AMED-funded projects

Project summaries 2021

Uncovering ancient viruses in our genome

A method employing machine learning is able to dig up viral ‘fossils’ in the human genome that had previously gone undetected

© 2021 Keizo Tomonaga

A new approach to scouring the human genome for sequences derived from ancient RNA viruses has found previously undiscovered viral sequences lurking in our DNA.

Roughly 8% of the human genome can be traced back to infections by ancient viruses in our ancestors. Scientists are keen to find out more about this viral-derived genetic material because it provides a valuable window into our past.

Until now, techniques used to locate DNA derived from viruses have looked for matches between stretches in our DNA and known viral sequences, but this approach misses genetic material from unknown and extinct viruses.

Now, in an-AMED funded study, Keizo Tomonaga of Kyoto University and co-workers have developed a new strategy for finding virus-derived sequences.

They compared the DNA sequences of endogenous RNA viruses and other regions in the human genome and found differences in their patterns in the occurrence of nucleic acid combinations of a certain length. “We found that ancient RNA viral sequences still retain similar patterns in nucleic acid combinations to those of extant RNA viral sequences,” says Tomonaga. “We also showed that this can be used to differentiate viral-derived sequences from other regions in the human genome.”

Using machine learning, the team screened the human genome for RNA viral insertions based on this characteristic. “We discovered virus-derived sequences that hadn’t previously been detected in animal genomes,” says Tomonaga. “Our analysis sheds light not only on the origin and diversity of viruses, but also on the impact of viral infection on the evolution of hosts.”

The team is now identifying the functions of the newly identified sequences. They also intend to use their method to find as-yet-unknown viral sequences in the genomes of animals such as bats, which act as a reservoir of many pathogenic viruses.

Researcher: Keizo Tomonaga

Host Institution: Kyoto University

AMED Funding: Japanese Initiative for Progress of Research on Infectious Disease for Global Epidemic (J-PRIDE)

Stem cell–derived organoid promising for treating short bowel syndrome

A rodent study demonstrates the potential of using small intestinal organoids for treating short bowel syndrome

© Shinya Sugimoto

An organoid grown from stem cells shows promise for treating a life-threatening condition that commonly occurs after surgical removal of the small intestine, an AMED-funded rodent study has shown.

The small intestine is vital to our health, being the main organ for absorbing nutrients during the digestive process. It sometimes has to be surgically removed — when it becomes blocked, is infected, or develops tumors — but this can lead to a dangerous condition known as short bowel syndrome (SBS). About half of the people who develop SBS need to permanently receive nutrients intravenously, which can result in serious complications that reduce quality of life, and can even be fatal. Transplantation is currently the only treatment capable of curing SBS, but donors are few and the rejection rate of transplanted small intestines is relatively high.

Now, a team led by Toshiro Sato of the Keio University School of Medicine has demonstrated, in rodents, a promising new way to treat SBS. It involves implanting an organoid that mimics the small intestine’s nutrient-absorbing ability.

The team developed organoids using stem cells from a human small intestine. When these organoids were transplanted in a mouse large intestine (or colon), a ‘small intestinalized colon’ developed that could perform some of the nutrient-absorbing functions of the small intestine. Surprisingly, these transplanted organoids sprouted villi — finger-like projections that help absorb nutrients.

The researchers found that intestinal failure was significantly reduced in rats with SBS that received the organoid.

“Our study provides proof of principle for using small intestinal organoids for regenerative purposes,” says Shinya Sugimoto, a member of Sato’s lab. “This offers a feasible strategy for treating SBS in humans. With a view to developing a clinical application, we plan to check safety and do a proof-of-concept study using a larger animal model.”

Researcher: Shinya Sugimoto and Toshiro Sato

Host Institution: Keio University School of Medicine

AMED Funding: Advanced Research & Development Programs for Medical Innovation

A new strategy for fighting cancer

A novel cancer treatment that uses RNA snippets is showing promise

© MOLEKUUL/SCIENCE PHOTO LIBRARY

Recent progress in an exciting new cancer treatment that uses short snippets of RNA has been reviewed in an AMED-funded study.

Short pieces of RNA, called microRNAs, don’t code for proteins — rather they influence the expression of multiple genes. Several microRNAs have been associated with various cancers. Specifically, gene aberrations are thought to give rise to the abnormal expression of microRNAs, which in turn aid the development and progression of cancer by turning off the expression of target genes.

MicroRNAs thus offer a hitherto untapped way of treating cancer. “Recent studies have shown that controlling the expression of cancer-associated microRNAs is a promising way for treating various cancers that show poor responses to other treatments,” notes Jun Inoue of the Tokyo Medical and Dental University (TMDU).

Now, Inoue and TMDU colleague Johji Inazawa have reviewed recent progress made in this emerging field and point to future possibilities.

In their review, Inoue and Inazawa note that several microRNA-based therapies are being developed. Such therapies can either suppress cancer-causing microRNAs (which are upregulated in cancers) or introduce synthetic microRNA that mimic tumor-suppressing microRNAs (which are downregulated in cancers).

“Unlike conventional molecular-targeted drugs and antibody drugs that just control one molecule, microRNA-based therapies have the potential to produce unprecedented therapeutic effects through simultaneously controlling the expressions of several cancer-promoting genes,” says Inoue.

Researcher: Jun Inoue and Johji Inazawa

Host Institution: Tokyo Medical and Dental University

AMED Funding: Project for Cancer Research and Therapeutic Evolution (P-CREATE)

Using a crappifying method to generate better microscopy images faster

A technique for artificially degrading images will help apply deep learning to enhance low-resolution microscopy images

© 2021 Uri Manor, Linjing Fang, Sammy Novak and Amy Cao

Using deep learning to enhance low-resolution microscopy images has become a lot easier thanks to a new method for generating training data that involves artificially degrading images. This method was developed as part of an AMED-funded study led by Yoshiyuki Kubota of the National Institute for Physiological Sciences.

Microscopes suffer from an ‘eternal triangle of compromise’ due to trade-offs between image resolution, illumination intensity and imaging speed. This problem is particularly troublesome for point-scanning systems, the most widely used systems for high-resolution imaging.

Deep learning is a promising way to boost the resolution of low-resolution images, but it requires collecting large volumes of training data.

Now, to generate the large amount of training data needed for deep learning, a team led by Kubota has developed a computational filter they affectionately dubbed a ‘crappifier’. “The crappifier allows us to generate training data much more easily from pre-existing data,” explains Uri Manor, a member of Kubota’s team. “We trained a deep learning-based AI system using crappified data to enable undersampling when imaging biological samples.”

Using their technique, the team was able to obtain images up to 16 times faster than before. “Seemingly impossible imaging projects can now be completed within our lifetimes,” says Manor. It will be especially helpful for large imaging projects and for imaging living samples that are sensitive to high light levels, such as mitochondria.

Importantly, the method does not require expensive equipment, making it highly accessible to labs.

“This is but one of many examples of how deep-learning-based AI is making possible what we never would have imagined to be possible before,” says Manor. “The future of AI in biological research is very exciting and we expect to see many other breakthroughs in microscopy and beyond.”

Researcher: Yoshiyuki Kubota

Host Institution: National Institute for Physiological Sciences

AMED Funding: Strategic Research Program for Brain Sciences (SRPBS) / Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS)

Mouse memory enhanced by skipping food every second day

Fasting every other day linked to improved long-term memory in mice

© THOMAS DEERINCK, NCMIR/SCIENCE PHOTO LIBRARY

Making mice go hungry every second day boosts their long-term memory, an AMED-funded study has found. This finding may have implications for human health and could lead to therapies that slow mental decline.

Originally identified as an age-suppressing gene, Klotho has been linked to both aging and long-term memory. However, it was unknown whether these two effects are connected.

Now, a team that included Makoto Kuro-O of Jichi Medical University in Japan has observed the effects of intermittent fasting on mice by feeding them every other day. After three months of this intermittent fasting, mice exhibited improved long-term memory retention compared with mice that had been fed daily.

On a neurological level, this was observed as upregulation of Klotho in the hippocampus — a brain region primarily associated with memory.

“We discovered that intermittent fasting improved long-term memory in mice compared to a matched control,” explains Kuro-O. “The improvement was associated with increased neurogenesis and expression of the gene Klotho in the hippocampus.”

This long-term memory improvement was not simply due to reduced calorie intake, since mice fed daily with the same reduced-calorie diet as the intermittent-fasting mice did not exhibit such an increase in long-term memory.

The team believes that their results highlight the central role that Klotho plays in generating new neurons in adults.

These findings may one day help human health and memory. “It may be possible to slow cognitive decline and extend life span by using drugs to maintain or enhance endogenous Klotho expression,” says Kuro-O.

Researcher: Makoto Kuro-O

Host Institution: Jichi Medical University

AMED Funding: Advanced Research & Development Programs for Medical Innovation

Supplying oxygen to mammals through the gut

Oxygen can be administered through the butts of mice and pigs, raising the possibility of helping patients with respiratory failure in the future

© KEVIN MACKENZIE/UNIVERSITY OF ABERDEEN/SCIENCE PHOTO LIBRARY

Mice and pigs can respire via their intestines instead of their lungs — a finding that may one day help patients with severe respiratory problems.

Certain aquatic creatures such as sea cucumbers and freshwater catfish can breathe through their rectums in low-oxygen environments. But this ability has never been observed in mammals.

Now, in an AMED-funded study, a team led by Takanori Takebe of the Tokyo Medical and Dental University has come up with a way to administer pure oxygen through the rectums of mice and pigs.

Mice and pigs given intestinal oxygen survived longer in low-oxygen environments than those without intestinal oxygen, with 75% of the mice surviving 50 minutes of low-oxygen conditions, which normally would be fatal. Furthermore, animals given intestinal respiration had more oxygen reach their hearts and displayed fewer signs of oxygen deprivation, such as skin discoloration.

“This is the first study to demonstrate that the mammalian gut can be repurposed for breathing,” notes Takebe.

The process also worked when the team substituted the intestinal gas ventilation system with a liquid-based alternative made up of perfluorochemicals, an alteration that may make the technique more feasible for use in humans.

“Sadly, many people having been suffering from hypoxic condition during the pandemic,” says Takebe. “Although the technique’s safety needs to be thoroughly evaluated, I hope we will be able provide an alternative option to conventional artificial respiratory support for patients as soon as possible.”

The team is currently conducting preclinical trials with a view to testing their technique in a clinical setting.

Researcher: Takanori Takebe

Host Institution: Tokyo Medical and Dental University

AMED Funding: Research Program on Emerging and Re-emerging Infectious Diseases


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