Science Report 007

Decoding the Language of the Genome 01

What Have Bacterial Genomes Got to Do with Us?

In 2003 when the world celebrated the completion of human genome mapping, Craig Venter, an American geneticist who was instrumental to the project’s success, had already moved onto his new target: Marine bacterial genomes.

He stunned the public in April 2004 with the announcement that he and his team discovered 1.2 million new genes following their research voyage around the Sargasso Sea. The news signaled a new era of metagenomics – genetic analysis of microorganism samples directly taken from a particular location to gain a broad understanding about the environment. Metagenomics differs from the traditional genetic research in that it puts microbes found in the wild straight through a sequencing machine instead of using microbes cultured in laboratories.

Because microbes have direct control over both our bodies and environments, decoding microbial genomes and their relationships to the surroundings can pave the way for so many scientific breakthroughs from the medical to pharmaceutical fields. Some people are already anticipating agricultural, construction and various other applications of the information that metagenomics can provide.

With the speed and the scale of genetic analysis increasing ever more, thanks to the emergence of next-generation sequence technologies, how can we expect to benefit from metagenomics? --- A leading expert from the National Institute of Genetics will explain.

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Ask an Expert: Dr. Ken Kurokawa (National Institute of Genetics)

Dr. Ken Kurokawa is professor at the National Institute of Genetics (NIG) and the director of the NIG’s Center for Advanced Genomics. Since 2014, he has serviced as a director of "Hadean Bioscience," a project funded by the Grant-in-Aid for Scientific Research on Innovative Areas . He currently represents Advanced Genomics Center of the NIG. Dr. Kurokawa, who studied geology and tectonics in the undergraduate and master’s programs, holds a bachelor’s degree from Tohoku University and a Ph.D. from Osaka University. He joined the NIG in 2016 after serving as associate professor at the Nara Institute of Science and Technology and as professor at the Tokyo Institute of Technology. After founding Japan’s first full-scale metagenomic project in 2004, Dr. Kurokawa published the analysis of the human intestinal microbiota from 13 Japanese individuals. Dr. Kurokawa is known for developing the metagenomic analysis technique he used for the project to study how microorganisms in the soil and hot spring waters change in relation to the environment. Click here for his bio.

What Is A Genome Anyway?

A genome refers to the entire set of an organism’s genetic information, and consists of deoxyribonucleic acid (DNA). DNA is comprised of four nitrogenous bases known as AGCT (adenine, guanine, cytosine and thymine). AGCT are attached to DNA’s double helix in a sequence unique to each species. The human genome contains about 3 billion bases. Candidatus Carsonella ruddii, a parasitic microorganism, has the smallest genome discovered to this day with 159,662 bases, which is equivalent of the number of letters contained in a typical Japanese 24-page broadsheet morning newspaper.

A codon, or a genetic code, is a sequence of three bases. Each codon can attract a specific amino acid, and its base sequence order dictates which one of the 20 amino acids it can attract. Codon patterns are transcribed from DNA into messenger RNA (mRNA), which are then translated to create a chain of matching amino acids for the production of protein. This DNA-to-protein flow of genetic information is universal among all species.

"Yes, that’s all species – including us humans,” Prof. Ken Kurokawa of the National Institute of Genetics says, “Genome is a bridge between data and its physical manifestation.”

Microorganisms as a Dependable Research Tool

The most fascinating aspect of the genome, Prof. Kurokawa says, is that it lends an objective yardstick to define all species on equal terms. In genomic studies, all living matter from humans to microbes boil down to A, T, G and C.

And in the metagenomics, “those four chemicals can add infinite layers of meaning to the environmental context that you are trying to understand,” Prof. Kurokawa says.

For example, people will know what conditions their digestive systems are in by analyzing their human intestinal metagenome.

“We could tell you what the temperature inside your stomach is by just looking at the genomic analysis of your intestinal metagenome without ever taking the body temperature,” says Prof. Kurokawa. “The analysis can also show you the pH value (hydrogen-ion exponent) and humidity levels of the environment, which helps you get a good handle on the sanitary condition of your surroundings. On top of that, if you take time series data, you will be able to see how the environment has changed over time, as well,” Prof. Kurokawa says.

In short, microbial genomes contain a treasure trove of information useful for gaining insights into the world around us. Metagenomics attempts to deliver that information to us through multidimensional analysis and interpretation of data.

But how can microorganisms offer this much data to decipher?

“That’s because microbes always respond to environmental factors – the sole controlling factors in changes to organisms – in the same, specific manners,” says Prof. Kurokawa. “You can always count on microbes to provide the most objective data. Metagenomes just have no room for human manipulations.”

For the same reason human microbiota can help determine the condition of digestive systems, microorganisms can contribute to soil research.

“We conducted research on the waterfront microbial communities along the entire 138-kilometer Tama River from the Okutama Lake in the western edge of Tokyo through the Haneda Airport on the Tokyo Bay. We then integrated socio-environmental data into it, such as population distributions and crime rates of the areas. This provides us a comprehensive picture on the community environment. We are now working to develop technology that enables us to assess a neighborhood environment simply from taking a look at its microbial community structure,” Prof. Kurokawa says.

This illustrates how metagenomics can layer countless individual data sets covering ranging topics to generate multifaceted yet cohesive information, Prof. Kurokawa says.

“By using the genome as an equal gauge for all living matter, you can create linkages among various research fields and industries,” Prof. Kurokawa says. “And, that’s the crux of the premise of metagenomics,” he says.

The Tama River system supplies about 20 percent of Tokyo’s drinking water. Photographed here is a downstream section of the river where Prof. Kurokawa and his students conducted research. Prof. Kurokawa credits the students for the successful analysis of the riverfront microbe genomes.

Human and Microbial Genomes: We Are All in This Together

Success of metagenomics depends on the sizes and scopes of accessible databases. There are currently 170,000 samples of microbiome available to the public, and Prof. Kurokawa’s lab is building a “microbe GPS” that shows the environmental contexts for the organisms when the data is plugged into it.

“We already have catalogs of microbes from all corners of the globe. By layering other types of information to the data, we should be able to figure out to a reasonable degree what the presence of certain microbes means for the environment,” Prof. Kurokawa says.

He believes the “hologenome” approach that includes human genomes into the mix for data analysis is also a powerful method for understanding the environment.

“Our human cells and the microbes are all made from the genomes, and they cohabitate in the same environment. The idea of treating all the genomes and environmental data as part of one big system and decoding the relationships among them is growing into this new approach,” Prof. Kurokawa says.

The Hakuba Hoppo Hot Spring in Hakuba Village in Nagano Prefecture gushes out through sepentinite, featuring 50 degrees Celsius (120 degrees Fahrenheit) water with high hydrogen and alkali (pH11), content. This hot spring environment is believed to run parallel to that of the hadean Earth. A group of scientists is conducting metagenomic research on the microbial community that thrives in the boiling water bubbling 600 meters (1,968.5 feet) underground inside of the sepentinite. The work is beginning to shed light on the primitive metabolic system.

Understanding the Earth Environment to Understand the Origin of Life

Prof. Kurokawa has always approached genetic studies with a simple mantra: To understand life, one must understand its environment.

With that same principle, Prof. Kurokawa is now tackling the origin of life study, envisioning the hadean Earth between 4.6 billion-4 billion years ago.

“The reason life scientists can’t begin to fathom how life began on Earth is because we don’t know anything about the Earth environment of that time,” Prof. Kurokawa says.

So, some leading scientists in geology, earth science, life science and planetary science decided to get together and discussed the matter.

“We found out that hadean Earth surface environment was inhospitable to life. Seawater was highly acidic with a pH value of zero, and melted rocks were swirling in it, like iron inside a blast furnace. Forget the life-nurturing image that we have of the oceans today. Even if life was born, it wouldn’t have survived too long in the harsh environment,” Prof. Kurokawa says. “The scientific evidence collected thus far suggests that life may have emerged amid the process of ferocious chemical reactions triggered by radioactivity inside a geyser-like spring on a continent in the primitive era.”

But, Prof. Kurokawa points out that scientists still have a long way to go to decode how life began.

“How the genome became responsible for carrying self-replicating information remains a mystery,” Prof. Kurokawa says.

The Hadean Bioscience Project, in which Prof. is involved as the NIG’s representative, has many images and videos that explains origin of life with computer-generated graphics and animations. Click here for “The Whole History of the Earth and Life” series on YouTube.

The Center for Advanced Genomics: The Axis of International Academic Collaborations for Genomic Analyses

The Center for Advanced Genomics is Japan’s central institution for genomic studies. As one of the country’s 19 inter-university research organizations, the center provides universities and researchers with access to databases containing voluminous genome data compiled with the use of next-generation sequencing technologies. The center promotes resource-sharing and joint research among all genome research institutions and also undertakes large-scale sequencing and analysis projects in response to requests by universities. The center opened in October 2011 in Mishima City in Shizuoka prefecture and has since conducted various cutting-edge genome research in collaboration with other relevant organizations.

The Center for Advanced Genomics

Interviewer: Rue Ikeya
Photographs: Yuji Iijima unless noted otherwise
Released on: Nov. 10, 2017 (The Japanese version released on July 10, 2017)

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