I always had an inherent interest in development from a very early age. I used to grow plants, make hybrids between different strains and became intensely interested in Lepidoptera. My removal from science education at school took me away from this career path – in fact, I ended up studying Classics. Although I was always interested in biological phenomena, I was put into Classics because they had spare teachers in the subject. Fortunately, I was able to get back into biology later on by pursuing a PhD in zoology. The work I undertook as a doctoral student wasn’t standard zoology – it was nuclear biology, in fact, which is at least somewhat related to cancer.
One of the pleasures of doing research is when some unexpected experiment proves successful – as most exploratory experiments are, of course, unsuccessful. An example of one that wasn’t is the unexpected great success of injecting purified mRNA into eggs and oocytes of Xenopus, the African clawed frog commonly used as a model organism. All the predictions were that this could not possibly work because of the huge amount of RNA in such cells. But then again, I knew that every species is different – so experimentation is always worth a try!
The range of experimental possibilities, especially at the biochemical level, has changed out of recognition during my time in science. When I started it was not possible to analyze any individual gene activity; all we could do was measure ribosomal and transfer RNA transcription. Now it is possible to determine the activity of each individual gene and even in individual cells. All this has happened during my time in science. I would say that technology has changed out of recognition in the last half-century. Now, we’re able to answer questions in a way that could never have been done 50 years ago.
I was lucky that my experiments gave me an opportunity to reconsider the conventional dogma of the time. To be able to do this is itself an enormous incentive to continue work in a field.
Of course, my results were challenged by experts in the field – and this was entirely justified. In response, I extended my experiments and used genetic markers, which allowed me to prove beyond reasonable doubt that the results I had originally obtained were indeed valid.
The question that most interests me at the moment is what causes the differentiation of nearly all cells in the body to be so stable. I want to understand the mechanisms involved in stabilizing the differentiated state of cells and that resist nuclear reprogramming. If we knew how those mechanisms worked, we could improve nuclear reprogramming for cell replacement therapy and hope to discourage cells from leaving their normal differentiated state to become aged or cancerous.
Even with the remarkable Yamanaka procedure (in which four transcription factors – Myc, Oct3/4, Sox2 and Klf4 – were introduced to mature cells to “reprogram” them into induced pluripotent stem cells), only a very minor proportion of cells make the change imposed by transcription factors. It would be of great interest, both scientifically and clinically, to understand what normally keeps cells firmly anchored to their intended destination so as to prevent disease and aging from causing cell change.
If all of the work you do fails to answer the question you’ve engaged, there comes a time when you have to acknowledge that and give up. A large proportion of my time in science has been devoted to experimental approaches that have not been successful, and have therefore been set aside.
However, an experiment that doesn’t prove the hypothesis is not the same as a “failed” one. In my case, I was much attracted to working further on any result that seemed at the time not to be explicable. There is always something very rewarding in being able to understand what happens when an experiment either doesn’t work or gives the unexpected conclusion. Therefore I recommend anyone now to pay special attention to any of their failed experiments.
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