In May of 1990 we got our first hints of the presence of a physical wave in the ectoderm. By the end of 1991 we had the entire trajectory of that first wave well documented. There were also long stretches of time between, waiting for the embryos to reach the correct stage for filming. We had classes and teaching duties and grants to write at the laboratory. At home, we had children who needed things from us like school lunches, stories before bed, hugs and clean clothing. Still, the differentiation waves occupied our thoughts in every spare moment.
We scoured the literature over several months collecting every related paper we could find. Google did not exist in those days and there were no online journals to download articles in a PDF form. Finding papers meant hours of searching physical indexes or the limited, mostly keyword, computer searches that existed in those days. PubMed was a brand new tool. Using it was like being the proverbial kid let loose in the candy store. Once a reference was located, we had to walk to the library and pull out physical copies of journals, carry them to a photocopier, and make a paper copy to work from. We would read that copy carefully, underlining or highlighting critical components. Each paper had multiple references to follow up on which meant more trips to the library. If the journal was not available in our library, and it often wasn’t, we could try ordering it through interlibrary loan and it would arrive after a few weeks or months. (We would often find ourselves wondering why we ordered a particular paper once it finally came.) We would also contact the author and ask for a reprint. Most scientists were using email by that time and so our requests were acknowledged in a day or two with a promise to drop a reprint in the mail. Some of the scientists, especially those in key papers by senior members of the field, had to be petitioned in formal politely worded paper letters. Each workday, one of us would run to check the mail to see what eagerly awaited gems had arrived by “snail mail”. We would also trek to the library to see what precious items may have arrived via interlibrary loans. Our desks were soon piled high with towers of papers covered with notes. After six months of hard work, we found enough clues from the literature to create a plausible pathway between microfilament contraction and changes in gene expression. Still we were left with a lot of unlabeled arrows in our original nuclear state splitter model. Molecular biology of eukaryotic cells was in its infancy back then. Like genetics, the field was exploding. We published the collected ideas as a working model in our paper, “Nuclear state splitting: a working model for the mechanochemical coupling of differentiation waves to master genes”, in 1993.
While theoretical papers are easy to publish in fields like physics, and it is quite respectable to do so, in biology theoretical papers are generally viewed with disdain. More than one colleague advised us to not publish the idea until we had more data. We knew we would have a very difficult time finding any standard journal to publish a mere idea. We did find a welcoming colleague in Russia, Lev Beloussov, who has a long history of investigating the physics of amphibian embryos. We therefore published our idea, in Russian first, in the journal Ontogenez. Our English version appeared in their “translation” version of the journal a few months later, the Russian Journal of Developmental Biology, though of course that was the original and the Russian version was the translation. We took the opportunity of the delay to prepare an Addendum to the English version.
As the years passed, and biochemical, molecular biological and genetic knowledge grew in great leaps and bounds, more new pathways and interactions and proteins were collected and catalogued. It was not unusual to have a student spend their entire PhD characterizing a single protein within a complex pathway. Once the knowledge of the proteins was combined with the genetic sequence producing the proteins, families of biochemical components were discovered and their evolution and relationships across species were explored. Not surprisingly, the protein carefully studied in one organism often turned up in another organism in a closely related form. All too frequently this homologous protein would have an entirely different name or function ascribed to it by some other PhD student or postdoctoral fellow and his or her supervisor. Since the early days of the field, the general amount of knowledge of scientists studying these processes has doubled about every five years. We have tried to follow all of these developments as they came out and, while we found a lot of new detail, we never found anything contradicting the general layout of our first nuclear state splitter model. In fact, the more the scientific community learned, the more correct our original working model appeared to be and the more blank arrows in our model acquired names. Today, there are no blanks. There was very little interest from anyone else in our early model. It is so easy to not see the forest for the trees, especially when you are trained to focus on leaves. Those were exciting and giddy days full of new discovery and heady wonder. It doesn’t matter if no one else listens to us. There is only one test the counts. Every idea or theory must be tested against nature and in the end nature will prove us right or wrong.
Natalie circa 1990 with an old Mac of similar vintage.