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The development of computational tools and methods to analyze and interpret DNA methylation has earned Rice University computer scientist Vicky Yao a prestigious National Science Foundation CAREER Award. 

The five-year award, this one for $790,000, is granted to fewer than 400 American academics each year who are expected to make significant contributions to their fields of study.

Yao, an assistant professor of computer science at Rice’s George R. Brown School of Engineering, plans to develop machine learning methods and build open-source software to help biomedical researchers analyze DNA methylation, an important biological process by which a methyl group is added to cytosine, one of DNA’s four bases. These small modifications affect gene expression and show region-specific patterns. Yet they’re dynamic, changing with age and in response to environmental factors such as air quality, diet, and exercise.

This interests Yao, who wants to sift through the more than 28 million DNA methylation sites in the genome to find “fingerprints” representative of distinct tissues and cell types and how these translate into essential downstream functions.

“I’m grateful for the NSF award because this is somewhat of a new direction for me,” said Yao, who joined Rice in 2019 with backing from the Cancer Prevention and Research Institute of Texas and has co-authored high-profile papers applying machine learning methods to uncover once-hidden molecular processes responsible for arthritis and neurological disease.

Methylation occurs throughout the body, and gaining a better understanding of this fundamental biological process will help researchers who study development, aging, and disease, she said.

“DNA methylation is a natural interface between the environment and what happens on the DNA level, and there can be many downstream effects,” Yao said. “You inherit your DNA from your parents -- your A, C, G, and Ts -- and these are fixed aside from mutations which can cause disease. But methylation is a natural way to change or reverse things without adjusting the actual genome.

“It plays such a big role in regulation that it is often referred to as the ‘fifth base of DNA,’” she said. “Methylation clearly can change whether a gene is expressed or not, but it’s also relatively stable. This means we can use it as a biomarker to help orient where we are in the body and, interestingly, begin to pinpoint how environmental stimuli affect our cells.”

She said much of her research takes advantage of public genomics data repositories that span a wide variety of conditions and experimental setups. “One of the challenges is to combine different data types that measure methylation marks in different regions of the genome,” Yao said. “We need to first develop computational methods to integrate the data from different platforms to get a more complete picture of DNA methylation across the genome in different cells.”

Another part of the project will be to build software tools that allow biomedical researchers, even those with no programming experience, to explore patterns involving methylation and how to take advantage of them.

Yao said her group will adapt deep learning methods to infer methylation patterns, find location-specific hallmarks of methylation in healthy tissue and cells and tie these CpG sites -- adjacent cytosine and guanine base pairs that are most often altered through methylation -- with specific biological functions.

“Getting this grant is really exciting for my group,” she said. “This project will open up new research directions that enable us to work on a lot of interesting downstream applications, like how environmental factors can affect individual cells.”

An ambitious academic, clinical, and industry research program that will provide new insights into our understanding of Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS), was launched today by Tánaiste and Irish Minister for Enterprise, Trade, and Employment, Leo Varadkar T.D. The research is supported by the Irish Government through a Science Foundation Ireland investment of €5 million which will be leveraged with an additional €5 million from industry partners.

Precision ALS, which is led by two SFI Research Centres - ADAPT and FutureNeuro - involves world-class Irish-based researchers in clinical science, data science, and artificial intelligence (AI). The researchers will work in partnership with TRICALS, an independent consortium of leading ALS experts, patients, and patient advocacy groups across Europe.

Speaking at the launch, Tánaiste and Minister for Enterprise, Trade, and Employment, Leo Varadkar T.D. said: “This project straddles clinical research and industry and will combine the best of our technologies, the best of our ideas, and the best of our medical expertise with to potential to change lives for the better. It will develop tools that facilitate clinical trials based on precision-medicine, and has the potential to produce benefits for other rare conditions and diseases, supporting job creation and reducing drug costs.”

The program, which will advance data-driven prediction models for the progression of the disease in patients and next-generation data analysis that facilitates clinical insights and treatment, will include the participation of national and international industry partners, charities, and patient organizations.

Simon Harris T.D. Minister for Further and Higher Education, Research, Innovation, and Science welcomed the announcement, saying: “The Covid-19 pandemic has taught us the value of research and the difference it can make to people’s lives. This is a perfect example of the impact research and innovation can have. By supporting and harnessing these types of advanced research projects we will ultimately see the benefits across society.”

Speaking at the launch, Professor Philip Nolan, Director General of SFI said: “The SFI Research Centres were developed to create a critical mass of excellent research in areas of national importance and to ensure this research has tangible benefits for our health, our society, and our economy through collaboration between academia, government and industry across the island of Ireland and internationally. I am delighted to welcome the launch of Precision ALS, which will deliver outstanding science in the area of personalized and precision medicine, focused on neurodegenerative disease. This collaboration will directly benefit healthcare and patient communities, and yield new knowledge, approaches, and treatments with the potential to improve the lives of many.”

Precision ALS will provide an innovative and interactive platform for all clinical research in ALS across Europe, that will then harness AI to analyze large amounts of data. As the largest international multimodal dataset aimed at precision medicine for this condition, Precision ALS will address the issues with gathering new data at scale in a timely and cost-effective manner across multiple international sites to present that data in real-time to clinical scientists.

Director of the Precision ALS research program and Professor of Neurology at Trinity College Dublin, Professor Orla Hardiman said: “Despite significant advances in pre-clinical models that help us understand the biology of disease in animals, the success of clinical trials has been disappointing. ALS is a disease that only affects humans, and there is increasing recognition of the need for a Precision Medicine approach towards drug development. We know now that ALS is heterogeneous, meaning that it has different causes and different patterns of progression. Large numbers are required to understand these differences. Using “big data” analyses, Precision ALS will provide an in-depth understanding of the factors that drive heterogeneity, and in doing so will for the first time allow us to target new and innovative treatments to specific patient subgroups.

Precision ALS is a unique program that brings together Clinicians, Computer Scientists, Information Engineers, Technologists, and Data Scientists. The researchers will work together with leading pharmaceutical, data science, clinical research, medical device organizations, and the HSE to generate a sustainable precision medicine-based approach towards new drug development that will have many benefits including better clinical outcomes for patients and reducing the economic cost of these diseases.

On completion, Precision ALS will be a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other diseases that face similar precision medicine-related challenges.

A fresh analysis of the possible cooling effect of the sulfur dioxide injected into the atmosphere by the Hunga Tonga-Hunga Ha'apai volcano in January 2022 has concluded that the impact will be much smaller than initially thought—but the researchers responsible add some major caveats to this conclusion. 

An undersea volcano at Hunga Tonga-Hunga Ha'apai (HTHH) erupted violently on 15th January 2022, which raised wide public concern about its impact on global climate. Sulfur dioxide (SO₂) injected into the stratosphere after volcanic eruptions are oxidized and converted to sulfate aerosols. These aerosols linger there for one or two years and while there, work to reduce incoming solar radiation, resulting in a short period of global cooling.

The surface temperature returns to normal as the volcanic aerosols dissipate, and so a single volcanic eruption is not enough to alter the long-term global warming trend, unless there are clusters of a volcanic eruption that can persist through centuries as is suggested have happened during the Little Ice Age in the past millennium. 

The largest volcanic eruption of the last 500 years, the eruption of Mount Tambora in Indonesia in April 1815 caused the so-called “Year Without a Summer” in the following year in many parts of the world. There is a reduction in annual mean surface temperature over the tropics and northern hemisphere by 0.4-0.8°C.

But the Tambora eruption emitted 53-58 teragrams (Tg) of SO₂. Satellite measurements of the eruption at HTHH—which has erupted multiple times over the past century—showed that its volcanic ash has reached an altitude of 30 kilometers deep into the stratosphere, with a total mass of only about 0.4 Tg.

One previously reported initial estimate placed the reduction in global surface air temperature at between 0.03 and 0.1°C over the next one to two years as a result of the HTHH eruption.

 “This reported initial estimate may have overestimated the impact as it did not take into account the location where the eruption occurred, which alters the spatial distribution of stratospheric sulfate aerosols—a variable that can alter results substantially”, said Tianjun Zhou of the Institute of Atmospheric Physics at the Chinese Academy of Sciences, “This is because southern hemisphere volcanic eruption emissions are largely confined to circulating in the same hemisphere and the tropics, with less of an impact on the northern hemisphere. This, in turn, leads to a weaker global cooling than those of northern hemispheric and tropical volcanoes”.

To arrive at a more accurate assessment, modeling needs to take into account the latitude of the release of sulfate aerosols. Correcting for this however was something of a challenge, as there are few southern volcanic eruptions similar to that of HTHH in the historical record. Fortunately, climate-model simulations that use large southern volcanic eruptions in the last millennium overall provided a useful reference. In this way, the researchers found a significant correlation between the intensity of 70 selected volcanic eruptions over the last millennium and the global mean surface temperature response in the first year after the eruption.

They then picked six particularly large tropical eruptions in model simulations and scaled the surface temperature response in line with the intensity of the 1991 Mount Pinatubo eruption where 20 Tg of SO₂ were ejected. The results of the model simulations were found to be similar to real-world observations, suggesting their modeling work was on the right track.

These results were then scaled down for the HTHH eruption with its stratospheric injection of 0.4 Tg of SO₂. The final results showed that the global mean surface temperature will decrease by only 0.004°C in the first year after the HTHH eruption. This is within the scope of the internal variability of the climate system.

The cooling in the southern hemisphere will be stronger than in other parts of the world, with the strongest cooling of more than 0.01°C occurring in parts of Australia and South America. The cooling over most of China will be less than 0.01°C.

This means that the eruption of HTHH will not be strong enough to overwhelm the longer-term global warming tendency.

The researchers did include one caveat however to these conclusions: This would be the case if the HTHH eruption is a one-time-only event. No explosive eruptions have been detected at HTHH since the Jan. 15 event so far. However, it may become active again in the future as this volcano has erupted many times over the past 100 years.

“As a result, we should keep monitoring the activity of HTHH in the coming days, months, and years,” said Professor Zhou.

In line with such monitoring efforts, the team will be extending their research by running some experiments based on ideal cases (scenario hypothesis in their simplification, but useful to make the models easier to understand) to try to reveal the potential climate impact of a larger HTHH volcanic eruption should they occur soon.