How does our body manage to make a vast array of diverse anitibodies?

Antibodies are proteins, which are encoded by genes; one gene one protein.  The human genome contains fewer than 50,000 genes, and yet we seem to have capability to make unlimited diverse antibodies as the need arises.  This puzzle was solved by Susumu Tonegawa who was awarded a Nobel Prize in Medicine in 1987.

Our immune system has evolved a unique genetic mechanism that enables it to generate virtually unlimited number of different antibodies by joining separate gene segments together before the codes (nucleotides sequence) are transcribed into messenger RNA, which are then translated into a different language—sequence of amino acids of a protein, or antibody in this case.

We all know it was Salvador Luria who sent James Watson to to meet with Crick.  It is less well known that both Luria and Renato Dulbecco had a strong impact on Tonegawa’s career.  In his autobiography (A Slot Machine, A Broken Test Tube), Luria wrote about his stay at Indiana University,

And my very first graduate student in Bloomington, in 1947, was a thin young man named Jim Watson, of twice double-helix fame—for his discovery of DNA structure (for which he shared a Nobel Prize with Francis Crick) and for the excellent book he wrote about that discovery.  With me Jim worked on the reactivation [of killed bacteriophage] phenomenon.  My role in arranging Watson’s fateful move from Copenhagen to Cambridge has been recounted many times in books on the DNA story.  That I arranged the move is true; that it was arranged when I met the British spectroscopist John Kendrew, and that John and I were congenial because we both were socialists is also true.

When the U.S. Immigration wouldn’t extend his stay in the States, it was Dulbecco sent him to to work with Niels Jerne.  On his Nobel Lecture in 1987, Tonegawa began with

One day in the fall of 1970, I received an airmail letter from Renato Dulbecco who was travelling in Europe. At that time I was a postdoctoral fellow in his laboratory at the Salk Institute. The letter, written on stationery of the Hotel Hassler in Rome said:

“Dear Susumu,

I don’t know what arrangements you have made for after your departure from La Jolla [where Salk Institute is] at the end of the year but I would like to mention to you another possibility. The Institute of  Immunology in Basel, Switzerland will start operating in a month. They already have an excellent collection of immunologists, but have not yet built an adequate background in molecular biology. I talked about you to Niels Jerne, the Director, and they are interested in having you there …

Thanks partly to this remarkably prophetic letter and partly to the immigration law that prevented me from remaining in the U.S.A., in February 1971 I found myself in this cozy Swiss town almost completely surrounded by immunologists.

Luria later recruited Tonegawa to MIT where he was at the time of his Nobel Prize award.  Tonegawa also bridged the molecular biology to immunology.

Antibody doesn’t always confer immunity or protection: even a Nobel laureate had a misconception about it

The invention of polymerase chain reaction or PCR by Karis Mullis (see photo) propelled the genetic science to a higher level—a quantum leap.  Mullis has been ‘carried away’ after he was awarded a Nobel Prize in Chemistry in 1993.  He has since made outrageous anti-science statements, saying things without merit and without taste.  I honored him sarcastically with a ‘Flamboyant Flame’ Intellectual Cologne (see the article of ‘Intellectual Cologne’)

Ted Koppel on ABC’s ‘Nightline,’ once said, rightly so.

Take all MVPs from professional baseball, basketball, and football.  Throw in a dozen favorite movie stars and a half dozen rock stars for good measure, add all the television anchor people now on the air, and collectively, we have not affected the current good or the future welfare of mankind as much as Kary Mullis.

In his Dancing Naked in the Mind Field (published 1998), questioning HIV causes AIDS, Mullis wrote,

I read the Papers in Science for which they had become well known as the AIDS doctors, but all they had said there was that they had found evidence of a past infection by something which was probably HIV in some AIDS patients.  They found antibodies.  Antibodies to viruses had always been considered evidence of past disease, not present disease.  Antibodies signaled that the virus had been defeated.  The patient had saved himself.  There was no indication in these papers that this virus caused a disease.  They didn't show that everybody with the antibodies had the disease.  In fact, they found some healthy people with antibodies.

His writing (as late as 1998) revealed he had misconception of antibody.  He only knew “Antibodies to viruses had always been considered evidence of past disease, not present disease.”  Little did he know that some viruses are smarter than he is (or all of us) and can master their genetic know-how to evade our immune system.

He wrote, “they found some healthy people with antibodies.”  It has been a common knowledge that HIV patients with antibody may remain ‘healthy’ until they fell ill with AIDS (after CD4 count drops to certain level).  And yet Mullis used this phenomenon refuting HIV as the cause of AIDS.  Ironically PCR (Mullis’ great invention) greatly helps the advancement of HIV research.

He did admit that “It was a little out of my field of biochemistry, and these men were specialists in retroviruses [HIV]”  This turned out to be his only correct statement.

Wearing a Nobel laurel, Mullis’s words carry weight and general readers would believe in every word he utters.  Thus he is recklessly irresponsible.  Reading may be hazardous to your mind or health.

Comparing with Young Abe Lincoln: a grandiose delusion of mine?

Lincoln’s mother died when he was 9-years-old and his step mother, Sarah Bush Johnston, raised him like her own (“She was all of a mother to him [Lincoln].  He was her boy more than any born to her.” She brought three of her own children when she married Thomas Lincoln.) She lived to see her step son became the greatest President in the country, and survived him four years.  Lincoln once said of her, “All I am, and all I hope to be, I owe to my darling mother!”

The most amazing characteristic of his life is the expansion of his mind through the written words, which lifted him out of the Indiana’s wilderness, where “books ain’t as plenty as wildcats in these parts o’ Indianny.” 
Carl Sandburg wrote,

“At age of 7 the young Abe would lie on the dry leaves [his soft bed] at night contemplating what ‘independent’ or ‘predestination’ means. . . . His father talks about the waste of time in ‘eddication’; . . . but the stanch [staunch], yearning stepmother, Sarah Bush Lincoln, comes between the boy and the father.  And the father listens to the stepmother and lets her have her way. . . . The farm boys talked about how Abe Lincoln was always reading, digging into books, stretching out flat on his stomach in front of the fire place, studying till midnight and past midnight . . .”

Lincoln told Dennis Hank (his cousin), “The things I want to know are in books; my best friend is the man who’ll git me a book I ain’t read.”

My family: June 1956 (lunar calendar) on the birthday of my maternal grandmother

My mother often said she never had to ask me to read the books because I was always reading.  The electric outage was common and routine in the village, Xia-tang (下潭) where I grew up; many times a week and often lasting for hours.  I recall my mother would discourage me reading with a candle light saying it would hurt my eyes.

While attending the Chia-yi Middle School and High School, for a while I lived with my second sister and biked to school and after school I often diverted to the city library or ‘People Service Station’ (民眾服務處, sponsored by KuoMing Party [國民黨], thus a propaganda site) where newspapers and magazines are provided.  I was never happy or satisfied as the books were so limited and scarce; I could hardly find books of poignant interest.  My second sister was my very first teacher (first grade—there was no kindergarten in our village) and she would say if I read I would go places.

Lincoln would read between the plow handles and would be reading while walking, and would stop in the middle of the road from time to time until he got it straight.  During my middle school days (grade 7 to 9) and part of high school years I rode a primitive small train (used to haul the sugar canes as well as passengers) from Po-tzu to Chia-yi where my school locates.  It took the train one hour to travel the distance of about 10-11 miles.  Then all the students walked 30 minutes from the train station to the school in files; we usually formed 3 rows and I always stood in the middle so that I could walk and read all the way to school without worrying being hit by the cars or bikes.

Lincoln’s family moved from Kentucky to Illinois when he was 18 years of age, Carl Sandburg wrote,

“Two of the wagons had two yoke of oxen each and one wagon had four horses.  On the wagons were Tom and Sarah Bush Lincoln [Lincoln’s step mother], her three children, . . . Abraham Lincoln on and off an ox wagon with a goad coaxing or prodding the animals and bawling at them to get along.  They stopped where night found them, cooked supper, slept, and started at daybreak.  What with the ground freezing at night and thawing in the day, the oxen and horses slipped and tugged, the wagon axles groaned, the wooden pegs and cleats squeaked—a journey, Lincoln said later, “slow and tiresome.” . . . After traveling over 200 miles to Macon County, Illinois. . . . ”

We moved from Xia-Tang (下潭) to Po-Tzu (朴子) when I was at my fifth grade and water buffalo was our U-Haul.  I vividly recall that once the water buffalo suddenly stopped and defecated exactly in front of me; then I realized why my sisters gave me the honor of sitting in the middle in charge of the water buffalo.  Lincoln said their journey was “slow and tiresome,” but, ours was “slow but exciting,” as I thought we’re moving into a big city (朴子).

Our ox-vehicle (牛車) is a 4-wheel “medium sized car”, fancier than the photo shown; the water buffalo is essentially the same.

You may have noticed that I used quotes excessively on purpose in my writings; I constantly write down something on a piece of paper, on the notebook or type into computer.  Abe Lincoln apparently also had this habit.  He might even write on the fire shovel by using a piece of charcoal, and later copied into a piece of paper or notebook.

Lincoln was born and raised in a log cabin; the house in which I was born was comparable.  Jo and Sean saw the house in which I grew up until my fifth grade when we moved to the ‘big city’—Po-tzu, 朴子 (We never had a running water inside that house.  I saw a similar water pump in Harvard Yard some years ago; I was an expert using it, even though my left thumb was once half crushed operating it.) 

Jo and Sean also met my playmate and without the benefit of communication with him when we visited Xia-tang (下潭); they marvelled at the skill of chewing and spitting 檳榔; they could appreciate the two sets of mind made all the more difference by readings only. 

Our large family all slept in the bed room—the one and only; I now may call it ‘master bed room.’  The youngest one had the privilege of sleeping next to my mother; when my younger sister was born, I asked to sleep at the feet of my mother near the edge of the bed.  (I do not recall this, but my elder sisters attest to it.)  A wrong turn, I would be on the hard, shinning dirt floor, which impressed and amazed Jo and Sean.  Carl Sandburg also described “the floor was packed-down dirt” in Lincoln's home.

The house in which I was born was in the even smaller village; the mud house was torn down and a new modern-looking house was built in the same site when Jo and Sean visited; they did see the chickens running around in the front yard of the house.  

I was born at the end of WWII, at which time Taiwan was still occupied by Japan, making us in the Axis camp.  Bombing by American airplanes became more often and intense, and that is why my mother retreated to the small village where I was delivered to this world by my father.  The mud house was literally built by the mud mixing with the shells of the rice, and no cement at all.  

Jo and Sean had visited the village and field where my father studied while having his water buffaloes grazing.  He knew the only way could lift him out of the desolate swamp was through education to expand his mind.  It was extremely difficult to enter the only medical school in Taiwan then—the one that became the now prestigious National Taiwan University College of Medicine after the Japanese surrendered at the end of WWII—as the Japanese, being the ‘occupier’, reserved most of the spots for Japanese living in Taiwan .   

My father (photo at his medical school days) managed to enter that medical school through his motivation and determination and Jenny and Jason Lin’s grandfather was his classmate.

Love in Space and in Shakespeare's Works

While in space in December 2006, Commander Oefelein received an email form Capt Colleen Shipman, “I will have to control myself when I see you.  First urge will be to rip your clothes off . . .”—now you know why the astronaut has to wear special protective clothes : )

The space suit is designed to be torn-resistant and fire-resistant as passion is ‘hot’ (heat-producing and fire hazard)

NASA has been criticized not doing a good job in monitoring the mental health of astronauts.  In my view, NASA knows their astronauts better and is very ‘considerate’ in allowing the astronauts to receive emails from their ‘loved’ ones when they are in space.  And the names of the ‘loved’ ones have to be pre-approved by NASA.

For those who are puzzled how this astronauts space love triangle could have happened, take hint from the Preface of Shakespeare’s Works that Samuel Johnson wrote in 1765:

Upon every other stage the universal agent is love, by whose power all good and evil is distributed and every action quickened or retarded.  To bring a lover, a lady, and a rival into the fable; to entangle them in contradictory obligations, perplex them with oppositions of interest, and harass them with violence of desires inconsistent with each other; to make them meet in rapture and part in agony, to fill their mouths with hyperbolical joy and outrageous sorrow, to distress them as nothing human ever was distressed, to deliver them as nothing human ever was delivered, is the business of a modern dramatist.  For this, probability is violated, life is misrepresented, and language is depraved.

From the evolutionary gene change to my childhood story

After reading the article about the genes regulating metabolism, Janice wrote, “Now that food is abundant, we’d have to override those formerly rational evolutionary impulses and tell ourselves not to eat all available food.  So restricting our diets is rational and irrational.”  I think she got my points.

We often lament how difficult it is to shed a pound or two, some, pointing to food, even said, “I put on 2 pounds just look at it!”  Each gene may have several alleles all with same function but some variation.  The process of burning glucose to yield energy (ATP) is quite complex with numerous steps, thereby involving many enzymes and genes.  Let me take you back to millions of years ago when cave was still our home.  Let assume there were 4 sets of alleles in the gene pools, each set of alleles (of genes) produces enzymes with different proficiency—judged by how many ATP produced upon burning of one molecule glucose.

Those with alleles 1 will have to burn twice as much glucose to yield the same amount of energy as those with allele 4.  Natural selection is about the ‘survival of the fittest,’ when food was scarce; the allele 4 is the fittest; and they survive to reproduce.

During my talk at Bible Class, I used an example comparing mom and me with those living in the cave.  There are two persons and 4 refrigerators / freezers in this house, not counting the small refrigerator.  Provided there is a big storm, we can survive for months without leaving the house, those living in the cave wouldn’t be so lucky; and only those evolved efficient and proficient genes survived over the eons.

Millions of people are still starving around the world. So the genes we developed over the long evolutionary history to make the storage of energy expedient and efficient and the expenditure of it economical are still favorable to them or even to me.  Let me tell my childhood story.

I really do not have to go far to use the un-developed or war-torn countries as an example.  I can simply use my own childhood story (This is something Jo wanted me to write; this was when I grew up in that village that Jo and Sean once visited. Janice and Joy never had the good fortune to do so.)  I vividly recall that all children in every household were excited for a feast, which is defined as ‘having a chicken on the table' on certain religious days; anticipation was on the air.  In those days all meats (pork or poultry) were so scarce and expensive; having meats on the table often signifies special occasions.  On special religious days all these ‘sacrifices’ had to be dedicated to Buddha or many generations of ancestors before we could enjoy it.

The eldest son of my eldest sister is only 5-6 years my junior and we all lived in that village and my sister’s family might join us for the ‘feast.’  Unfortunately a chicken only has two legs, so my mother often had to hide at least one leg for me and one for my younger brother, lest my sister’s son, Ming Hong, grabbed it.  My sister told this story saying how much my mother loved me!  And she didn't have the luxury to show her affection to her own son!

You can never imagine that there was much more love than protein in that little chicken leg.  Chickens were also lean and mean without much food available in those days