You have received numerous awards, including the Breakthrough Prize in Life Sciences and the Lasker Award, for your discovery of VEGF and for your role in the development of therapeutic antibodies against it. Can you briefly tell us what is VEGF is and how it was discovered? How has your research evolved more recently? We will provide references for those that want more details.
I was a postdoc in Richard Weiner’s lab at UCSF between 1983 and 1985. I used to go to a local slaughterhouse to collect bovine pituitary glands. At that time, the goal was to isolate endothelial cells for bioassays. However, I accidentally also isolated folliculo-stellate cells, a poorly understood cell population from these glands, and cultured them. There was an early observation that these cells were frequently associated with blood vessels, and so I decided to test the effects of conditioned media from these cells on endothelial cells. It was a long-shot experiments but to my delight I detected a strong mitogenic effect. At the time it was extremely laborious to isolate and purify an unknown protein, and many people discouraged me from pursuing this finding. However, I was able to perform some initial characterization of this mitogenic factor that convinced me that it was likely different from other endothelial cell mitogens.
Later I was hired by the biotechnology company Genentech, which allowed scientists to have an unusual amount of freedom compared to other companies. I was given as a main project the preclinical development of the hormone relaxin, a candidate for induction of cervical ripening and facilitation of labor, but I was also allowed to pursue personal scientific interests on weekends and during spare time. I decided to continue working on the folliculo-stellate growth factor as my personal project. Unfortunately, the relaxin project did not go very well, but at least within six months we were able to fully purify and determine the N-terminal amino acid sequence of the follicular cell-derived growth factor, that we called vascular endothelial growth factor (VEGF) to indicate its selective mitogenic effects on endothelial cells. It was a novel protein that had no match with any known protein at the time. After this, I was allowed to work on VEGF as my main project. In the following years we were able to make many advances, including the identification and cloning of the members of the VEGF family and of their receptors, structure function studies and elucidation of the role of these proteins in angiogenesis in mice and humans. We developed Ab drugs that are now FDA approved and standard of care for the treatments of cancer and eye diseases such as age-related macular degeneration.
I am now continuing to work on different aspects of angiogenesis. Among my interests are the study of endothelial cell heterogeneity and the elucidation of the role of molecules that regulate angiogenesis in combination with VEGF. Standard anti-angiogenesis therapies that target VEGF alone have been successful, but not all patients respond to them, and combinations of drugs are likely to be needed for more effective therapies. Endothelial heterogeneity is becoming more evident with the increase in data coming from single-cell RNA sequencing and from other technologies. The two problems are related because different combinations of signals might play a role in different organs and vascular beds.
Could the strategy you used for the discovery of VEGF be extended to other components of cell-cell communications? Many additional technologies are available now, some of them recently discovered.
Yes, and within my lab we have been working on other components of angiogenesis signaling. For example, we have recently published work on the role of LIF in angiogenesis, which is also tissue specific. Analysis of single-cell RNA seq data played a supporting role in this research.
The strategy used in the VEGF discovery started from an activity detected in a tissue and in a cell type, followed by protein purification and functional studies. Proteomics has certainly advanced much in recent years and the strategy could be extended to other aspects of cell-cell communication.
More generally, what could we do to advance the understanding of cell-cell communication? Would this knowledge produce large medical benefits? How could we know if our knowledge of cell-cell communication is complete or very close to complete?
There are many new and potentially relevant experimental technologies available now, I am familiar with some of them, and I have mentioned them, but I also look forward to reading how other scientists will answer these questions. Cell-cell communication is a fundamental aspect of biology and medicine and the knowledge integration needed is now beyond the capability of any individual scientist.
The medical benefits of advancing the understanding of cell-cell communication are clear because there are already many drugs acting on these signals or on their receptors. The drugs affect the disease-causing cells or the responses of the innate and adaptive immune systems. I would therefore say that most patients could potentially benefit.
We might not achieve a complete or near-complete knowledge but being able to predict accurately the response of patients to drugs and drug combinations targeting intercellular signals and receptors would show that our understanding has progressed substantially.
- Perez‐Gutierrez L et al. Endothelial Cell Diversity: the many facets of the crystal. The FEBS Journal. 2022 Oct 20.
- Domanskyi S et al. Naturally occurring combinations of receptors from single cell transcriptomics in endothelial cells. Scientific reports. 2022 Apr 6;12(1):1-7.
- Li P et al. LIF, a mitogen for choroidal endothelial cells, protects the choriocapillaris: Implications for prevention of geographic atrophy. EMBO molecular medicine. 2022 Jan 11;14(1):e14511.