Celebrating the 100^th anniversary of the Japan Endocrine Society and international collaborations

On the 100^th anniversary of the Japan Endocrine Society (JES), I extend my warmest congratulations and best wishes for the future. To put this centenary into historical context, it has been only 160 years since Gregor Mendel developed the three principles of heredity, predating the discovery of genes, which are the basic functional units of heredity. The DNA era started approximately 80 years ago, and it is only 70 years ago that Watson and Crick, together with Rosalind Franklin, published their seminal paper on the structure of the DNA double helix. This has also transformed the field of endocrinology.

My journey into endocrinology began in the early 1990s. Before that, during my PhD at the Institute of Human Genetics in Heidelberg University, under the guidance of Prof. Thomas Cremer and Prof. Friedrich Vogel, I developed a keen interest in the unique features of sex chromosomes while conducting in situ hybridisation to define their evolutionary relatedness. Sex chromosomes have a block of sequence identity known as the pseudoautosomal region at their ends. During my postdoctoral work at the MRC Genome Unit in Edinburgh, Scotland, we isolated and described the first telomere-adjacent sequence in the pseudoautosomal region (PAR1) of the sex chromosomes in 1985. This discovery, guided by Prof. Howard Cooke, helped to define the molecular end of these chromosomes and opened a whole new field of research into telomere biology and aging.

As in all fields of scientific development and at all times, progress comes by new methodology and technology advances. I learned how to use pulsed field gel electrophoresis (PFGE), a technique for mapping the genome and physically ordering DNA probes on a chromosome, in the lab of Prof. Hans Lehrach at the European Molecular Biology laboratory (EMBL) in Heidelberg and at the Imperial Cancer Research Foundation (ICRF) in London. PFGE revealed that the PAR1 region encompasses 2.7 Mb of DNA while the PAR2 region encompasses 0.33 Mb of DNA. Segments of DNA up to one million base pairs in length could now be cloned in yeast cells using yeast artificial chromosomes (YACs). The PAR1 region also exhibits one of the highest recombination frequencies in the human genome, likely because of its high GC content and unusual repeat structure. Because of these structural features, many deletions occur in this region.

In 1994, at a Y chromosome workshop held at King’s College in Cambridge, England, Dr. Tsutomu Ogata (now Professor Emeritus at Hamamatsu University) and I presented our work. At that time, I was a group leader at the Institute of Human Genetics in Heidelberg (director: Prof. Friedrich Vogel). Tsutomu discussed deletion mapping in the pseudoautosomal region and proposed a 700 kb region, defined by deletion breakpoints in several patients with either short stature or normal height (Drs. Koji Muroya, Yoshimitsu Fukushima, Naomichi Matsumoto, Atsuko Yoshizawa and Nobutake Matsuo also contributed to this work). I shared new data on the PAR1 map and molecular data of this region, along with a previously undescribed genomic island. Tsutomu and I decided immediately that our research interests were well aligned and began a long and productive collaboration. At that stage I got into contact with the JES for the first time.

The rest is history. Ercole Rao, a PhD student, together with Birgit Weiss used cDNA selection and exon amplification to identify exons of a novel gene that we called SHOX, for short stature homeobox gene, through positional cloning. Positional cloning uses sequencing and bioinformatics to locate the position of a disease-associated gene on a chromosome when nothing is known about the role of the encoded gene. This approach was being employed in numerous research laboratories at the time to identify genes that encode diseases. The work on SHOX was further strengthened by Dr. Maki Fukami of Keio University in Tokyo (now vice-director of the Research Institute, National Center for Child Health and Development in Tokyo), who joined our lab for almost five years (1995–2000) to support the cloning and sequencing of SHOX, after which she embarked on an independent project to identify a novel gene that underlies X-specific intellectual disability.

Our original research on SHOX gene identification was published in 1997 and has been cited 1,200 times and more than 500 papers in PubMed followed, dealing with the functional or clinical aspects of this gene. I was also invited to present this work to the Endocrine Society meetings in Japan. It is now well established that SHOX deficiency is the most common monogenic growth disorder, associated with isolated and syndromic forms of short stature. Its diverse clinical manifestations include isolated short stature as well as Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia. SHOX deficiency also contributes to the skeletal features of Turner syndrome. Before the link between SHOX deficiency and short stature was firmly established, growth hormone was already being used successfully to treat short stature in Turner patients. Subsequently, a clinical trial showed that growth hormone is also an effective treatment in children with SHOX deficiency.

More than two decades of research has determined that SHOX integrates different aspects of bone development, growth plate biology, and apoptosis. Expression levels of SHOX are tightly regulated, and almost half of the pathogenic deletions affect enhancers, some of which are quite distant from the gene locus. The clinical severity of SHOX deficiency is highly variable, ranging from low–normal stature to profound mesomelic skeletal dysplasia, and is generally more severe in females. To elucidate the factors that modify disease severity/penetrance, we found that variants in the CYP26C1 gene act as genetic modifiers for SHOX deficiency, again together with our Japanese colleagues.

SHOX is not expressed in mice, so chicken and zebrafish have been used as animal models, along with micromass cultures and primary cell lines, to study SHOX function. Pathway and network analyses have identified interactors, target genes, and regulators. The inter-relationship between SHOX and SHOX2 and their regulatory effects on Fgfr3, natriuretic peptides, and other molecules has raised further interesting questions. SHOX is a transcription factor that is expressed in embryos and in many organs and tissues in adults, so is likely playing a role from embryonic to adult stages. Further investigation is now needed to determine its involvement in other clinical phenotypes.

My laboratory has also contributed to the identification and characterisation of more than 30 other clinically interesting genes. For example, we identified SLC20A1, SLC15A4 and other genes underlying the aetiology of combined pituitary hormone deficiency or ZBT, TRPC4AT and other genes underlying congenital hypothyroidism, as well as genes associated with tall and short stature phenotypes. We have also identified and functionally characterised novel genes associated with intellectual disability and autism spectrum disorders, such as SHANK2 and FOXP1. This work has addressed specific questions in human genetics, neurobiology and functional biology during development.

Last but not least, I would also like to share my thoughts and advice with young colleagues. Science is such an exciting and rewarding career! It can be challenging at times, but it is an inherently optimistic endeavour pursued by dedicated individuals who share the hope that new discoveries will bring opportunities for better patient care. When selecting a lab to work in, it is crucial to choose a team of individuals who are not only passionate about their work but also committed to making a difference. And if you are a woman, it is important to ensure that your supervisor supports men and women equally. Remember, you deserve to work in an environment that values and respects your contributions! Travelling abroad and fostering international collaborations can broaden your perspective on science and the world. Bringing individuals from different backgrounds together to solve a scientific problem can be very fulfilling. Shared goals and respect for different cultural backgrounds can enrich your life in many ways. In times of political uncertainty, science can also provide hope and comfort. The international scientific community is a prime example of how our global society can function with mutual respect by building bridges and creating partnerships.

I wish all readers of Endocrine Journal a very happy 100^th anniversary. Ad multos annos!

Biographies