The human body is a truly wonderful place to live, if you can fit in it. It’s warm and protected and, because humans are so clever at finding all the best stuff with their massive brains, you can be assured that, no matter where you nestle to raise a family, there will be some pretty great nutrients coming your way. Little wonder, then, that so many microorganisms choose to make their permanent residence inside of us – by cell count, for every one human cell in you there are ten microorganisms – and while usually that’s a fine and even quite beneficial thing, there are some guests who treat our innards less like a treasured family home and more like a shady one night Air BnB.
When those organisms attempt to invade, consume, or rupture our own cells, it’s up to our body’s defense systems to deal with them. The problem is, microbes are incredibly clever at disguising themselves and there are very many different types of them. How, using purely chemical means, is an immune system to deal in a targeted way with such a rich variety of potential invaders? Until Marian Koshland (1921-1997) came on the scene in the early 1950s, the standard explanation for the startling adaptability of antibodies was the Instructive (or Instructional) Model. This explanation, originating from Nobel Laureate Linus Pauling, held that all antibodies were the same protein, but when they approached a microbe antigen they folded themselves into the shape of that antigen and then locked in shape.
For some two decades that explanation held the stage until, at a conference of the Federation of American Societies of Experimental Biology, a woman stood up to give an oral presentation. Though not entirely unknown, Marian Elliott (who had married fellow biochemist Dan Koshland in 1946), was only a few years out from her PhD and held a position as a mere Associate Bacteriologist at Brookhaven National Laboratory. But Koshland was devoted to absolute experimental precision – no result was to be announced until it was checked and counter-checked, and every rival explanation for the data eliminated. When she said something, as the immunological world would soon come to know, it could be taken as an ironclad expression of the best practices currently available.
The scientists present drilled the young biochemist with questions, unwilling to believe that somebody so comparatively unknown could, with one series of beautifully precise experiments, topple a theory originating from the great Pauling.
At that meeting, Koshland announced that, by virtue of unbelievably minute work in comparing different rabbit antibodies, she had discovered small but significant differences in the amino acids present in them, a result which was impossible under the theory that all antibodies were identical proteins that simply bent themselves to the required shape. The scientists present drilled the young biochemist with questions, unwilling to believe that somebody so comparatively unknown could, with one series of beautifully precise experiments, topple a theory originating from the great Pauling. Question after question, however, she held her ground, explaining her experimental methods and procedures for eliminating rival hypotheses, until by the end of the session the assembled great minds rose in a standing ovation for her, her work, and her bravery in the face of the marshaled forces of scientific orthodoxy.
From then on, it was impossible to think of antibody diversity the same way. Koshland’s result pointed a whole new direction forward in thinking about how antibodies are formed, and therefore how best to study their structure and workings. For forty years after that announcement, Marian Koshland would play a vital role in investigating the links between genetics, biochemistry, and immunology in a manner that squeezed every moment for its full measure of potential.
The origin of that keen drive for accomplishment paired with an instinct for fine detail is difficult to pinpoint within the sparse details of her early story. Born in 1921 to a hardware salesman and a teacher of Danish extraction, the parts of her home life that get stressed the most in accounts from her family and friends were its limitations, rather than its opportunities. Her father was a Southern Baptist of particularly narrow views who did not shy away from corporal punishment and had strong racial prejudices. Naturally smart and self-directed, it appears that Koshland did not come into her own until she fell in with a group of Jewish boys in high school to whom academic challenge and intellectual bravery were the sinews of life truly lived. They challenged her to broaden her horizons and make the most of her mind, and she blossomed from the encouragement.
She made up her mind to go to college, but for a family who had been hit hard by the full force of the Great Depression, a full scholarship was the only viable option. She knew she had to limit herself to the East Coast because of the cost of travel, which cut out of consideration the excellent public schools on the West Coast. The Eastern public colleges at the time were suffering a down tick in reputation, but one of her teachers assured her that, if she applied to a small private school, she had a good chance of getting a full scholarship, and could thereby get the benefits of excellent instruction she craved within the confines of affordability dictated by circumstances. She ultimately chose Vassar, where she lived in a co-op dormitory and sewed her own clothes to save money, and took on secretarial work to pay for her daily living expenses.
The Vassar experience, however, wasn’t panning out quite as planned through her first two years. The instruction was dull and repetitive without a real connection to living science questions. Her sophomore year, however, a new instructor arrived from Yale, Catherine Dean, who specialized in bacteriology and immunology, and was able with her enthusiasm for research and trust in her students to fire the ambition of a rapidly growing core of science enthusiasts.
Koshland began reading about new theories concerning antibodies and their startling capacity to recognize wildly different pathogens. She determined to continue her studies on the next level, but was again hampered by issues of cost. After some research, she found that if she took an all-night bus to Chicago she could just about afford the trip to the University of Chicago, where she enrolled initially to study medicine, but soon found herself bitten thoroughly by the Research Bug. She reinvented herself as a bacteriology research student and, shortly after receiving her MS from the University of Chicago in 1943, she took a job with the wartime Colorado Airborne Diseases Project to look into developing a possible vaccine for cholera. Not only was this work important for fighting cholera, but the research about how mucosal antibodies in the stomach work to combat diseases like cholera would prove useful in the development of the oral polio vaccine later.
Uncovering the mechanisms for the immune system’s startling antibody selectivity became a life’s cause for her…
Developing a vaccine for cholera focused Koshland’s attention on antibodies and the emerging field of immunology. Uncovering the mechanisms for the immune system’s startling antibody selectivity became a life’s cause for her, and she was not long in producing substantial results in spite of growing familial responsibilities. In 1946 she married bacteriologist (and heir to the massive Levi Strauss blue jean fortune) Daniel Koshland. Her father was aghast at her decision to marry a Jew and declared he would not attend the wedding, until her mother threatened separation if he made good on his declaration. The couple proceeded to have five children, but thanks to Daniel’s fortune they were able to hire a daytime nanny to watch after the kids and keep the house clean while Marian and Daniel were off at their respective labs.
Marian and Daniel, however, laid it down as an ironclad rule that everybody was to be back at home and ready for family dinner every day of the week. Marian would come home, cook up a meal for seven, then the family would spend an hour or two talking together around the dinner table, chatting about their day and defending their views about developments in the world, before finally everybody retired to their separate corners of the house, Marian more often than not to stay up late writing up paper work or keeping up with the latest journal developments.
Marian knew her emotional limitations, realized that she was not a physically affectionate or overtly demonstrative individual, and made sure to hire a nanny who would make up for her own shortcomings, somebody who could provide all the hugs and sympathy that never quite came naturally to her. The arrangement worked beautifully until 1965 when Daniel was offered a position at Berkeley. Until then, the family had been happily ensconced in a small town with access to Brookhaven, where both Marian and Daniel worked. The children’s beloved nanny was there, as were all their friends. Marian was involved with the local League of Women Voters, and Daniel was school board president. Everybody was happy, and when it came down to a vote, everybody except Daniel elected to stay. Marian, however, soon changed her mind, telling Daniel that she’d rather he be in her debt than she in his.
So, it was off to Berkeley and a new life, often frustrating for the children, and a new residence in Lafayette where neither Marian nor Daniel elected to involve themselves with the local community in order to concentrate their efforts towards their research and their regular and sacrosanct family time. Marian had by this point already done the crucial work determining the amino acid variability source of antibodies’ amazing specificity, and could likely have had a full-time position at Berkeley but consciously made the decision to continue half-timing until her youngest child was old enough to not need her. She did not receive a full-time position until 1970.
Marian and Daniel were notable for the vast differences in their publication styles. Daniel tended to release results as soon as he was pretty sure they were solidly established, and relished wild ideas. Marian did not publish any result until it was absolutely sure, with every alternate explanation investigated and discarded. The result was work that could be taken as gospel by members of the immunological community but that frustrated colleagues in her lab who wanted more publications under their belt. Between the high standards she set for her lab’s work, and the increasing administrative responsibilities she undertook as Head of the Graduate Affairs Office and Chariman of the Department of Microbiology and Immunology, one would suppose that her career path followed that of most scientists in a similar position – a gradual settling into a personal orthodoxy that allowed things to flow smoothly while freeing up time for the demands placed on senior researchers. Late in her career, however, Koshland saw the power of the emerging field of recombinant DNA, and took a sabbatical to the lab of David Baltimore to pick up the new techniques to use in her own research. She learned the procedures within a year and brought them back to her Berkeley lab, where she employed DNA cloning to sequence the J-chain gene, which has a role to play both in how antibodies are secreted and how they form polymers.
Marian Koshland was a woman who honored clear thinking, and delighted in taking up multiple intellectual positions with her interlocutors to keep them off their toes and force them to shore up their beliefs from multiple perspectives. Not one to give praise when there were even the slightest of corrections to be proffered, she was generally acknowledged as someone who could frighten and inspire in equal measure, who deeply cared about the truth enough to insist upon its accurate representation, and about people enough to always be trying to make them better, instead of weighing them down with insincere puffery. She worked until the bitter end, graduate school papers strewn across her hospital bed even as cancer was going about its dread business within her body. After her death in 1997, both UC Berkeley, where she did so much of her crucial work, and Haverford College, where she sat on the Board of Trustees for twelve years towards the end of her career, dedicated buildings in memory of the woman who looked within the human body’s capacity to heal itself, refused to accept reigning explanations, and gave us our first glimpse of how we keep our most unruly visitors definitively at bay.
FURTHER READING: There is a marvelous resource assembled at the instigation of Dan Koshland after the death of his wife in 1997, Marian E. Koshland: 1921-1997: Oral History Transcript: Retrospectives on a Life in Academic Science, Family, and Community Activities (2003). It features interviews with her children, husband, and co-workers covering multiple aspects of her life, along with several documents of interest, including a very brief article she wrote about her career. As a work in the public domain, it’s available at a reasonable price from a number of those delightful public domain printers that skulk about Amazon doing their priceless work.