In her postdoctoral work in the Alon lab, Lahav investigated the response of p53 to DNA damage. p53 is highly studied due to its role as "guardian of the genome"; in response to DNA damage, p53 activation may lead to a delay in the cell cycle to allow DNA repair, or may cause the cell to undergo senescence or apoptosis. Previous work had shown that the feedback loop between p53 and its regulator Mdm2 could theoretically cause oscillations in the level of p53. Oscillations were in fact observed in cells exposed to radiation, using a Western blot technique that measures the average p53 level in a population of cells. Lahav developed a novel system for following p53 levels and Mdm2 levels simultaneously in individual living cells and demonstrated that individual cells show discrete pulses of p53 after gamma irradiation. Genetically identical cells showed different numbers of pulses: 0, 1, 2 or more. Although the size of the pulse does not change with increasing levels of DNA damage, the average number of pulses does increase. In later work, Lahav showed that these pulses are not an autonomous oscillation intrinsic to the p53:Mdm2 feedback loop, but are recurrently initiated by upstream signals of continuing DNA damage. This finding suggests that p53 may measure the intensity of some signals in a digital manner, not in an analog manner. Lahav then discovered that DNA damage caused by UV-irradiation results in a different p53 behavior, leading to a single pulse that increases in size and duration with increasing damage. This led her to hypothesize that the dynamic behavior of p53 contained information on the nature of the damage to DNA and determined the nature of the response by the damaged cell. She developed a method for forcing a cell damaged by gamma irradiation to adopt the p53 dynamics seen in UV irradiation, based on precisely timed additions of the Mdm2 inhibitor Nutlin-3. Cells damaged using gamma irradiation without drug treatment showed cell cycle arrest and then recovered, while the same cells treated with drug to simulate UV-type p53 dynamics entered senescence and failed to divide. These results led Lahav to investigate whether the schedule of drug administration might affect the response to common types of combination therapy in cancer, in which drugs are given in combination with radiation therapy. She found that if radiation was given shortly after addition of an Mdm2 inhibitor the treatment enhanced the effect of radiation, whereas a longer gap between the two treatments led to resistance. There is growing consensus that dynamics are important for signaling in multiple biological pathways. Lahav has measured the cell-to-cell variation in p53 response in colon cancer cells responding to damage by the chemotherapeutic drugcisplatin and has argued that this variation may underlie the phenomenon of fractional kill, in which a fraction of cancer cells survive chemotherapeutic treatment and subsequently grow, causing a recurrence of the cancer. Lahav joined the Department of Systems Biology at Harvard Medical School in 2004. In 2017 she was appointed Deputy Chair, and in 2018 Dean George Q. Daley appointed her as Chair of the Department. In the announcement of her appointment, Daley highlighted "her pioneering role in developing computational and quantitative experimental approaches to studying the fate and behavior of human cells in disease and health at the single-cell level."
Contributions to mentoring
Lahav is an advocate for improved mentoring in science. As an assistant professor, she initiated a peer-to-peer mentoring group at Harvard Medical School. She has written on the challenges of combining the role of a mother with the demands of a research career. She served as Junior Faculty Liaison for Faculty Development at Harvard Medical School from 2013 to 2018.
