basic science

As an early career researcher, I feel that I lack some critical background knowledge of foundational studies and scientists in research. Most of my blog posts will focus on recent papers or topics, and I’ll dig into the history of that topic to find out how we got to where we are.

Many fantastic papers have been published on the circadian clock lately. Drs. David Montaigne and Bart Staels recently published a Viewpoint on the topic of the circadian clock and cardiovascular disease in Circulation Research.¹ My basic understanding of the circadian clock is that transcription factors, CLOCK and BMAL1, are critical proteins. Light is sensed at the retina and the optic nerve transmits a signal to the suprachiasmatic nuclei then throughout the body. Since light (historically) came from the sun, these proteins and the clock functions generally oscillate with day and night. Knocking out or mutating clock proteins can alter metabolism, immunity, and a slew of other systems.

A 2013 paper published in Circulation by Xiaoyue Pan and colleagues showed increased atherosclerosis in mice where the CLOCK protein was mutated, thus disrupting the circadian rhythm.² The mechanisms appeared to be elevated ApoB48 particles and increased macrophage cholesterol scavenging. In 2009, a Circulation paper by Ciprian Anea and colleagues showed increased collagen deposition and fibrotic remodeling after arterial ligation in the carotid artery of BMAL1 knockout mice.³ Finally, a 2018 Cell Metabolism paper by Carla Winter showed that myeloid cells behave in a circadian fashion.⁴ These are impressive recent papers, but how did we get to this point? I wanted to gain a better understanding of where the science of biological clocks began.

My first stop was the “circadian clock” page on Wikipedia, but it was lacking any historical context.⁵ Next, I found a review on Pubmed from 1993 by a scientist named Colin Pittendrigh in the Annual Review of Physiology entitled, Temporal organization: reflections of a Darwinian clock-watcher.⁶ This review was more of an autobiography than review, but it was a joy to read. I would suggest reading the entire review, but I’m going to summarize some it here. After reading a few paragraphs it became evident that Colin Pittendrigh might be a prominent figure in the science of biological clocks. I did a quick search (the Wikipedia page for “Colin Pittendrigh”) and found this in the second sentence, “…father of the biological clock…”, which came from a Stanford press release upon Pittendrigh’s death.^7,8

What I found in Pittendrigh’s 1993 “reflections” was that he was an extraordinary scientist, and an interesting man. Pittendrigh begins by recounting how he became interested in biology. Living in the north of England, he kicked a soccer ball through the window of the town hall and needed to replace it. Needing money, he entered a contest for the best wild flower collection from the local Boy Scouts and won. This sparked his biological interest. During high school, Pittendrigh discovered Charles Darwin’s works which greatly influenced him. He says that his Darwinian beliefs later survived exposure to Lamarckian convictions of a college professor. During wartime in the 1940s, he was in Trinidad and was instructed to focus on breeding vegetables for the campaign. Later, he studied Malaria by focusing on habits of mosquitoes, and eventually he studied drosophila behavior. During these experiences, he observed periodicity in the behaviors of these organisms.⁶

With influences from colleagues, Pittendrigh reasoned that the biological clock must be endogenous.⁶ During his time at Princeton and Stanford, Pittendrigh published many papers including five in the journal, Science. Almost all of these were published on the circadian oscillations of plants and animals; however, he had other interests, as well. Notably, a 1965 Science paper titled, Proposed Biological Exploration of Mars between 1969 and 1973.⁹ Pittendrigh’s career in science was monumental, although he didn’t discover the proteins involved in biological clocks. The CLOCK protein was discovered in 1993 and BMAL1 was discovered in 1997, the year after Pittendrigh’s death.^10,11 These discoveries undoubtedly wouldn’t have been made without the pioneering work of Colin Pittendrigh.

Dr. Pittendrigh’s life and discoveries are remarkable and in his writing, he constantly references others that were instrumental to his ideas and discoveries. With mounting pressure to have first or last author publications in our time (forgive the pun), it is easy to overlook others who make scientific progress possible. And although Colin Pittendrigh did not study cardiovascular diseases, his findings are having an impact on cardiovascular medicine now. This highlights the interdisciplinary nature of science and how ideas from diverse fields impacts others. It is always beneficial to read papers, attend seminars, and speak with colleagues from diverse fields to broaden our own experimental approaches and ideas.

References:

1. David Montaigne & Bart Staels. Time to Check the Clock in Cardiovascular Research and Medicine. Circulation Research. 2018; 123:648–650
2. Xiaoyue Pan, Xian-Cheng Jiang, and M. Mahmood Hussain. Circulation. 2013 Oct 15; 128(16): 1758–1769.
3. Anea CB, Zhang M, Stepp DW, Simkins GB, Reed G, Fulton DJ, Rudic RD. Circulation. 2009 Mar 24;119(11):1510-7
4. Winter C, Silvestre-Roig C, Ortega-Gomez A, Lemnitzer P, Poelman H, Schumski A, Winter J, Drechsler M, de Jong R, Immler R, Sperandio M, Hristov M, Zeller T, Nicolaes GAF, Weber C, Viola JR, Hidalgo A, Scheiermann C, Soehnlein O. Cell Metab. 2018 Jul 3;28(1):175-182.e5
5. https://en.wikipedia.org/wiki/Circadian_clock
6. S. Pittendrigh. Temporal organization: reflections of a Darwinian clock-watcher. Annu. Rev. Physiol. 55, 17 16-54. 1993.
7. https://en.wikipedia.org/wiki/Colin_Pittendrigh
8. Stanford University News Service. https://news.stanford.edu/pr/96/960325pittendrig.html 1996.
9. Pittendrigh CS. Proposed Biological Exploration of Mars between 1969 and 1973. Science. 1965 Apr 30;148(3670):667.
10. King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL, Turek FW, Takahashi JS. Positional cloning of the mouse circadian clock gene. Cell. 1997 May 16;89(4):641-53.
11. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (March 1997). “Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway”. The Journal of Biological Chemistry. 272 (13): 8581–93.