Predicting severe weather and the impacts of climate change will be faster and more accurate than ever before, thanks to the confirmation of £1.2 billion government funding to develop a state-of-the-art supercomputer, Business and Energy Secretary and COP26 President Alok Sharma announced today (17 February 2020).

Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells. Their findings are published in the Biophysical Journal.

A cell's identity is driven by which DNA is "read" or "not read" at any point in time. Signaling in the cell to start or stop reading DNA happens through proteins called transcription factors. Identity changes happen naturally during development as cells transition from an undesignated cell to a specific cell type. As it turns out, these transitions can also be reversed. In 2012, Japanese researchers were awarded the Nobel prize for being the first to push a regular skin cell back to a stem cell.

A fuller understanding of molecular processes towards stem cell therapies

Until now, it is unknown how the conversion of a skin cell into a stem cell happens exactly, on a molecular scale. "Fully understanding the processes with atomic details is essential if we want to produce such cells for individual patients in the future in a reliable and efficient manner", says research leader Vlad Cojocaru of the Hubrecht Institute. "It is believed that such engineered cell types may in the future be part of the solution to diseases like Alzheimer's and Parkinson's, but the production process would have to become more efficient and predictable." {module INSIDE STORY}

Pioneer transcription factor 

One of the main proteins involved in stem cell generation is a transcription factor called Oct4. It induces gene expression, or activity, of the proteins that 'reset' the adult cell into a stem cell. Those genes induced are inactive in the adult cells and reside in tightly packed, closed states of chromatin, the structure that stores the DNA in the cell nucleus. Oct4 contributes to the opening of chromatin to allow for the expression of the genes. For this, Oct4 is known as a pioneer transcription factor.

The data from Cojocaru and his Ph.D. candidate - and the first author of the publication - Jan Huertas show how Oct4 binds to DNA on the so-called nucleosomes, the repetitive nuclear structures in chromatin. Cojocaru: "We modeled Oct4 in different configurations. The molecule consists of two domains, only one of which is able to bind to a specific DNA sequence on the nucleosome in this phase of the process. With our simulations, we discovered which of those configurations are stable and how the dynamics of nucleosomes influence Oct4 binding. The models were validated by experiments performed by our colleagues Caitlin MacCarthy and Hans Schöler in Münster."

One step closer to engineered factors

This is the first time computer simulations show how a pioneer transcription factor binds to nucleosomes to open chromatin and regulate gene expression. "Our computational approach for obtaining the Oct4 models can also be used to screen other transcription factors and to find out how they bind to nucleosomes", Cojocaru says.

Moreover, Cojocaru wants to refine the current Oct4 models to propose a final structure for the Oct4-nucleosome complex. "For already almost 15 years now, we know that Oct4 together with three other pioneer factors transforms adult cells into stem cells. However, we still do not know how they go about it. Experimental structure determination for such a system is very costly and time-consuming. We aim to obtain one final model for the binding of Oct4 to the nucleosome by combining supercomputer simulations with different lab experiments. Hopefully, our final model will give us the opportunity to engineer pioneer transcription factors for efficient and reliable production of stem cells and other cells needed in regenerative medicine."

Math reveals the potential answer to a persistent evolutionary mystery

Experts have been unable to explain why cells from bacteria to humans leak essential chemicals necessary for growth into their environment. New mathematical models reveal that leaking metabolites - substances involved in the chemical processes to sustain life with the production of complex molecules and energy - may provide cells both selfish and selfless benefits.

Previously, biologists could only say that leaking is an inherent property of cell membranes caused by fundamental rules of chemistry.

"It is in the nature of membranes to leak, but if leaking is undesirable, why has evolution not stopped it? This question of 'Why?' was never solved," said Professor Kunihiko Kaneko, a theoretical biology expert from the University of Tokyo Research Center for Complex Systems Biology.

The research team used calculations that can measure the changes in multiple factors over time, called dynamical-system modeling, in combination with supercomputer simulations. In this modeling, the researchers considered the nonlinear processes for cell growth where a cell takes in external nutrients and converts them to cellular body and energy by intracellular chemical reactions, by representing the cellular state as the concentrations of intracellular chemicals including nutrients, enzymes, and components to synthesize cellular body. All calculations assumed that the model cells were in a steady state of growth where their internal metabolism and relative concentration of chemicals inside the cells were all stable. {module INSIDE STORY}

The calculations were designed to identify what types of chemical synthesis pathways would become more efficient if some of their components leaked out to the environment. The mathematical models of chemical synthesis paths are simpler than the complex branching pathways in living cells, but allow researchers to look for fundamental patterns.

Researchers identified two such model chemical pathways with catalytic reactions that use enzymes to enhance the reaction rate, which they call the "flux control" and "growth-dilution" mechanisms. In both mechanisms, leaking one essential upstream chemical component of the pathway allows the end product to be produced more efficiently. Thus, leaking is something cells do to selfishly enhance their own growth.

"In theory, the flux control mechanism enhances the pathway for biomass synthesis by the leakage of an essential chemical in an alternative branching pathway, whereas the growth-dilution mechanism enhances the biomass synthesis by the leakage of the precursors of biomass (e.g., amino acids) essential for cell growth. These are a result of the balance between chemical reactions and concentration dilution associated with cellular volume growth," said Jumpei Yamagishi, a first-year graduate student who has worked in Kaneko's laboratory since his undergraduate years.

The models that the research team created so far only consider one type of cell at a time. However, leaking upstream components might become a problem for cells living only with identical types of cells leaking the same components.

"In many cases, if all cells are leaking the same molecule, their environment will become 'polluted.' But if multiple cell types live together, then they can leak one chemical and use a different chemical leaked by the others," said Kaneko.

This mutually beneficial exchange of leaked essential nutrients may be a selfless way to enhance the growth of the whole community of cells.

"Our work may partially answer why the natural environment is so different from artificial lab conditions where bacteria are grown in pure monocultures, but we will need additional models to be sure," said Yamagishi.

The researchers are planning to design more complex mathematical calculations to better simulate natural conditions where multiple types of cells coexist to see if that reveals other types of synthesis pathways that benefit from leaking.