A printer’s son in New York
Herbert Aaron Hauptman was born in New York City on February 14, 1917, to a Jewish family. He was the oldest of three sons of Israel Hauptman, a printer, and Leah Rosenfeld Hauptman, a sales clerk in a department store. His interest in science and mathematics began, as he put it, as soon as he had learned to read, and it never left him.
He attended Townsend Harris High School, a selective public high school, won the Belden Prize gold medal in mathematics in 1935, and took his bachelor’s degree in mathematics at the City College of New York in 1937. One of his classmates was a chemistry student named Jerome Karle. Hauptman earned a master’s degree in mathematics at Columbia University in 1939.
Marriage and war
In the autumn of 1940 Hauptman went on a blind double date and, by his own cheerful account, preferred his friend’s date. She was Edith Citrynell, a future teacher, and they were married within weeks, on November 10, 1940. They had two daughters, Barbara, born in 1947, and Carol, born in 1950.
During the Second World War he served as a U.S. Navy ensign in the Southwest Pacific, where he was trained as a weather forecaster. After one day of firefighter training he was made fire marshal in the Philippines, an assignment that nearly cost him his life twice. He carried a calculus book with him to the Pacific and studied it in his rare spare moments, keeping his mathematics alive through the war. The experience of war left him with a lasting dislike of military adventures, and in later years he actively protested American involvement in the Vietnam War.
Partners at the Naval Research Laboratory
After the war Hauptman decided to pursue an advanced degree and a life in basic research. In 1947 he joined his old classmate Jerome Karle at the U.S. Naval Research Laboratory in Washington, D.C., while studying for a doctorate in mathematics at the University of Maryland. Karle was a physical chemist; Hauptman was a mathematician. As Hauptman later wrote, their backgrounds complemented each other nicely, and together they decided to tackle the central obstacle of X-ray crystallography, the phase problem.
Crystallographers shine X-rays through a crystal and measure the pattern of spots they produce. The intensity of each spot can be measured, but the phase of each scattered wave cannot, and without the phases the pattern cannot be converted into a map of where the atoms are. Many scientists believed that the information was simply lost and that the problem could never be solved from the measured data alone.
Solving the unsolvable
Hauptman and Karle showed otherwise. Starting from the simple physical fact that the density of electrons in a crystal can never be negative, they found that the measured intensities themselves constrain the possible phases. Hauptman brought the decisive mathematical tool: probability. They worked out joint probability distributions of the quantities measured in an X-ray experiment and used them to estimate the most likely values of the missing phases. They also introduced the ideas of structure invariants and seminvariants, special combinations of phases that do not depend on where one chooses to place the origin of the crystal’s coordinate system and that link the observed intensities to the phases needed. With these tools they worked out recipes for fixing the origin in every one of the centrosymmetric space groups, the symmetry classes into which such crystals fall. Their approach built on an equation published by David Sayre, giving it a rigorous probabilistic foundation. In plain terms, they showed that the pattern of spot intensities, which everyone could measure, contains enough hidden information to make educated, testable guesses about the phases, and that those guesses can be checked and refined until a clear picture of the atoms emerges.
Their 1953 monograph, Solution of the Phase Problem I: The Centrosymmetric Crystal, contained the main ideas, and Hauptman’s doctoral dissertation at Maryland, on an n-dimensional Euclidean algorithm, grew out of the same work. Extensions to other kinds of crystals followed in later years. Together these became known as the direct methods of crystal structure determination.
Years of doubt
For many years other scientists were sceptical of the work, and it was largely ignored. A mathematician claiming to have solved a problem that chemists considered insoluble met with disbelief, and the calculations the method required were difficult before modern computers. It took the practical successes of the 1960s, many of them achieved by Isabella Karle at the Naval Research Laboratory, and the spread of computers to make the methods widely accepted.
By the 1970s crystallographers around the world were using direct methods, including on biological molecules, and they became the standard way to solve the structures of small and medium-sized molecules. In 1985 Hauptman and Jerome Karle shared the Nobel Prize in Chemistry for their outstanding achievements in the development of direct methods for the determination of crystal structures. It was unusual for the chemistry prize to go to a mathematician.
How it changed medicine and chemistry
Knowing the exact shape of a molecule is the starting point for understanding how it works and for designing new ones. Before direct methods, solving a structure could take months or years; afterwards it often took days, and today, with computers, it can take hours. Chemists use the methods to determine the structures of new compounds, natural products, vitamins and hormones, and pharmaceutical researchers use crystal structures to confirm what they have made and to understand how drugs fit their targets.
As the president of the University at Buffalo put it when Hauptman died, his work continues to have monumental implications for the design of therapeutic drugs. Crystallography laboratories around the world use software built on the probabilistic ideas he and Karle introduced, usually without a second thought.
Buffalo
In 1970 Hauptman left the Naval Research Laboratory to join the crystallographic group of the Medical Foundation of Buffalo, a private research institute in western New York. He became its research director in 1972, succeeding Dorita Norton, and later its president. In his Nobel autobiography, written in 1985, he noted simply that his work on the phase problem continued to that day; it would continue for another quarter of a century. There he formulated the neighbourhood principle and the extension concept, which deepened the probabilistic theory, and from the 1980s he worked on combining direct methods with other techniques to solve the far larger structures of proteins and other large biological molecules.
Later he reformulated the phase problem as a minimal principle and, with colleagues including Charles Weeks and George DeTitta, applied it to larger and larger molecules. In 1994 the institute was renamed the Hauptman-Woodward Medical Research Institute, honouring him and the benefactor Helen Woodward-Rivas. He was also a research professor at the University at Buffalo, where he held appointments in structural biology and computer science. The computer science appointment was fitting: methods that had once required weeks of hand calculation now ran as programs, and the bigger the molecule, the more the mathematics depended on computing power.
Humanist, artist and Jewish New Yorker
Hauptman grew up in a Jewish family in New York and went through the city’s free public colleges, the path that took many children of Jewish immigrants into science. In adult life he described himself as an atheist and a secular humanist. In 2003 he was one of 22 Nobel laureates who signed the third Humanist Manifesto, and in 2006 the American Humanist Association gave him its Isaac Asimov Science Award. He also received the medal of the Jewish Academy of Arts and Sciences in 1986 and was made a fellow of the academy, and Bar-Ilan University in Israel awarded him an honorary doctorate in 1990.
Outside science he loved hiking in the Blue Ridge Mountains of Virginia and listening to classical music. His great hobby was making stained-glass models of geometric solids, including stellations of the Platonic solids, inspired by mathematically defined shapes. A permanent collection of his stained glass is displayed at the institute that bears his name.
Later years and legacy
Hauptman wrote three books, nearly 170 peer-reviewed papers and chapters in dozens of others, and presented his work at more than 280 meetings. He shared the American Crystallographic Association’s Patterson Award with Karle in 1984, received the National Library of Medicine Medal in 1986 and the Dirac Medal of the University of New South Wales in 1991, and was named Citizen of the Year by the Buffalo Evening News in 1986. He was elected to the National Academy of Sciences in 1988 and received honorary degrees from universities in Poland, Israel, Italy and the United States, including the University at Buffalo in 2009. He came to work at the institute every day until he was well into his nineties, mentoring younger scientists and staff.
He died in Buffalo on October 23, 2011, at the age of 94, survived by Edith and their daughters. The University at Buffalo called him widely considered the most important scientist ever to have lived in western New York. His legacy is a mathematical key that unlocked the shapes of molecules, turning a problem many thought impossible into an everyday tool of chemistry and medicine.
Sources & further reading
Herbert A. Hauptman, Biographical, NobelPrize.org · Obituary: Herbert A. Hauptman (1917–2011), American Crystallographic Association · Hauptman obituary, UB Reporter, University at Buffalo · Herbert A. Hauptman, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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