to spend time with my mom. I was bit worried that you'll cry and not let me go. Few hours before I was about to depart, I held you in my arms and explained to you that I'll be going away to India for a while. You were so understanding, so calm. We played together for a while and when the time came, you hugged me tightly, kissed me and we bid goodbyes. You didn't cry at all. I was so amazed that you were such an understanding girl, so mature than your age.

Usually eating by hand is messy for you and time consuming process. That is understandable as you are yet to develop that kind of dexterity in your fingers, coordination between fingers and tongue. But one time at dinner, you saw me eating rice chicken curry with hand and you said I want to eat using hand as well. Your mom was at first not happy but I convinced her to come around. She was more concerned about the mess that'd be. You started eating by hand. There was the usual clumsiness. Then both mom and I coached you how to pick up rice curry mix into your fingers and 'push slide' the content into your mouth while the tongue helps to take it in. We showed 1 demo and voila! That was enough for you to understand the mechanics. After that you were flawless in your technique. I distinctly remember I looked at mom and silently we acknowledged that you have managed to excel in this also, so quickly. You were eating like a pro desi, eating using hand. No mess, clean plate.I was feeling very content in my heart at that moment. You made me happy, again!!

At this age(3.5yrs), you have started showing your slyness with a pinch of cuteness that is irresistible. You love food. There is no denying it. You are the one to finish breakfast early in the day, and I make a note to have my breakfast with you at the same time. Mom, however, wakes up late so she ends up having breakfast by herself after an hour or so and she usually like bread peanut butter which you happen to like as well. You are aware that doesn't like you gorging on her breakfast also. So when mom starts to eat hers, you slowly drop whatever you are doing, and cheekily sit on mom's lap, buttering her up with constant "I love you" and a cheeky smile. You are actually saying lot of things, without saying anything. Your gazing eyes, constantly switching from her plate to her eyes, would be trying to make a point. Then you'd cheekily just touch the side of the plate, like a harmless gesture of checking the waters. The next move would be slightly more pervasive, like touching the apple slice, adjusting the sandwich piece, or plucking the banana between the bread slice. At this point Mom (or I) would just cave in, and offer you a bite or handover apple slice. Mission accomplished. Very cheeky indeed.

Within a week (3yr 7m) you have managed to surprise me more than I could imagine. You are now able to count to 100 without any mistake. Not only saying the numbers out loud, you even attempted and wrote numbers from 1 to 100. Thats just amazing. It was brave, very courageous of you to take that challenge. Yes, it was you who blurted out "I want to write to 100 today" and then proceeded to do just that. Not only on the scholarly side of things, but outside of it too you managed to surprise me. I took you for biking. This time I took out my bike too, intending to bike alongside of you. It was a gamble but I wanted to see what you can do. You had been able to stop biking and balance without falling over, also able to turn the bike around but you needed help starting the bike, with the pedal push and balancing at the same time. This time, you were able to do that by yourself too. With the minimal of guidance, hints about how to position the pedal, how to keep one feet on the higher pedal and push while maintaining balance with the other foot and slowly rising it to the other pedal, and voila, next thing I see you are already riding ahead and I had to scramble to get on my bike to get ahead of you to clear the road ahead for any oncoming traffic, for you. I enjoy these types of small victories. These small small things build characters, it builds strength and the right mindset so that you are ready for the big things. 

Today(3yr 7m) you counted to 100 and without any mistake and today was the 10th time you've done so. You are also able to ride the bicycle all by yourself. Your feet is barely touching the ground but you are able to stop and start the bike by yourself, and also turn around. You've never needed training wheels. You started riding the balance bike since 2 years old and then pedal bike since 2.5yrs old. At this age, you are able to write upper and lower case letters with <5 mistakes which is amazing. More practice and you'll be perfect. You are also speaking with me in flawless Oriya. You fumble once in a while but it's much much better. You are talking in English with everyone else but as soon as you turn to me, you speak in Oriya automatically. Even my friends are surprised to see you speak with me in Oriya and it's so cute, I simply melt inside. All I'd say is keep it up. 

4-5yr Old

Your biking has improved so much it just amazes me. The other day I took you to a bike trail. From where we park, the trail extends in both North and South direction. Until now I've only taken you to the South side of the trail for biking which is mostly flat and you've done pretty well. I run alongside you while you bike. You are never an arms away from me and I'm always watchful to ensure in case you fall, I'm there to catch you before you hit the ground. Till now, rarely has been the case for that. This particular Saturday I thought I'll have you bike the North side. Things are going well and I notice this side of trail goes alongside the Guadalupe riverway. Whenever a car-bridge comes along, the bike trail goes downhill, under the bridge and right next to the water and then after the bridge, goes uphill. Both downhill and uphill are steep and there are 5 such bridges along the route. We approached the downhill and you were little apprehensive and doubtful. I calm your nerves and encourage you that you can do it. Nothing to be scared. When the downhill is steep like this, all you need to do is focus on balancing the handle and go easy on pedaling. You followed the instructions to the T and you are having so much fun. I'm literally sprinting to catch up with your bike's speed at the slope. At the end of downhill you are excited and happy. Then comes the uphill. I see the steep and in my mind I'm thinking this is too much to ask for a 4yr old. I'm prepared to push you along if I see you are not able to get over the hump. But I wait until the last minute. Then to my amazement I find you are pushing yourself, pedaling hard on the pedals, one round at a time and with words of encouragement from me, you are able to reach beyond uphill onto the flats. My god! The strength this little girl has. Not just one, you conquered 5 such downhill and uphill slopes and wanted to keep going further. But my running was at a limit and we turned around. You biked the same 5 slopes on your way back too and without requiring my help at any time. 

My second child and your younger sister is born. Its been 3 months since the birth and I'm flabbergasted at how easy you are around Kiana. You are like the perfect big sister. Calm, understanding and helpful. Initially I was concerned that you'd feel neglected, since the newborn will demand so much of mom-dad's attention most of the time. I was worried you'd feel we are being unfair but all those concerns proved to be baseless because you have been so accommodating. You've never complained why we are giving more time to Kiana and not you. You are so much mature, it surprises me everyday. Not only understanding, but you are helpful too, bringing up milk bottle for Kiana, playing with her, talking with her etc.

Notes from "Cancer: Emperor of All Maladies" Part - II

Hormones typically work by binding to receptor in a target cell. ER was the estrogen receptor in cells for binding estrogen. Some breast cancer cells had high levels of ER while some didn't (ER+ve and ER-ve tumors). Thats why only some breast cancer cases responded with ovary removal (i.e hormonal treatment) while others didn't. There was little enthusiasm to treat cancer with hormonal treatment, in favor of chemotherapy.

Adjuvant Chemo: Treating with chemo even after all traces of cancer cells are gone. 50% of women without therapy relapsed but only 33% relapsed with adjuvant chemo.

Both hormonal and adjuvant treatment were not cures. Eventually patients relapsed, even after long remission period.

The death rates for other diseases like cholera, TB, malaria, typhus, scurvy, pellagra etc had dwindled because humans have learned about how to prevent these. The same couldn't be said for Cancer.

Between 1962-85, cancer deaths had increased by 8.7%, primarily attributed to increase in smoking rates in 1950s resulting in increase in lung cancer.

For vast majority of cancer, more intensive regimens of standard chemo treatment did not necessarily mean more survival.

NCI (national cancer inst.) had neglected prevention of cancer over treatment of cancer.

If nearly all men smoked and only some of them developed cancer, then how can one connect the link? Such cause effect relationship was only reserved for diseases where there is a known pathogen and a known carrier, like malaria. To establish linkage, studies were conducted by grouping people into smokers and non-smokers and watching them. After 10-15 years, we count the number of people having cancer in both groups. Doll and Hill created master list of doctor's cohort, dividing it into smokers and nonsmokers. Each time a death was reported, the cause of death was noted and this tabulation was maintained for extended period of time.

Watching evolution in action: Collecting moths across marshy areas of oxford. Mark them and release, then recapture them next year the marked moths and their descendent unmarked moths. There were changes in moth color, wing size, shape etc. Dark colored moths - better camouflaged on pollution-darkened trees - tended to be spared by predatory birds, thus demonstrating "natural selection" in action.

By 1960s, gross annual sale of cigarettes in America peaked at $5billion. Tobacco company began to tout the benefits of filters added to the tips of their cigarettes, after they were concerned of the tightening link between tar, tobacco and cancer. Tobacco company released "A frank statement", a full page ad saying "Experiments with mice showed link between smoking and lung cancer and not humans" which was incorrect because Doll and Hill had performed the studies on humans, not mice. The double standard was evident a decade later when more and more 'human' studies showed the link, the tobacco company countered that smoking had never been effectively shown to cause lung cancer in , of all things, mice.

Strategy of tobacco companies: Obfuscation of facts and reflection of self-doubt.

Tobacco companies were pouring money into research of faction of scientists who believed all diseases, including cancer, were hereditary. Smoking was just exposing the inherent aberration. 

In lung cancer patients, the lung contained layer upon layer of precancerous lesions in various states of evolution. As smoke travelled through the lung, the outermost layers, exposed to highest concentrations of tar, began to swell and thicken. Within this thickened layers, next stage of malignancy was found - abnormal cells with ruffled or dark nuclei in irregular patches. 

Nearly 1mil men and women were involved in the trials to establish connection of smoking with lunch cancer. Relationship was found to be the strongest. Ever since the failure to regulate alcohol during prohibition era, congress had conspicuously disabled the capacity of any federal agency to regulate an industry. Few agency wielded direct control over industry, with the FDA being an exception, but cigarettes have escaped being categorized as a drug. 

Tobacco industry were claiming freely that new filter tips were safe from cancer. Federal agency could not directly control tobacco but FTC, federal trade commission, could regulate tobacco advertisements. And this debate forced advertisements to also accompany the health advisory warning. Tobacco industry wanted to instead be regulated by congress rather than FTC, believing they could pay their money to congressmen for buying their loyalty easily. Tobacco was the economic lifeblood of southern states and the industry had financed multiple political campaigns before. Congress blunted FTC strong message in label to a mere "It 'may' cause health hazard". And so it was proved. The politicians were far more protective of narrow interests of tobacco than of broad public health interest. 

1949, congress had passed Fairness Doctrine, i.e since airwaves are public resources, any public broadcast media had to allow fair airtime to opposing viewpoints on controversial issues. FCC started regulating airtime given to tobacco ads and forcing broadcasting networks to give equal airtime to anti-tobacco ads. Internal report leaked from tobacco industry showed the threat from FCC and it proposed "Doubt is our product since it is the best means of competing with the body of fact".

Frustrated, in 1970, tobacco industry voluntarily pulled tobacco ads from networks. Last cigarette commercial was broadcast on TV on Jan 1 1971 at 1159pm.

Between 1954-84, 300 cases were filed against tobacco company by smokers asking for compensation for cancer but not a single case went against them. Then Rose Cipollone filed charges saying tobacco company knew about the risks but they kept this info hidden from public. This case allowed attorneys to scourge internal documents of the tobacco companies. They found that many cigarette makers not only knew about the cancer risks, but they actively tried to quash internal research that proved it. Fred Panzer, the PR manager at Tobacco Research Instt had laid out their strategy to combat the growing health concern. (1) Create doubt about the health charge without actually denying it (2) advocate the public's right to smoke (3) encouraging objective scientific research to resolve the question of health hazard.

In 1994, in a first, the state of Mississippi filed suit against several tobacco companies seeking to recover over a billion dollars of health care costs incurred by the state from smoking related illness. Tobacco industry is now targeting developing countries due to loose legislations and overall poverty.  

When mesothelioma cases were compared to controls, this cancer appeared to be clustered in certain professions: insulation installers, firefighters, shipyard workers, heating equipment handlers and chrysolite miners. The causal agent: exposure to asbestos.

In 1971, another carcinogen was found. Diethylstilbestrol (DES). DES was prescribed to pregnant women in 1950s to prevent premature deliveries (although it wasn't proved conclusively to be of any effect). A generation later, women diagnosed with vaginal and uterine cancer were questioned, it was found that their mothers had been given DES. DES had skipped a generation. It caused cancer in DES-treated women, but in their daughters, who were exposed to the drug in utero.

Is there an intrinsic property of all carcinogens, which could help us detect them apriori?

Sometimes a bacteria could acquire a gene mutation. Exposure to some substance might cause a higher rate of mutation. Ames found that chemicals that scored as mutagens were also carcinogenic: Dye derivatives, X-rays, benzene, nitrosoguanidine derivatives etc. The test wasn't perfect however because known carcinogens like asbestos or DES didn't cause mutation in bacteria cells. Common property of carcinogens: They altered genes.

Not only chemicals, but in 1960s it was found that chronic, smoldering inflammation caused by a human hepatitis virus could also cause cancer.

One blood antigen was present in several australian aboriginals and also found frequently in asians and africans but markedly absent in europeans and americans. It was called Australian antigen or au. Individuals carrying au often suffered from chronic hepatitis (inflammation of liver). These livers showed signs of injury and repair. Au was found to be neither a human protein or blood antigen. Au was a piece of viral protein floating in the blood, the sign of infection, therefore a person infected with this virus could turn from au-ve to au+ve. This virus turned out to be HBV. It was spreading through blood transfusion. HBV infection increased likelihood of liver cancer. It was therefore a live carcinogen. However, later it was found that the virus doesn't actually cause cancer, but the inflammation induced by the virus in the liver cells, and a cycle of death and repair was responsible for cancer.

Stomach inflammation, called gastritis was precursor to peptic ulcers and stomach cancer. In 1970s, it was common knowledge that bacteria do not grow in stomach. Upon examining biopsies of gastritis patients, the cause was found to be a new bacteria species called helicobacter pylori. But inoculated pigs didn't show signs of ulcers. So Marshall drank a solution of this bacteria himself and within few days fell violently sick. Biopsies proved he got gastritis. And thus the bacteria was associated with the disease and soon after it was linked with stomach cancer as well. An antibiotic was developed which reduced occurrence of gastric cancer in young men and women but not much useful for older patients in whom the inflammation had progressed to the point that eradication of bacteria made little effect.

Question is how could DES, asbestos, radiation, HBV, H.pylori all converge on cancer in different populations and in different organs?

As hormones rise and fall cyclically, the cells shed by cervix changed their shapes and sizes cyclically as well. Observing this you can foretell precise stage of menstrual cycle. In nearly every case of cervical cancer, when Papanicolaou brushed cells of the cervix, he found aberrant and bizarre forms with abnormal, bloated nuclei, ruffled membranes and shrunken cytoplasm that looked nothing like normal cells. Thus a new test for malignant cells was born: Pap smear. Cervical cancer typically arises in outer layer of cervix, then grows in a flaky, superficial whirl before burrowing inward into surrounding tissues. Pap smears were used to detect early and therefore cure cancer by simple surgical procedure. 

Primary prevention: disease prevented by attacking its cause i.e stop smoking or vaccine against HBV. Secondary prevention: disease prevented by screening early, like pap smear, mammography. However with screening tests like these, there was always a debate of overdiagnosis and underdiagnosis. 

Women above 55 had benefited from mammogram screening with a reduction in breast cancer deaths by 20%. Not much benefit in younger women. 

"If a man dies, it is because death has first possessed his imagination".

The toxicity of chemotherapy drugs was limited by the sensitivity of bone marrow. Sometimes patients would be left with no normal blood forming cells because the chemotherapy drugs were too toxic to kill cancer as well as all remnants of normal bone marrow cells. This ceiling was breached when doctors could transplant bone marrow from donors. Sometimes even the new bone marrow cells would attack any residual leukemia left in the patient, thinking it as foreign pathogen. This trifecta of assaults, obliterative chemo, marrow transplant and attack on tumor by foreign cells was fashioned into a treatment procedure of its own, called STAMP (Solid Tumor Autologous Marrow Program) . Soon this treatment was applied for host of cancers, not just leukemia, and remissions were more durable. However tests over the next 2 decades proves that this treatment was also not the cure, as patients often relapsed. 

March 1981, 8 cases of highly unusual form of cancer called Kaposi's sarcoma was reported. However all these cases were violent variants that had exploded into bleeding, metastatic blue-black macules spread all over the bodies. All 8 were homosexuals. The 8th person even had a very rare pneumonia called PCP. PCP only occurs when immune system becomes severely compromised. And then more such cases arose from other parts of the country. This was AIDS. In the early days, the first doctors responsible for treating AIDS patients were oncologists. AIDS patient were treated with chemo, just like any cancer patient.

Jan 1983, in the biopsy of a lymph node of an AIDS patient, signs of a virus were found. It was a retrovirus. An RNA virus that could convert its genes into DNA and lodge into human genome. HIV. 

Genes can move from one generation to next, being carried on chromosomes. In certain bacteria species, genes could also be transmitted laterally between two organisms, even from dead inert bacteria, which means some inert chemical was responsible for carrying genes. This chemical was DNA. 

Central dogma of molecular biology: The unidirectional flow of genetic information. DNA->RNA->Protein. This is universal rule, found in bacteria to humans. 

Some forms of cancer, like breast and ovarian, tended to run in families. 

X-rays was found to vastly increase rate of mutation in genes. X-rays also caused cancer. So a link came to surface. Could cancer be a disease of mutations?

Most of time, when a virus leaves the body, it doesn't leave any footprint behind, our DNA is left untouched. However, RSV (Rous Sarcoma Virus) was different. After infecting cells, it physically attaches itself to cell's DNA thereby altering the genome. The virus was nothing but a single strand of RNA. Thus it was found that RNA could generate DNA. The genes of retroviruses exist as RNA outside cells. When they infect a cell, they make DNA copy of their genes and attach this copy to cell's genes. This DNA copy, called a provirus, makes RNA copies and virus is regenerated to form new virus. Finally the single gene in RSV that was causing the cancer was identified. This gene was called src. The first oncogene. Src worked by encoding a protein which works by modifying other proteins by attaching a phosphate group, to these proteins. This phosphate group attachment acts like a ON switch for the protein. Often one turned on protein would then turn on another protein and so on. A confluence of many such activated switches produced powerful signal inside a cell to change its state from non-dividing to a dividing state. 

Later a nearly identical version of viral Src was found to be lodged firmly in normal cell's genome. RSV had likely picked up an activated Src gene from a cancer cell and carried it in the viral genome, creating more cancers. Virus then acted as a courier. 

Proto-oncogene: precursor of a cancer causing gene. They are normal cellular genes until a mutation induced by chemical or x-rays caused cancer not by inserting foreign genes into cells, but by activating such endogenous proto-oncogenes.

• Humans have 46 chromosomes - 23 matched pairs, one inherited from each parent. In CML, the 22nd chromosome has its head lopped off. The missing head had attached itself to tip of chromosome 9, and a piece of 9 had conversely attached itself to 22. This flip-flop transposition of two pieces is called Translocation. Abl gene was on 9th and bcr gene was on 22nd chromosome. Bcr-abl was the oncogene causing CML.
• To find out correlation of genes and cancer a particular type of hereditary related cancer was chosen I.e retinoblastoma. Its a variant of eye cancer with the tendency to erupt in same family across generations.RB has 2 variants: an inherited familial form and a sporadic form. The familial one is the inherited form, with family history I.e fathers, mothers, cousins, siblings etc also showing the cancer. This form of RB affects both eyes. But then RB was also seen in some patients who had no family history (sporadic form) and this one typically affects only one eye. Familial form typically happens at 2-6months after birth and develops rapidly. Sporadic one developed at 2-4yrs old children and grows slowly. Why? Only 1 genetic change required to develop ‘inherited’ RB but 2 genetic changes required to trigger sporadic RB. Every human has 2 pairs of chromosomes therefore 2 copy of every gene, including ‘rb’ gene. In sporadic RB, both copies of rb gene needs to be inactivated through mutation in each copy of the gene. Therefore it develops later in life. Children with inherited RB, they are already born with one defective rb gene therefore require only one mutation to trigger, therefore develops much earlier. (2-hit theory of cancer)
• Why single mutation in src causes cancer but 2 mutations for rb? Src activates a function in cell division and rb performs suppression of cell division. So 2 classes of genes. (1) Oncogenes which acts by virtue of abnormal cell division (2) anti-oncogenes (or tumor suppressor) which acts by suppression of division. Accelerator and brakes in car. 1 mutation needed for oncogene and 2 needed for antioncogene to activate(or inhibit) their functionalities.Jammed accelerator and failed brakes.
• ras gene was derived out of a human cancer cell (an oncogene), from a patient who died of bladder cancer. rb gene (for retinoblastoma) was also isolated from human cancer cells which is anti-oncogene
• rb gene was also found to be mutated in other cancers like lung, bone, breast, bladder and esophageal etc. between 1983-93, many other cancer genes were isolated-myc, neu,fos,ret,akt (all oncogenes) and p53, vhl, apc (all anti-oncogene).
• Experiment to  induce cancer in mouse by mutating gene: Myc gene was activated in mouse but mice developed only small unilateral breast cancers and that too, late in life. Mice typically developed cancer only after pregnancy, suggesting that environmental influences such as hormones are also strictly required to achieve full transformation. Only active myc gene isn’t sufficient.
• How cancer grows: Transitions in the stages of cancer was paralleled by same transitions in genetic changes. Transition from Premalignant to invasive state was correlated with same sequence of activation and deactivation of genes.cancer is slow march of one gene mutation to next. Cancer cells not only divide uncontrollably but also migrate and invade other organs. Genes encode proteins. Proteins work like small molecular switches. Protein A may turn off protein B which will then turn on C which will turn off D and so on. Such pathways exists in normal cells for normal growth. Similarly in cancer cells, a permanent activated gene will turn on one protein which will then permanently activate another protein which will then permanently deactivate another protein and so on. Certain activated signaling pathways in cancer cells could also induce neighboring blood vessels to grow and then the tumor grows in grape like clusters around those vessels. This is called angiogenesis.The “motility genes” activated by cancer cells are the very genes normal cells use when they require movement through the body such as when immuno-logical cells move to sites of infection. Tumor angiogenesis exploits the same pathways when blood vessels are created to heal wounds. 
• 6 rules of malignant growth
• Self sufficiency in growth signals.
• Insensitivity to growth inhibitory signals
• Evasion of programmed cell death(apoptosis)
• Limitless replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis.
• Treating cancer: achilles’s heels of cancer
• Accumulation of mutations are driving factor of cancer.We’ve to target the hyperactive genes.
• Cancer cells depend on activated pathways for propagation. We’ve to find a way to inhibit the pathway.
• Cancer cells have developed resistance to drugs over the course of cell division. We’ve to mix and match the drugs
• APL cancer cells are left immature. Then a maturation agent, trans-retinoic acid was found. APL patients were given this drug. The cancer cells matured in 4 days, and then having fully matured, the cells began to die out. Remission lasted weeks and months.A combination of chemotherapy and trans-retinoid acid produced no relapse at all in 75% of patients. APL oncogene encodes a protein that is tightly bound by trans-retinoid acid. This binding immediately extinguishes the oncogene’s signal in APL cells.
• Genentech could engineer a human gene into a bacterium, say, and use bacterial cell as a bioreactor to produce vast quantities of that protein. Thus in lab proteins could be made instead of extracting from animals.
• Cancer cells that become dependent on the activity of a gene for their growth can amplify that gene by making multiple copies of the gene in the chromosome. This phenomenon is called oncogene amplification. Her-2 was highly amplified in breast cancer samples. We could divide breast cancer into 2 categories. Her-2 amplified (her-2+ve) and her-2 unamplified(her-2-ve). Then came a anti-Her-2 drug.When her-2 antibody was injected into a her-2+ve cancer patient, the tumors disappeared.
• Women treated with Herceptin along with standard chemotherapy drugs showed remarkable benefit.
• Every kinase attaches a phosphate tag to unique set of proteins in the cell, thus they act like master switches in cells, turning “on” some pathways and turning off some other.Staurosporine inhibited dozens of kinases by binding to a pocket present in most kinases.could such a drug be developed to inhibit cancer specific kinases? A drug was found that could cure bcr-abl positive leukemias.This drug is Gleevec
• In some cases, patients had developed resistance to Gleevec and therefore were relapsing. How can cancer cell become resistant to a drug that directly inhibits its driving oncogene? These cells acquire mutations that specifically alter the structure of bcr-abl, creating a protein still able to drive the growth of the leukemia but no longer capable of binding to the drug. The a new kinase inhibitor was developed to target air-all, dasantib, and this one helped cure leukemia in Gleevec resistant patients.
• In individual specimens of breast and colon cancer between 50-80 genes are mutated, pancreatic cancers had 50-60 and brain cancers had 40-50. Only few cancers like AML, 5-10 genetic mutations found.Set of mutated genes can vary from one breast cancer sample to another. But not all mutations actually cause cancer. Most of them are bystander/passenger mutations which has no impact on cancer. “Driver” mutations are the ones which actually contribute to cancer. 
• Cancer’s immortality is borrowed from normal physiology. Human embryos possess a tiny population of stem cells that are capable of immortal regeneration. In few weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood and then through yet unknown mechanism, lull itself back to sleep.

Notes from "Cancer: The Emperor of All Maladies" - Part I

• In US, 1 in 3 women and 1 in 2 men will develop cancer in their lifetime
• Sidney Farber, father of modern Chemotherapy
• Leukemia is cancer of WBC
• Cancer is disease caused by uncontrolled growth of a single cell. This growth is unleashed by mutations in DNA. In cancer cell, the circuits to regulate cell division and cell death is broken.
• Malignant growth and normal cell growth is so intertwined that its a modern day medicine challenge to distinguish between the two.
• Mutations in cancer genes accumulate with age, therefore cancer is intrinsically related with age.
• Virchow discovered Leukemia in 1847. Initially he called it Weisses Blut (white blood) but later changed it to Leukemia, from Leukos (greek word for white).
• Hypertrophy: Getting bigger by increasing in size. Hyperplasia: Getting bigger by increasing in number. In animals, fat and muscle grow by hypertrophy and liver, gut, skin etc grow by hyperplasia
• Normal WBC can be divided into 2 categories: Myeloid or Lymphoid cells. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are cancer of respective cells. ALL is cancer of immature lymphoid cells. Cancer of mature lymphoid cells is called Lymphomas
• Leukemia can be measured, by drawing sample of blood and just counting the WBCs. Therefore drugs can be given and potency can be assessed.
• In 1949 winter, an antibiotic Streptomycin was purified out of a clod of mold from a chicken farmer’s barnyard.
• William Halsted was pioneer of radical mastectomy in the 1890s.
• Neglect in the field of cancer research was also a factor of its slow prominence in society.
• Cancer was present in 19th century but it was overshadowed by more common illnesses like TB, influenza etc.
• In 1926, cancer became 2nd most deadly in US, after heart disease.
• Anemia is caused by lack of iron but there are variants of anemia that are caused by lack of other molecules. Pernicious Anemia is caused by lack of vitamin B12.
• Folic acid is crucial building block for DNA and therefore for cell division. Blood cells are produced by most fearsome rate of cell division - more than 300 billion cells a day - genesis of blood is dependent on FA. In absence of FA, production of new blood will cease, like what was observed men and women in Bombay due to lack of vegetables in diet. If FA accelarates leukemia, an antifolate will block it therefore stopping leukemia. Basis of Sidney Farber’s chemotherapy.
• Subbaroa’s team could create slight variants of FA, which possessed counter intuitive properties. Such decoy molecules bind to the enzymes and block its action like a false key jamming the lock.
• Antifolate could stop leukemia but remission was inevitable.
• Metastasis: migration of cancer cells from one site to another. Meta-stasis I.e ‘beyond stillness’ in latin.
• Every generation of cancer cells creates a small number of genetically different cells. When a chemotherapeutic drug or immune system attacks cancer, mutant clones that can resist the attack, grow out. Fittest cancer cell survives and cycle continues.
• In 1862, Edwin Smith found the 2500BC papyrus in Egypt which had mention of a tumor in breast.
• Atossa, queen of Persia, was struck by breast cancer in 440BC.
• Also 1000 yr old mummy was found to have spicules in bone, without question, sign of bone tumor, osteosarcoma. Likewise there were other ancient artifacts showing signs of cancer presence.
• Still historically, less mention of cancer. Cancer is age related disease but human lifespan was very less in ancient societies.
• Civilizations did not cause cancer, but by improving human lifespan, it has unveiled it. Longevity is not the only factor. Our capacity to detect cancer earlier and earlier and attributing deaths accurately to it has also dramatically increased its prevalence in modern society.
• Due to modern life culture, some cancers have increased and some have decreased. Stomach cancer was very common in early 19th century because of carcinogens found in pickling reagents and preservatives but modern refrigerators and hygiene policies have reduced it. In contrast, lung cancer has increased because of smoking.
• In the time of Hippocrates, around 400BC, a word for cancer first appeared in medical literature: karkinos (greek for crab). The tumor with its clutch of blood vessels reminded Hippocrates of a crab dug in sand with its leg spread in circle.
• Another greek word, onkos: meaning mass or burden, reminding of tumor especially, which gave birth to field of oncology
• Disease of Depression or melancholia (medieval name for depression) was attributed to be cause of imbalance of black (melas) bile (khole). Only other disease resulting from black bile is cancer.
• Autopsy: (greek) to see for oneself
• Early 19th century cancer surgeons were hesitant to perform surgery but between 1846-1867, two discoveries made surgery viable options for curing cancer. 1 anesthesia in 1846 and antiseptics in 1867.
• Early 20th century, many locally restricted cancers (primary tumors without metastatic lesions) could be removed by surgery. Uterine, ovarian, breast, prostate, colon and lung. If they were removed before they invaded other organs, surgeries produced cures in significant fraction of patients.
• Post surgery recurrences had accumulated precisely around the margins of original surgery, as if minute remnants of surgery had been left behind. This led to the rise of Radical surgery
• Women with metastatic cancer is not going to be cured by radical mastectomy. Women with small confined cancer does benefit from local mastectomy
• Of the 76 breast cancer treated the radical way, only 40 survived more than 3 years.
• X-rays can shatter strands of DNA or generate toxic chemicals that corrode DNA. Cells either die or cease to divide.
• X-rays were ineffective for cancer that had metastasized. X-rays could be used for local tumors. Leading to growth of radiation oncology. 
• Radium was infused with gold wires and stitched directly into local tumors to produce higher levels of X-rays. Surgeons implanted radium pellets into abdominal tumors. By 1930s and 40s, America had a surplus of radium.
• Radiation oncology had 2 limitations: X-rays could only be targeted for local tumors and X-rays themselves were causing cancer. Evidenced by “radium girls”, watch factory workers who developed cancer of jawline, leukemias, bone, tongue, neck etc.
• The dye chemical, Aniline and Aniline derivatives was used to dye animal tissue and it was found out that the dye was selectively coloring some parts of cells, leaving others untouched, binding to some, sparing others. This raised the question. What if some chemical can be found that’d only kill bacterial cells, sparing normal human cells.
• The survivors of mustard gas attack in 1919 were found to have dried up bone marrow, almost zero WBCs. Men were anemic.
• In early 1950s Joseph Burchenal and Mary Lois Murphy tried 6-MP on children with ALL. Cure was temporary, lasting only few weeks.
• National Fundraising effort was started to tackle Polio. Roosevelt, radio personalities, Hollywood starts all collaborated. Within few weeks, 2680000 dimes had poured into White House by citizens. By late 1940s, John Enders nearly succeeded in culturing polio virus in his lab and Sabin and Salk, building on Enders’s work, were ready with first polio vaccine.
• Mary Lasker was called fairy godmother of medical research because of her work to elevate cancer and corr. Research into public limelight.
• Goal directed strategies, like the Manhattan project, is useful during wartime but is of limited use during peacetime.
• A focused drug -discovery unit for anti cancer drugs was instituted in 1954 after much lobbying by Laskerites. Cancer Chemotherapy National Service Center (CCNSC) between 1954-64 would test 82700 synthetic chemicals, 115000 fermentation products and 17200 plant based derivatives.
• Like penicillin mold, which produces penicillin, bacteria also produce antibiotics to wage chemical warfare on other microbes. Once such antibiotic came from rod-shaped microbe called Actinomyces. Waksman called it Actinomyces-D
• Actinomyces D, combined with X-rays, was effective for Wilms’ tumor metastasis, a rare form of kidney cancer. WIlms’ tumor was first metastatic solid tumor to respond to chemotherapy.
• Mycobacteria, germs that cause TB, would become resistant to antibiotics if the drugs were used singly. Same was found to be true for cancer. Therefore a combination of 2-3 cytotoxic drug combination was sought for chemotherapy.
• Choriocarcinoma - cancer of placenta, in pregnant women.
• Li used chemotherapy to treat choriocarcinoma and used the level of Hcg hormone as a tracker of cancer level. He administered chemo until hcg level went to zero. It was found out that patients who had stopped the drug early inevitably relapsed but patient on Li’s protocol remained free of disease. A fundamental principle of oncology emerged. Cancer needed to be treated long after every visible sign of it had vanished.
• Leukemia children treated with VAMP showed great recovery and showed no sigh of cancer cells in blood. But after few months, children came back to hospital with complaints of headache, dizziness, numbness, seizures etc. Bone marrow biopsies were clean but turned out leukemia cells had invaded the nervous system causing quick and unexpected death. Brain and spinal cord are insulated by a tight cellular seal called blood-brain barrier. This is body’s mechanism to keep poisons away from brain. But this defense mechanism also kept VAMP out of nervous system, therefore cancer cells grew uninhibited in nervous system while it was getting cleaned up from rest of body. A very small percentage of patient survived with VAMP, possible because the cancer was treated well before it could invade nervous system.
• Hodgkin’s disease is cancer of lymph glands- a lymphoma. It infiltrates lymph nodes locally, one by one. Other cancers are unpredictable for e.g Lung cancer may start as a spicular nodule in lung and then suddenly ambulate in brain, pancreatic cancer goes faraway to bones and liver. But Hodgkin’s moved more orderly, affecting one node to another, gland to gland, region to region.
• Hidgkin’s could be treated with radiation, but it’d always relapse with affected lymph node immediately contiguous to original radiated area. This gave rise to assigning staging of cancer. Further the stage if faraway lymph node was affected, thereby also reducing chances of cure and recovery. And subsequently, treatment was adjusted as per staging of cancer.
• One side effect of chemotherapy emerged. Several patients cured of Hidgkin’s would relapse with a second cancer - typically an aggressive drug resistant leukemia. 
• In 1961, Pinkel and his team developed 4 innovations to checmotherapy.
• Combinations of drugs is better than single drug but sometimes we need combinations of combinations I.e 6, 7, or even 8 different chemical poisons combined. 
• If needed, inject chemotherapy directly into nervous system to get over the blood brain barrier.
• Add high dose radiation to skulls if needed, to clear last remnants of residual cancer cells.
• Continue chemo even months or years after cancer is cured.
• With above regimens, results were impressive. Even some patients (30%) never relapsed at all. 
• Cancer of scrotum was prevalent among chimney sweeps, Marie curie, radium girls etc, these observations led to Theory of somatic mutations of cancer I. Environmental carcinogens induce permanent cell structure change thereby causing cancer.
• Experimenting with spindle cell sarcoma, Rous found that injecting tumor from one chicken into another causes cancer to transmit. He kept on filtering the cells through finer and finer sieves before transmitting but still was able to transmit cancer. He found that not only environmental carcinogen, but even viruses (which are very very minuscule and therefore can skip through the sieve of the filter) can cause cancer. His virus was later named Rous Sarcoma Virus (RSV).
• First cancer causing virus found  in humans was Epstein-Barr virus (EBV), which causes mono.
• Religious movements or cult are founded on tetrad of elements: Prophet, prophecy, book and revelation.
• National Cancer act, signed Dec 23 1971 by Nixon. Flood of money authorized for cancer research, $400mil for 1972, $500m for 73, $600m for 74, was a monumental achievement.
• Cancer’s spread is erratic and unpredictable. 
• A major trial across US and Canada with 1765 patients confirmed that rates of breast cancer recurrence, relapse, death and distant metastasis were identical for 3 groups of treatments: radical mastectomy, simple mastectomy, surgery followed by radiation.
• Variants of thyroid cancer continued to make thyroid hormone. Even though cancerous these cells remembered their former selves. 
• Normal prostate cells require testosterone therefore malignant prostate cells require testosterone too. When Huggins removed testicles of prostate cancer bearing dogs, the tumors involuted within days. Therefore Huggins proposed that cancer can be controlled by controlling hormones. Huggins developed hormone therapy: injecting synthetic estrogen into males to stop the production of testosterone to cure prostate cancer. This was called chemical castration. Hormone therapy patients also relapsed once they developed immunity to hormone. Only about 2/3rds of all women with breast cancer responded to when their ovaries were removed.

Don't do Micro-Parenting

 Micro Parenting is a crime:

Raising a child is not trivial. Almost every parent I've come across seems to be under so much duress with their children. However, I disagree.

I've a 3yr old myself and I feel a breeze. The key to successful parenting is to do minimum parenting.

Please bear in mind I speak with experience raising my 3year old only, in my household. Granted some kids are extra difficult than others, and some folks extra patient with their kids than me. So things may vary.

My parenting style is simple: Minimal intervention, maximal exposure

Contrast this with my wife, who is a torch bearer of micro parenting. What is my kid doing every second of the day, she has to know. She is obsessed. It feels like she is always scared if something will happen to the kid. Even when the kid is in daycare, my wife is constantly monitoring through the webcam. That I feel is bit extreme.

Anyway, coming to the parenting point. 

We've to understand some qualities that kids generally have. First and foremost, they are hungry for learning, they are inherently brave because they want to try out everything and also, they are intrinsically independent. That is a very key feature. Notice how they progress from skidding to crawling to walking to running. They are always looking to do things of their own. And its criminal if you don't let them. Kids are like a dry sponge ball, ready to absorb anything. All we've to do is roll the ball into a puddle.

When I take my daughter to park, I let her do most of the things by herself. Yes, when she first tried to climb the rock structure, I helped point out where she can keep he feet and which rock to grab onto etc, but after 1-2 times, she was able to do of her own. Now having conquered the basics, I've noticed that when we go to a new park and a different rock climbing structure, she is able to climb it independently. All I do is stand below, fully attentive, ready to catch her if in the rare case she slips.

Contrast that to my wife. Everytime, and I mean every single time, she'll be holding and lifting her up, constantly guiding her where to put feet and where to hold. What does this micro managing do? It makes the kid dependent. Suddenly they feel like they'll not be able to climb if mother were to disappear into thin air right now. Its like deer caught in a headlight. 

My wife actually does have that fear, which induces panic and then leads to bad decisions. Consider the case where you are driving and suddenly google maps stops working. Which highway, which street, where to go, what to do now? For many years, my wife was scared to fill gas in the car. Even after I showed her the entire process and offered to accompany her first few times to calm the nerves but still, if it were possible to avoid doing this by some means, she would avoid. And avoiding is easy. There is always help available, for e.g pick up the phone and ask brother-in-law or friend if they can help fill the gas for her and done. Thats all well and good, but its not independence. If suddenly you are driving and find yourself in a situation where you've to do it, you'll have a panic attack. If kids don't learn to be independent, they'll grow up with this panic attack always lurking in their shadows.