James Watson and Francis Crick worked out the spiral structure of DNA in 1953, but they were not proved right until Dr. Alexander Rich used X-rays to produce a distinct image of the famous double helix in 1973. After he saw it, Dr. Watson phoned Dr. Rich to thank him; it was the first good night’s sleep Dr. Watson had enjoyed in 20 years.
For nearly six decades, Dr. Rich, who died at 90 on April 27 in Boston, doggedly investigated DNA and RNA, the fundamental molecules of life. He helped puzzle out the structure of collagen, a protein that is abundant in ligaments and skin, and he discovered that DNA can exist in an odd zigzag form, which he called Z-DNA. His work provided insights into how cells manufacture proteins, and laid the groundwork for techniques that scientists use to identify, manipulate and replace bits of genetic material. Diagnostics for H.I.V. infection and tests for genes that cause breast cancer are among the technologies built on his discoveries.
“I can think of no one else who has made as many major contributions to all facets of modern molecular biology,” said Dr. Robert C. Gallo, a co-discoverer of the AIDS virus and a professor at the University of Maryland.
In 1995, President Bill Clinton awarded Dr. Rich the National Medal of Science, the highest scientific honor bestowed by the federal government.
His death was announced by the Massachusetts Institute of Technology, where he had been a professor since 1958.
Alexander Rich was born on Nov. 15, 1924, in Hartford, the son of immigrants from Russia who never finished high school. He grew up in Springfield, Mass. His father, Max, ran a dry cleaning business that faltered during the Depression, causing the family to move several times. His mother, the former Bella Shub, died when he was around 14; he went to live with an aunt and uncle.
Dr. Rich attended a technical high school, where his education largely focused on how to operate machine lathes and other industrial equipment, preparing him for a manufacturing job. But an English teacher, noticing his curiosity and drive — Dr. Rich was working the graveyard shift at a military firearms factory in Springfield — encouraged him to join an after-school science club and later urged him to apply to Harvard. It awarded him a scholarship, and he enrolled in 1942.
He interrupted his studies when, during World War II, he enlisted in a Navy officer training program, which sent him to a hospital on a submarine base and then to Syracuse University Medical School. He was discharged in 1946 and, after returning to Harvard, received a bachelor’s degree in biochemical sciences in 1947 and a medical degree in 1949.
Dr. Rich moved to the California Institute of Technology as a research fellow in the lab of Linus Pauling, who would receive the Nobel Prize in Chemistry in 1954 for his work on chemical bonds. Dr. Pauling was locked in the race to figure out the structure of DNA, a competition he would lose.
In his search for clues about the configuration of DNA, Dr. Rich turned to an analytical tool called X-ray crystallography, which uses X-ray beams to determine the location of atoms in a molecule. Dr. Pauling had used the method in his groundbreaking work on chemical bonds.
But the equipment at Caltech was not well suited to analyzing long, fibrous molecules like DNA, and, as Dr. Rich soon learned, he was late to the race. Five months after Dr. Rich started his work, Dr. Watson and Dr. Crick announced that they had completed their cardboard model of DNA. Although theoretical, the model was accepted because it fit with everything that was known about DNA at the time.
Dr. Rich shifted his focus to the structure of RNA, the next big challenge in molecular biology. Scientists at the time understood that RNA translated genetic information in DNA into codes for proteins, but how this occurred was still a mystery.
Dr. Rich worked for a time with Dr. Watson, who briefly moved to Caltech after his DNA discovery, but the pair made little headway. After a while, Dr. Rich’s confidence wavered. “I had serious doubts whether I could, in fact, make important discoveries,” he wrote in a 2004 account of his research career.
In 1954 he moved to the newly formed National Institute of Mental Health as section chief in physical chemistry and continued to work on the structure of RNA. Realizing he needed better equipment for an experiment, he traveled to England to work with Dr. Crick and use the more powerful X-ray machine at the University of Cambridge.
Not long after Dr. Rich’s arrival, however, the scientists realized that they shared a curiosity about the structure of collagen and shifted their research. Using everything known about collagen at the time, they built a six-foot-tall wire model of the molecule and painstakingly calculated the approximate location of its atoms. At the end of the monthslong project, Dr. Rich felt his confidence return.
“I began to develop some self-assurance in my ability to carry out research and make discoveries,” he wrote.
More discoveries soon followed.
In 1956 he showed that two strands of RNA could spontaneously join together to form a double helix, and in 1960, two years after he moved to M.I.T., he showed that strands of RNA and DNA could join to form a double helix. These discoveries led to a method for comparing similarities between pools of DNA, laying the groundwork for diagnostic tests and many of the scientific tools used to detect genes in tissues.
After these discoveries, Dr. Rich took advantage of improvements in X-ray crystallography to produce the first image of the RNA double helix at atomic resolution. Because RNA and DNA are complementary molecules, the 1973 image confirmed the structure of DNA. “The uncertainty about the organization of the double helix was resolved,” Dr. Rich wrote.
A year later, he used X-ray analysis to solve the three-dimensional structure of one of three forms of RNA, all of which are critical to the manufacture of proteins.
Toward the end of his life he worked to unravel the mystery of Z-DNA, which, in addition to having a zigzag backbone, spirals to the left instead of to the right. Although its function is unknown, Dr. Rich and others found hints that Z-DNA has a role in some autoimmune diseases and certain viral infections, like small pox.
Dr. Rich was a member of the National Academy of Sciences, the French Academy of Sciences, the Russian Academy of Sciences and the Pontifical Academy of Sciences. He co-founded several biotechnology companies, including Repligen in 1981 and Alkermes in 1987.
Dr. Rich’s survivors include his wife of 62 years, the former Jane King; two sons, Josiah and Benjamin; two daughters, Jessica Rich Sturley and Rebecca Rich; and seven grandchildren.
Dr. Rich liked to recall the time he presented his collagen research at a scientific conference and ran into his old mentor. Dr. Pauling, he said, remarked that Dr. Rich had spent a long time in his lab without accomplishing much, but that he must have learned quite a bit.
“I felt that it was probably a fair assessment,” Dr. Rich said.
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