In 1987, American molecular biologists Jack Strominger and Don Wiley shocked the scientific world with a supreme example of the adage “A picture is worth a thousand words.”
For immunologists, their three-dimensional image of a protein published in the science magazine Nature may have been as exciting as the discovery of the double helix structure of DNA.
Introducing their findings, Nature wrote, “The general reader will understand why every immunologist’s pulse will race as he or she sees the three-dimensional structure … in this issue.”
The X-ray photo of the protein, called MHC (Major Histocompatibility Complex), captured the exact moment at which the protein had grasped a fragment of a foreign invader prowling the surface of a human body cell.
It was the first photographic record showing how invaders, such as bacteria and viruses, are recognized by the immune system.
“The day we saw the structure, everybody, including ourselves, (was) quite overwhelmed,” recalled Wiley in a recent interview in Tokyo. “You immediately knew that something very important (had happened).”
Their findings have not only provided a basis for understanding how the immune system works but have paved the way for the development of vaccines for many diseases, including AIDS, and treatments to prevent the rejection of transplanted organs.
For their achievement, the Science and Technology Foundation of Japan honored Strominger, 73, and Wiley, 54, with the 1999 Japan Prize. Among the 41 winners of the Japan Prize, including the three 1999 recipients, three have gone on to win Nobel Prizes for their academic achievements.
“Like the DNA structure, it solved a mystery,” said Strominger in the same interview, scheduled during a visit to attend the awards ceremony.
“Before that, nobody knew how foreign antigens (something broken down from bacteria and viruses) are shown to (and recognized by) the immune system. And there it was, that ended (the mystery),” Wiley said.
The two, both professors of molecular biology at Harvard University, were the first to determine graphically that MHC molecules function to tell specialized immune cells called T-cells of the existence of foreign intruders by binding to the intruding fragments.
“In one day, thousands of people, literally, changed their view on how everything worked,” Wiley said.
The elusive MHC molecule did not reveal itself easily. Its discovery was the result of 15 long years of tiresome lab work involving a number of postdoctoral fellows and graduate students.
In the early stages of their research, Strominger was twice refused funding for the project from the National Institute of Health on the grounds that the work was “too difficult.”
There were several other groups in the United States and Europe also working on the molecule’s structural analysis, but they dropped out of the race “in a short period of time.”
“Everybody thought it was tremendously difficult,” Strominger said, explaining that the MHC in the cell was hard to isolate as there was such a small amount of it.
Their success in an area in which so many others have failed appears to be an accumulation of small breakthroughs and assiduous efforts.
Their Harvard labs overcame obstacles by developing and refining techniques for cleaving the protein from cell membranes, purifying specific molecules and making them crystallize. Then they moved on to the next step — the most difficult — to improve the process to obtain a large sample.
The key was using a cultured cell line. By preparing a large quantity of cultured cells containing the specific MHC molecules, they were able to prepare a sample good enough for an X-ray to clearly show the protein’s structure.
After their discovery, researchers worldwide rushed into the field. Now, nearly half the articles appearing in immunology journals are on MHC and its applications, such as for designing vaccines, preventing organ transplant rejections and developing drugs for diseases of the immune system, they said.
“The structure told us how the immune system works. Not only told you that, it gave you a glimmer of how you might manipulate and how you might treat diseases,” Strominger said.