Editor’s note: We’ve previously described serendipity’s important role in the scientific discovery process. Because this phenomenon is such a strong recurrent theme in science, there are almost an unlimited number of stories about scientific progress in which serendipity was a major factor. One such story occurred recently in the lab of William Stallcup, Ph.D., here at Sanford-Burnham.
A few years ago, a collaborator in Italy gave the Stallcup lab a mouse model genetically engineered to lack the collagen VI protein. Collagen VI is part of the support scaffold surrounding fat tissue.
“Collagen VI is also one of the important binding partners for NG2, a protein we’ve long studied in our lab for its role in cancer,” relates Stallcup. “There was a report published showing that breast cancer progression is slowed in mice lacking collagen VI, which is the same phenomenon we have seen in mice lacking NG2.”
In addition, other studies reported that collagen VI loss leads to poor mammary fat cell function. That was similar to the Stallcup lab’s observations of altered fat cell behavior in the absence of NG2.
“So we thought there was a strong chance that loss of the NG2-collagen VI interaction in fat cells might provide a unified explanation for the poor fat cell function and reduced mammary tumor progression seen in both types of mice,” Stallcup says.
Yet the group could never reproduce the mammary tumor findings that were reported for the collagen VI knockout mouse, and so their theory could not be proved. They abandoned the project.
Being new to the Stallcup lab, postdoctoral researcher Claire Huang, Ph.D., was unaware of the NG2-collagen VI connection. At the same time, there were extra collagen VI-deficient mice hanging around after the unsuccessful mammary tumor studies. So Huang used them as controls for some experiments she was conducting on brain tumor progression in the NG2-deficient mice. These studies focused on the role of NG2 in the development of tumor blood vessels, and on the importance of blood vessel function in tumor growth.
Huang was surprised to see that the collagen VI-deficient mice had some of the same blood vessel problems that she saw in the NG2 knockout mice. She and other members of the lab talked it over. They realized that the NG2-collagen VI connection they were originally looking for in mammary fat cells had instead revealed itself in brain tumor blood vessels.
As it turns out, NG2 on the surface of blood vessel cells provides a means for binding collagen VI, which in turn provides a starting point for assembly of a structure called the basement membrane that stabilizes mature blood vessels. Deleting either NG2 or collagen VI results in loss of the interaction that helps build this key structure. These studies were published in Developmental Biology.
Another member of the Stallcup lab, postdoctoral researcher Weon-Kyoo You, Ph.D., quickly realized that this chance finding with the collagen VI-deficient mice provided a means of studying the details of basement membrane function in blood vessels. Once again using the brain tumor model, You measured basement membrane assembly in tumor blood vessels in normal mice and in the collagen VI-deficient mice.
According to You, “The thickness of the basement membrane was greatly diminished in the absence of collagen VI. In addition, the functions of the cells that make up blood vessels were impaired by the reduced extent of the basement membrane. Because of these structural flaws, the tumor vessels in the knockout mouse were very leaky, and did not provide an adequate blood supply to the tumors. As a result, tumor growth in collagen VI-deficient mice was much slower than in normal mice.”
You’s studies thus revealed that assembly of the basement membrane is one of the most important aspects of blood vessel development and maturation. This story has now been published in the American Journal of Pathology.
Keeping an open mind
Like most scientific publications, these articles downplay the role of chance in the discovery process, and instead describes a logical progression of thinking that leads to the final conclusions. Nevertheless, it’s fun and instructive for us to look behind the scenes and realize the extent to which lucky observations enable scientific advances.
Rather than cheapening the value of serendipitous discoveries, these examples emphasize the importance of keeping an open mind when experiments don’t go as anticipated. They also remind us to stay alert for opportunities to take our investigations in unexpected directions.
As the old saying reminds us, “Luck favors those who are well prepared.”