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Tributes following the death of Kiyoshi Nagai, of the MRC Laboratory of Molecular Biology

Kiyoshi Nagai has been described as an “ambitious” and “fearless” scientist by his colleagues at the MRC Laboratory of Molecular Biology, following his death at the age of 70.

A group leader at the Cambridge laboratory, and joint head of its Structural Studies Division from 2001-2010, Kiyoshi took on the seemingly impossible task of understanding the molecular mechanism behind gene splicing - an essential process in making proteins.

Kiyoshi Nagai in 2008. Picture: MRC Laboratory of Molecular Biology
Kiyoshi Nagai in 2008. Picture: MRC Laboratory of Molecular Biology

The work he began 30 years ago has recently led to a comprehensive understanding of this process by unravelling the puzzle of the spliceosome, a feat described by the LMB as “one of the greatest achievements in modern molecular biology”.

Kiyoshi’s Nobel Prize-winning colleague, Richard Henderson, said: “Kiyoshi was bold, ambitious and totally fearless scientifically, as well as immensely skilled experimentally. With his warm, supportive and perceptive personality, he and his research group formed a highly successful team.”

Born in Osaka, Japan, on June 25, 1949, Kiyoshi trained as a biophysicist at Osaka University, where he did his PhD research in Professor Hideki Morimoto’s group, investigating allostery in haemoglobin.

During his studies, he spent 18 months at the LMB under the supervision of John Kilmartin and Max Perutz, exploring the oxygen-binding properties of hybrid haemoglobin.

After returning to Japan and completing his PhD in 1977, he spent four years as an assistant professor in the Department of Physiology at Nara Medical School before the award of a Thomas Usher Fellowship in 1981 enabled him to return to the LMB, where he stayed for the rest of his scientific career.

Among his early achievements was to produce the first artificial haemoglobin mutant by working out how to overexpress beta-globin protein in E. coli, which is commonly used in laboratories as a single-celled model organism.

It was in 1984 that Kiyoshi was appointed as a group leader in the Structural Studies Division and turned his attention to gene splicing.

Seven years earlier, while Kiyoshi was finishing his PhD, biochemist Richard Roberts and geneticist Phillip Sharp - LMB alumni - independently made a discovery about gene splicing that was to later earn them a Nobel Prize.

They found that in eukaryotes - organisms like humans, animals and plants, whose cells have a nucleus enclosed within membranes - most genes that carry the genetic code for making proteins have much longer segments within them that are non-coding, known as intervening sequences, or introns.

In order for the genetic information in our genes to be read out, or expressed, first the DNA within them is converted into RNA in a copying process called transcription.

Both the expressed sequences, or exons, and the introns are transcribed into RNA.

But before the RNA transcript is decoded by the cell structure called the ribosome, the introns are removed.

The exon segments meanwhile are spliced together to generate one continuous protein-coding sequence.

The process - a fundamental step in gene expression - relies on a complex molecular machinery known as the spliceosome.

Kiyoshi Nagai in 2018. Picture: MRC Laboratory of Molecular Biology / Leo Hillier
Kiyoshi Nagai in 2018. Picture: MRC Laboratory of Molecular Biology / Leo Hillier

Discovered by Joan Steitz and named by John Abelson, both LMB alumi, the spliceosome has been compared to a film editor, chopping out the bits not wanted to make the final movie, before sending it to the director.

Kiyoshi dedicated decades of work to understanding the spliceosome - an immensely complex challenge. He first published on it in 1990, starting with relatively small proteins in isolation or bound to RNA, before learning how to express and assemble the components of a series of structures involved in assembling the spliceosome.

In 2009, a spectacular crystal structure - known as U1 snRNP - was revealed, offering the first glimpse of a key part of the architecture involved.

More structures followed, with the advent of electron cryo-microscopy techniques that enable atomic-level resolutions to be achieved without the need for crystallization, progress became much swifter, building up a complete picture of the spliceosome.

Earlier steps in spliceosome assembly have very recently been resolved by Kiyoshi’s team.

We can now follow an extremely intricate molecular machine as it very precisely removes an intron from what is known as precursor-mRNA , then ties together the two pieces to produce mature mRNA. This messenger-RNA carries the code for building a protein.

His former colleague, Tony Crowther, said: “As joint head of division with Kiyoshi between 2001-2005 I found Kiyoshi’s advice invaluable, as he had a sound judgment on scientific matters and a sympathetic and supportive approach to personal problems.”

And the Nobel Prize winner, Sir Venki Ramakrishnan, said: “Kiyoshi was a real scholar, as well as a bold and creative scientist. He was also a very kind, generous and thoughtful colleague.

“We first became friends when I came here on sabbatical in 1991-2, found we shared many interests including RNA biology and classical music, and it is in large part due to him that I moved to the LMB seven years later. When we were heads of the Structural Studies division together, I was struck by how thoughtful and conscientious he was, and what an excellent mentor he was not just to his own group but to young scientists throughout the division.”

Kiyoshi’s numerous honours included EMBO membership, fellowship of the Royal Society and The Biochemical Society Novartis Prize and Medal.

He was diagnosed earlier this year with inoperable liver cancer and confronted this with the same inspirational courage and strength with which he approached his scientific career.

He died peacefully on the evening of Friday September 27, in the presence of his wife Yoshiko and daughter Yuko.

A book of condolence has been opened by the Structural Studies divisional office at the LMB. Messages can also be sent directly to Jennie Lightfoot at jennie@mrc-lmb.cam.ac.uk.

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