Research developed through a $10 million effort sponsored by the National Institutes of Health

Within the microscopic boundaries of a single human cell, the intricate folds and arrangements of protein and DNA bundles dictate a person’s fate: which genes are expressed, which are suppressed, and — importantly — whether they stay healthy or develop the disease.

Despite the potential impact these bundles have on human health, science knows little about how genome folding happens in the cell nucleus and how that influences the way genes are expressed. But a new algorithm developed by a team in Carnegie Mellon University’s Computational Biology Department offers a powerful tool for illustrating the process at an unprecedented resolution. 

The algorithm, known as Higashi, is based on hypergraph representation learning — the form of machine learning that can recommend music in an app and perform 3D object recognition. 

School of Computer Science doctoral student Ruochi Zhang led the project with Ph.D. candidate Tianming Zhou and Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology. Zhang named Higashi after a traditional Japanese sweet, continuing a tradition he began with other algorithms he developed. 

“He approaches the research with passion but also with a sense of humor sometimes,” Ma said.

Their research was conducted as part of a multi-institution research center seeking a better understanding of the three-dimensional structure of cell nuclei and how changes in that structure affect cell functions in health and disease. The $10 million center was funded by the National Institutes of Health and is directed by CMU, with Ma as its lead principal investigator. 

The algorithm is the first tool to use sophisticated neural networks on hypergraphs to provide a high-definition analysis of genome organization in single cells. Where an ordinary graph joins two vertices to a single intersection, known as an edge, a hypergraph joins multiple vertices to the edge. 

Chromosomes are made up of a DNA-RNA-protein complex called chromatin that folds and arranges itself to fit inside the cell nucleus. The process influences the way genes are expressed by bringing the functional elements of each ingredient closer together, allowing them to activate or suppress a particular genetic trait.

The Higashi algorithm works with an emerging technology known as single-cell Hi-C, which creates snapshots of chromatin interactions occurring simultaneously in a single cell. Higashi provides a more detailed analysis of chromatin's organization in the single cells of complex tissues and biological processes, as well as how its interactions vary from cell to cell. This analysis allows scientists to see detailed variations in the folding and organization of chromatin from cell to cell — including those that may be subtle, yet important in identifying health implications.

“The variability of genome organization has strong implications in gene expression and cellular state,” Ma said.

The Higashi algorithm also allows scientists to simultaneously analyze other genomic signals jointly profiled with single-cell Hi-C. Eventually, this feature will enable expansion of Higashi’s capability, which is timely given the expected growth of single-cell data Ma expects to see in coming years through projects such as the NIH 4D Nucleome Program his center belongs to. This flow of data will create additional opportunities to design more algorithms that will advance scientific understanding of how the human genome is organized within the cell and its function in health and disease.

“This is a fast-moving area,” Ma said. “The experimental technology is advancing rapidly, and so is the computational development.” 

Technologies with low CO₂ emissions are the focus of energy transition. However, some of them consume enormous freshwater resources – water that won’t be available in sufficient quantities in many regions in the future.

Hydropower, biomass power generation, wind power, hydrogen, photovoltaics – these terms quickly come to mind when talking about the energy mix of the future. An energy mix that is supposed to combat climate change by limiting CO₂ emissions. However, the long-term consequences of such technologies for the water supply in a region are often overlooked, resulting from the fact, for example, that water is needed for cooling. Dr. Martina Flörke, Professor of Engineering Hydrology and Water Resources Management at Ruhr-Universität Bochum (RUB) in Germany, advocates not only looking at CO₂ emissions but also taking other environmental influences into account – how water resources are affected, for example. Together with her team, she used a model that calculates water supply and demand worldwide. Rubin, the RUB’s science magazine, published a report on her work. 

Predicting water supply until the year 2300

The model, called “WaterGAP3”, divides the Earth’s landmass into 2.2 million grid cells and thus has a geographical resolution of five arc minutes. At the equator, this translates into a cell size of nine by nine square kilometers. For each land cell, the researchers fed physiographic and meteorological data into the model, such as land cover, soil types, daily precipitation, temperature, and solar radiation. Based on this data, the algorithm simulates the terrestrial water cycle: how much precipitation in each cell infiltrates into the soil, evaporates, and how much contributes to runoff generation and is then available as direct and groundwater runoff in rivers and aquifers. The simulation allows us to look back to pre-industrial times and make forecasts up to the year 2300.

The team calculated the water availability worldwide, taking into account only renewable freshwater resources, i.e. no fossil deep groundwater reserves. They then contrasted the water supply with the intended water extraction. To this end, they also included 48,000 locations of energy production plants and their water withdrawals and consumption.

Calculating water requirements for energy production

To make a forecast for the year 2040, the researchers relied on four future scenarios that Greenpeace and the International Energy Agency had drawn up. Presented in 2014/15, these scenarios outline how the energy mix could develop in the future. One scenario, for example, describes which forms of energy would help to limit global warming to two degrees Celsius and relies heavily on photovoltaics, solar power plants, biomass power generation, wind, and hydropower.

The researchers reproduced this energy mix created by the four scenarios in their model. In the process, they assumed that in the future more electricity will be generated using this method at locations that, for example, already produce energy using photovoltaics today. “We can’t know, of course, at which sites more photovoltaic plants will be built in the future, so in our model, we can only work with the sites that currently exist – even though this is certainly a weak point because production will also take place at other sites going forward,” explains Martina Flörke.

However, this doesn’t affect the key points of the calculations: A deficit is to be expected at up to 42 percent of the locations because more water will be needed there in the future than is available. “And this doesn’t even take into account the fact that the water demand in these regions could also increase for other reasons, for example, because fields have to be more frequently irrigated due to the effects of climate change,” adds the researcher.

Mediterranean region must prepare for extreme drought

Water deficits are to be expected primarily in the west of America, in the Middle East and north of Africa, in southern Europe as well as in certain locations in the south and east of China and India. “In the Mediterranean region, in particular, it is very likely that extreme drought events will become more frequent,” says Flörke. Therefore, some of the locations that are currently being used for energy production must be fundamentally questioned. “The model analysis clearly shows that it would definitely not be beneficial to expand energy production at the current locations,” concludes the Bochum-based researcher. In addition, more efficient technologies, storage options for water and energy as well as alternatives to the use of fresh water, for example, treated wastewater, are needed.

WANDEL research project

The featured study was the focus of the research project “WANDEL – Water Resources as Important Factors of the Energy Transition at the Local and Global Level”, which was officially wrapped up at the end of 2020 and coordinated by Martina Flörke, first at the University of Kassel and then at RUB.