Remembering Robert Langridge, molecular computer graphics pioneer

Robert Langridge, PhD, a professor emeritus in the Department of Pharmaceutical Chemistry who was an icon in the field of molecular computer graphics, passed away just a few weeks after his 90th birthday on November 11, 2023.

Langridge was honored in 2018 with the UCSF Medal, the University’s highest honor, for ushering in a new era of biological experimentation and drug discovery. He received the award along with Peter Andrew Kollman, PhD, and Irwin “Tack” Kuntz, PhD, in recognition of the group’s collaborative spirit and pioneering research in the fields of pharmaceutical science and computational chemistry.

In the 1950s, there were two approaches to visualizing molecular interactions: Scientists built wire models or sketched them, and did the math calculations. In 1956, Langridge obtained access to an IBM 650 computer. Even though the machine had miniscule memory by today’s standards, Langridge loved programming and was able to reduce the computation time of his calculations from two weeks to thirty minutes.

Langridge became convinced that computers were here to stay. “Although there are many stories about Bob’s work on the beginnings of molecular computer graphics and how he became this amazing pioneer who recognized the potential of computers, he did that despite the scientific community not being very receptive,” said his wife Ruth Langridge, MAT, MA, PhD, a researcher at the University of California, Santa Cruz.

Langridge’s 1970 grant for a computer graphics lab at Princeton University established one of the first Research Resource Centers created by the National Institutes of Health. In 1976, he was recruited to UCSF, where he founded and directed the computer graphics lab until he retired in 1994. He pushed the field of pharmaceutical chemistry into the computational era—a daunting task in a time of room-sized computers.

“If you want to see with your own eyes the results of Bob’s work, pick out any magazine, video, or movie dealing with science or with many other features of everyday life,” said Professor Emeritus of Pharmaceutical Chemistry Kuntz.

Probing biology at the atomic level

Born in the small English village of Froyle in 1933, Robert Langridge was the first in his family to attend college, receiving his BSc in physics with first-class honors in 1954. In 1955, he published his first important paper in Nature, detailing the molecular structure of DNA based on x-ray diffraction data.

In 1957, Langridge received his PhD in crystallography from the University of London. His research was guided by Maurice Wilkins, who was studying the structure of DNA using the technique of x-ray diffraction. Wilkins shared the 1962 Nobel Prize with James Watson and Francis Crick for their discovery of the molecular structure of DNA.

As a graduate student, Langridge showed how the Watson and Crick DNA model could be modified to agree with x-ray diffraction studies of DNA. His dissertation on x-ray crystallographic model-building and computational studies of the structure of DNA included the first application of a stored program digital computer (the IBM 650) to the analysis of DNA structure.

Becoming a computational revolutionary

Christopher Springmann

, 1985

After coming to the United States in 1957, Langridge worked as a postdoc in biophysics at Yale University and in biology at Massachusetts Institute of Technology (MIT). In 1961 he set up a lab to study the structures of DNA and viruses at the Children’s Cancer Research Foundation in Boston, with faculty appointments at Harvard University and Harvard Medical School. Concurrently, in 1964 he collaborated on the original work in molecular graphics at Project MAC (now The Laboratory for Computer Science) at MIT.

In 1966, Langridge joined the University of Chicago as a professor of biophysics, and then moved to Princeton in 1968 as a professor of chemistry and of biochemical sciences. He established the first Computer Graphics Laboratory, the name and concept of which he brought with him in fall 1976 to UCSF.

“When he came to UCSF from Princeton, he didn’t bring any other personnel with him, and he didn’t bring any computer hardware with him,” said Professor of Pharmaceutical Chemistry Tom Ferrin, PhD, who took over UCSF’s Computer Graphics Lab when Langridge retired.

At UCSF, he developed a computer graphics system that produced some of the first pictures of molecular interactions in three dimensions, with the ability to rotate an image on the screen. Among the field’s milestones, Ferrin recalled the advent of color graphics as a quantum leap forward that allowed scientists to identify different chemical components and proteins. “He had to build everything from the ground up, which required a lot of bravery on his part.”

"Bob was the son of a gardener who bootstrapped himself up from the ground,” added Ferrin, who remembered Langridge as not only a pioneer of molecular computer graphics, but also as an ambassador for the technology. “He had the vision, and he knew that if he was going to realize the vision for his future and make his mark in science, he needed to do that in the United States, which also required a lot of bravery.”

The advent of interactivity

The ability to interact with graphic images was the breakthrough that allowed the viewer to gain insight into both molecular structure and function. It resulted from significant effort to develop software that could “meaningfully” display large molecular structures, like DNA and proteins.

“Interactive molecular graphics has always been the key to what we’ve done at UCSF, which is to make the user part of the graphics system…and allow the user to apply their knowledge and investigate parts of the molecular structure,” said Ferrin. “That wouldn’t be possible if you’re just looking at a drawing or an image on a printed page.”

Today’s UCSF scientists carry Langridge’s legacy forward with computational innovations that allow them to screen millions of potential drugs at once and observe molecular interactions in virtual reality.

“Bob’s expertise was in visualization, because computations alone just yield columns and columns of numbers. The insight comes from understanding what these computations mean,” Ferrin said. “There are countless antecedents along the way, but some brilliant scientists have come to the graphics lab, and they just haven’t yet seen the molecules that they’re so familiar with in an interactive 3D fashion, and then they’ll get some flash of insight from being immersed inside these complex 3D molecules, so it’s a very powerful technique.”

Inspiration and impact

Langridge’s work continues to have an enormous impact on scientific discovery. “He was a giant here at UCSF, and his legacy will be long and fondly remembered,” said UCSF Chancellor Sam Hawgood, MBBS.

“Looking back, it seems like Bob was always spreading the word about molecular graphics, and he was the perfect person to do it, because he was there from the very beginning,” said Ferrin.

Langridge served on the Computer and Biomathematics Research Study Section of the National Institutes of Health (NIH), and the Science and Educational Advisory Committee at Lawrence Berkeley Laboratories. He was a member of the NIH Computer Science & Telecommunications Board of the National Research Council and the NIH Council of the National Center for Research, as well as the council representative on the Advisory Committee to the NIH director.

In 1983, Bob collaborated with Industrial Light & Magic, the motion picture visual effects company founded by George Lucas, and used real-time, interactive graphics of DNA to generate the intro to the “Genesis” segment of Star Trek II. In 1989 he was elected fellow of the American Association for the Advancement of Science, and in 1990 to the Institute of Medicine of the National Academy of Sciences. In 2005, he was highlighted by Smithsonian Magazine as an innovator who made a difference.

“Computer graphics has become the paint brush that colors it all,” Kuntz said. “I can’t tell you what an honor it was to work with him, day after day, for so long.”

Teri Klein, PhD, a faculty member in the Department of Biomedical Data Science at Stanford University, described Bob as an incredible mentor and a wonderful human who “was one of a kind, and I have emulated him throughout my academic career.”

“He was my inspiration for our center, in science, in leadership, and in humanity,” said Ken A. Dill, PhD, distinguished professor Laufer Center for Physical & Quantitative Biology at Stony Brook University. “I am forever grateful for his brilliant and inspiring vision.”

Langridge is survived by his wife; three daughters Elizabeth, Catherine, and Suzanne; and five grandchildren. Details about his memorial service are forthcoming.

More

• Video, 7 minutes: 2018 UCSF Medals – Peter Kollman, Irwin “Tack” Kuntz, and Robert Langridge
• Video, 4 minutes: UCSF ChimeraX pushes drug discovery into virtual reality
• History of the Computer Graphics Laboratory (CGL) and Resource for Biocomputing, Visualization, and Informatics (RBVI)
• VR drug discovery makes precision therapy a reality