Immortal cells
At the University of Cambridge’s Gurdon Institute, Walfred Tang is busy with a kind of Darwinian project, isolating and studying germ cells, the most basic building blocks of human life.
Germ cells are the precursors of sperm and eggs, and play a defining role in foetal development. They are immortal, in a way, designed to reproduce indefinitely in order to generate a whole human after fertilisation, passing on genetic material, and providing an enduring link through generations via the germline.
Tang’s research spans germ cell development from how they form in embryos, how they help embryos form and segregate into different cell types to the process of embryo splitting and automatic formation, and germ line development. To unlock most of these answers, much of his study focuses on a specific scene in germ cells’ lifespan: that of the formative process of embryonic development.
The start of the germline
“An embryo is a very complex structure, and being able to follow that formation from a single germ cell is fascinating,” he explains, “The germline is a kind of spark, initiating an automatic process of precise splitting, chemical reactions, gene editing, and so on.” This process, epigenesis, is where germ cells begin the sequence of cell differentiation and organ formation, as well as delicate biological programming.
Primordial germ cells form a very basic embryo after fertilisation, with three zygotic germ layers, the ectoderm, endoderm, and mesoderm. Together, these form the brain and peripheral nervous system, the digestive system, soft tissue and circulatory system, and everything else in between.
Germ cells form when the three layers start to split, developing the embryo and starting the epigenetic programming process to edit genetic information. How this comes to be, or what enables this process to progress from stage to stage automatically, is still the focus of considerable research, since it holds the key for pluripotency, the ability to generate all cells.
Epigenetic modifications
As the inter-generational link, germ cells inherit several epigenetic marks during embryonic formation, such as DNA methylation. “Epigenetic programming serves to clean out the files,” Tang says, “Like formatting the hard disk for the next generation’s program to be written.”
Human cells undergo DNA methylation when isolated, so Tang reproduces these circumstances in the lab to see how the erasure happens and to what extent, finding it to be a very exact and comprehensive process, but never quite the same.
He also experiments with separating germ cells from stem cells, as germ cells do not go through extensive erasure in cell cultures, allowing scientists to take one step closer to gem cell solutions for full clinical use. The process is slow, careful not to disturb anything that might be useful for demethylation, even as Tang’s team tests locking out different genes to determine whether they are responsible for epigenetic programming.
Human germ cell development and embryology studies are usually done using mice because they are more accessible, with results then extrapolated to human conditions. Tang’s lab had a remarkable opportunity to work with human embryos, isolating stem cells to look at gene expression and DNA codes, as well as compare how the synthetic lab-grown cultures held up to the real thing.
“Ideally, we want to be able to generate germ cells solely from culture for stem cell research as well as for more targeted treatment delivery systems,” he says. The comparison study showed promise in this regard, finding that precursor cell generation in lab cultures were close to their development in embryos. However, in probing other research questions, contrasting mouse and human embryonic development clearly showed that there are certain critical factors key to human germ cell development unable to be studied in mouse subjects, but as the debate around use of human embryos continues, this level of testing remains rare.
Unlocking the germ cell's potential
Besides the pursuit of knowledge and understanding of perennial biological questions, Tang’s research would contribute to practical medical needs. Investigating germ cells’ unique properties, particularly what confers their immortal state, will be translated into ongoing research on how to activate certain sequences that would convert any cell into an embryonic stem or germ cell.
Detailed understanding of the mechanisms involved will also be valuable for the detection and eradication of immortal cancer cells, enhance infertility treatment, aid rejuvenation of diseased body tissues, and development of therapeutic agents to prevent or reverse ageing tissues as seen in Alzheimer’s or heart disease.
Germ cells have some interesting implications for cancer, as many cancers have germ cell roots which stay dormant until young adulthood when they become neoplastic and start to grow. Understanding the genetic programming of germ cells would shed light on the development of germ cell tumour cells, a key consideration in children’s cancer research.
As a newly minted PhD, Tang plans to spend more time on his current research, with some idea of exploring its more clinical links, particularly moving down the germ cell lifespan to see how they become cancerous. Though the relationship between clinical practice, research, and pharmaceutical applications is increasingly becoming closer as medicine becomes more targeted and personalised, Tang is still drawn to the relative freedom that academia offers. “No matter how many leaps forward we take, we always find that there is more to be understood,” he says.
Walfred Tang received his BSc degree in Biochemistry and MPhil in Anatomy at the Chinese University of Hong Kong. He recently completed his PhD in Physiology, Development, and Neuroscience at the University of Cambridge, and will begin a postdoctoral fellowship there to continue his research.
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