Ticket to America (II): Of Elephants and Enzymes

Cambridge, Massachusetts, 1971.

Soon after arriving at Harvard, I went to the office of Professor Frank Westheimer for the obligatory visit that all of us first year grad students were expected to make. According to the Chemistry Department’s tradition, it was better that our choice of doctoral advisor be informed by science and fit than by fixation with celebrity.

His office was spacious by the standards I’d gotten to know from the cramped quarters of my profs at RPI. He invited me to sit on a blue sofa placed over a large oriental rug. The walls were covered floor to ceiling with multicolored bound volumes of The Journal of the American Chemical Society (in red), Biochemistry (in green), and The Journal of Biological Chemistry (in blue), all of them with white spine letters.  In one corner was a mahogany stand-up desk, the first of its kind I’d ever seen. It held a 1940s typewriter next to which Westheimer, who endured life-long back pain, would stand for hours writing his pioneering papers. He was close to sixty years old when I met him that day in 1971. A tall and thin man, his plaid blue jacket and tie made him look like the central casting choice for a professor.

Behind the tall desk was a special part of his wall: the PhD theses of several generations of grad students were all neatly lined up, bound in red leather with golden letters. And next to that was a corkboard where he had pinned dozens of Polaroid shots of everyone who had come to visit him, with their names scribbled in black and blue. He freely admitted to having no memory for names, so this was his systematic method of dealing with the problem. His was a disconcerting contradiction: he was a sharp organic chemist, a science that flourishes on memory, yet he had a surprising inability to recollect simple names. I heard many an anecdote from scientists who had met Westheimer at a conference and were told, in a matter-of-fact tone, “I’m sorry, I should know your name but I’m terrible with names, so please remind me.” He would say this calmly, in a soft and caring tone, showing neither embarrassment nor shame. I have tried it and it works.

Westheimer was only one in a collection of impressive chemical stars that the Harvard Chem Department had assembled in mid-20th century. Perhaps the most famous one was Robert Woodward, who is considered by many to be one of the top two organic chemists of all time, the other one being Justus von Liebig, who had lived and worked in Germany a century earlier. Among other things, Liebig discovered that plants fix nitrogen from the soil and carbon dioxide from the air, and then invented nitrogen fertilizers. Talk about earth-shaking innovations. Woodward was in that league. By the time I was sitting in Westheimer’s office, Woodward, whose labs were downstairs, had already shown that, with good thinking and planning, a chemist could synthesize complicated natural products such as chlorophyll. For all of that, he had won the Nobel Prize in 1965.

I was at Woodward’s lecture in the early seventies when he finished the synthesis of the unbelievably complex Vitamin B12 molecule. The postdocs who had helped him came from many corners of the world. As he was slowly describing the masterly synthesis of this or that part of the molecule, he would name the postdoc, his or her nationality, and plant a small flag on the long desk between him and the audience. At the end, with dozens of multicolored flags from one end of the desk to the other, the lecture hall looked like a meeting of the United Nations Security Council.

Also in the building were the labs of E.J. Corey (we called him “E.J.”), who would get the Nobel Prize in ‘89 for advancing the theory of organic chemistry. Other neighbors included Konrad Bloch, Nobel ‘64 for figuring out the biosynthesis of cholesterol, and Bill Lipscomb, who would get a Nobel in 1976 (while I was still there), for his studies of boron. And across the quad in the bio labs worked James Watson, Nobel ’62 for figuring out that DNA was a double helix.

Put simply, the ten acres where I would live and work had some of the most insightful chemical brainpower on earth. I was quite intimidated to be sitting in Westheimer’s office that day. (I never felt comfortable calling him Frank until decades later. During my graduate life and for many years afterward he was Dr. Westheimer.) I felt small, surrounded by all that intellectual and professorial power.

After dutifully taking a Polaroid snapshot of me sitting on his blue sofa and making a big deal of waiting for its development, writing my name on it, and pinning it to his wall, he turned to me.

“So, you want to be an organic chemist, eh?” he asked.

“Mm, yes,” I said, “. . . always wanted to be one.”

“And who did you have in mind to be your advisor?” he added offhandedly.

“Well,” I replied, “I’m interested in synthetic organic, so I thought maybe Professors Corey or Woodward . . . ” Then I stopped, as it suddenly dawned on me that within the first fifteen seconds of our conversation, I had already turned him down. I flushed when I realized my pathetic ineptness.

“Ah! Excellent choices both,” said Frank, smiling. He let that linger for a moment. “But you know something? I think that synthetic organic chemistry is old.” And he added, in  what turns out to be the best piece of professional advice anyone has ever given me: “The future belongs to biology.”

Still reeling from my faux pas, I said nothing, embarrassed as I now was by my ignorance of the future.

Frank was one a group of pioneering mid-century scientists who bridged chemistry and biology. He and his colleagues were known as “bio-organic” chemists.  He understood that chemistry was chemistry, whether you applied its principles to oil and vinegar, or to enzymes and DNA. He refused to see biological cells as black boxes, where mysterious things happened. He insisted that the things that happened in there were not at all mysterious but operated under the same natural laws that controlled the bonding of oxygen and hydrogen to form water. He particularly loved enzymes. These are highly specialized biological catalysts: they speed up reactions between other molecules in a living cell, while remaining intact themselves. After facilitating one reaction, an enzyme is ready for the next identical one. Enzymes are like specialized workers on an assembly line, quickly repeating their task over and over. Frank spent a large part of his life puzzling over how enzymes do this and, once he understood, had a wonderful and straightforward manner of explaining it to the rest of us.

“How about if you take Konrad Bloch’s course on metabolism?” he asked. “It’s offered this semester and Konrad is one of the best teachers in our department. You do know who he is, right?”

“Yes, of course,” I lied. Easily.

“Konrad will teach you a lot about enzymes . . . they are one of the main areas of my research,” said Frank.

“OK,” I said. “I’ll sign up for it.”

“Great, here are some papers of the work we do in my group.  Read them and let me know if this is interesting to you. We would love to have you in our labs for your PhD work. And, you know? Even if you end up being a synthetic chemist, it’s always good to know biology.” And with that, he shook my hand and escorted me out of his office.

My appointment with Woodward, which was scheduled for the following week, had to be cancelled because the man had been called to Switzerland where he also had labs at the Zürich Polytechnic, and his reputation for never being around his grad students was confirmed. My appointment with E.J. went badly since, having heard from the scuttlebutt that he expected his grad students and postdocs to practically live in their labs, I had lost interest.

So, I gave up on celebrity and chose fit. Frank’s warmth and prescience had enchanted me. His feat went as far as getting me to leave behind my earlier fascination with polymers and instead develop a love for biological chemistry.

A lot of Frank’s top work was already behind him by the time I joined his lab, but his scientific passion was as fresh as in his early years. He had an inquisitive mind as sharp as any, and he insisted that no question was beyond pondering. He would sit in the company of his grad students and postdocs and suddenly, out of the blue, ask, “If someone wanted you to calculate the number of elephants in South Africa, how would you go about it?” He wanted us to develop a sense for doing quick order-of-magnitude calculations, a talent that is invaluable to working scientists. “Are we talking tens of thousands, or hundreds of thousands, or millions?” he would ask about all sorts of things, whether enzymes or elephants. He was the ultimate academic snob, believing in his heart that there simply was no other place in the scientific universe where intellectual life was as good and rich as in Cambridge.

And Frank was right, of course. The future did belong to biology. By 1977, when I finished my PhD on the enzymes of phosphate metabolism, the mechanism of DNA replication was well in hand. With that understanding came the ability to fragment DNA,  splice, and recombine the fragment into the DNA of another organism, and pretty soon folks were making human insulin in bacteria. This revolution in academic biology, in turn, sparked the interest of venture capital communities that founded the Genentechs and Amgens of the world. Thus, was born the biotech industry, as well as its need to have patent lawyers who understood biological chemistry.  That is a story for a whole different book, one which is coming out later in 2024. Stay tuned.

***

In 1988 Frank received the Priestley Medal, the highest honor in American chemistry. In the late nineties, in a vindication of his life-long conviction that the future belonged to biology, Frank saw the Harvard Chemistry Department renamed “The Department of Chemistry and Chemical Biology.” It must have been sweet for him. Sadly, he never got a Nobel Prize, an honor all of us students from his lab believed he was owed for his groundbreaking work.

In case you are wondering . . . the number of elephants in South Africa is in the low hundreds of thousands, not in the tens of thousands, but not in the millions either.