Regeneration and the Future of Biology Written by Bethann Wilson Edited by Shane Cowan Speaker: Dr. Alejandro Sánchez Alvarado at Science 2019
There are many unanswered questions in biology. Could life had started and failed multiple times? What kind of machinery was possible in the earliest, simplest organisms? Unfortunately, the fossil record for billion-year-old microorganisms is scant. Still today, we do not know what is currently possible in the context of biology. Only a handful of metazoan species has been studied extensively, and studies on these model organisms receive the lion’s share of funding. However, looking at just a handful of species across only a few phyla severely limits our knowledge of developmental biology. Non-conventional ‘model organisms’ can provide incredible information that benefits humans and the study of biology as a whole. For example, research on the protist Tetrahymena has lead to the discovery of telomeres, ribozymes, and epigenetic modifications. It may not appear as though humans have much in common with unicellular protists or microscopic worms, but because of our common origin, we truly are connected in many developmental ways. According to Dr. Alejandro Sánchez Alvarado, the difference between studying traditional and nontraditional model organisms is like “mapping already discovered continents vs finding new continents.”
Dr. Alejandro Sánchez Alvarado spoke to a large group of students, faculty, researchers, and scientists at Science 2019 at the University of Pittsburgh on October 18th. I found myself at the edge of my seat for his entire seminar. Dr. Alvarado is an investigator at the Howard Hughes Medical Institute and the scientific director at the Stowers Institute for Medical Research. He received his PhD in pharmacology at the University of Cincinnati and shortly after began using the planarian Schmidtea mediterranea- a small flatworm, as a non traditional model organism. He states that he chose this organism becaue it is bilaterally symmetric, has all three germ layers (layers that divide the body into different parts), has asexual and sexual reproduction, and has adapted to many different niches. In addition, this planarian has an incredible ability to regenerate new organisms no matter how many different fragments it is cut into. If you take a worm and separate it into 18 fragments, 18 complete animals will be present within two weeks.
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Dr. Alvarado and his team have identified a unique type of stem cell in S. mediterranea that is responsible for the organisms’ incredible regeneration. Neoblasts are adult stem cells that give rise to other cells. Most are pluripotent- they can multiply and differentiate into several kinds of cells. A specific neoblast, Nb2, can give rise to all kinds of cells in S. mediterranea. In fact, implanting a single Nb2 cell into an adult worm dying of radiation poisoning can rescue it from death. Even more interesting is Dr. Alvardo’s speculation on the Nb2 cells: they are not single types of cells, but instead, a dynamic state that certain other cells can turn into when the animal is wounded. In other words, similar pluripotent stem cells can become Nb2 when needed, such as when the animal is cut in half. These cells can express different genes depending on the need of the individual- there is evidence of transcriptional plasticity.
Is this phenomenon isolated to these tiny little flatworms? Dr. Alvarado set to find out by comparing zebrafish (a traditional model organism) to killifish (a non traditional model organism). They both can regenerate their tail fin if it is cut off. Zebrafish are found in India, while killifish are found in Mozambique. Killifish are unique because they live in a very non-hospitable environment: their ponds dry due to drought. Their eggs live in suspended animation until they are rehydrated. By comparing the genes that were upregulated and downregulated, Dr. Alvarado speculates that an enhancer is expressed when the individual is wounded. His lab used CRISPR to cut out the enhancer, and thus prevented regeneration in both species of fish. This raises the question- are enhancers for regeneration present in all vertebrae?
Studies such as these help pave the way for regenerative medicine. Why can’t humans regenerate lost body parts or damaged organs? One hypothesis by Dr. Alvarado suggests that the ancestral state for most multicellular organisms was regeneration. However, evolution favored the injury response over the regeneration response. At the end of his presentation, I found myself excited, as both a scientist and as a person, to experience and contribute to the future of biology. I want to follow the expanse of knowledge generated by non traditional model organisms. Finally, I want to thank Dr. Alejandro Sánchez Alvarado not only for his pioneering work in medicine, but also for attention to Pittsburgh and his inspiring talk.
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