In-depth research on intractable and rare diseases is an important part of efforts to promote and lead medical science and technology innovation in a way that facilitates medical progresses at a national level; it is also necessary for promoting the health and well-being of patients with rare diseases and implementing the Healthy China strategy. With more than 4 million cases preserved since its founding and expertise in delivering high-quality care up to international standards, PUMCH is well-positioned to do more to tame rare diseases: PUMCHers generation after generation have been bent on the typical rare diseases and scientific issues thereof and conducted systemic studies to explore frontier technologies that enable precision diagnosis and treatment. Such efforts have intensified since 2016: with the support of the state and relevant ministries, PUMCH took the lead in building a national collaborative system for clinical studies of rare diseases, which includes three major research platforms, namely the National Rare Diseases Registry System of China, the State Key Laboratory of Complex, Severe and Rare Diseases, and the National Infrastructures for Translational Medicine, as well as a clinical database and a biobank. The system has supported the national collaborative research on rare diseases and enabled leapfrog development of the research in China.
National Rare Diseases Registry System of China: The Scale Effect
In China, rare diseases are not that rare by the absolute number of patients, which is expected to exceed 20 million. Taking stock of the patient base is the first step for rare disease prevention and control, diagnosis and treatment and research.
In 2016, PUMCH President Zhang Shuyang led the “key special program of precision medicine research” under the National Key R&D Program for the 13th Five-year Plan Period devised by the Ministry of Science and Technology, and thus initiated “clinical cohort studies on rare diseases” and “research on the precision diagnosis and treatment technologies and clinical practices for major rare diseases among the Chinese population”. Building on those early initiatives, PUMCH took the lead in launching China’s first national rare disease registry-based study, which engages more than 20 top teaching hospitals in China, all working together on the platform of the National Rare Diseases Registry System of China (NRDRS). Currently, the platform has built a clinical database and a biobank, established 188 rare disease research cohorts, and registered 67,000 rare disease patients, and expanded the number of participating medical institutions from 20 to 101. It has now become one of the top three international rare disease repositories, providing decision-making basis for accurate typing, diagnosis, treatment and prevention of rare diseases.
The clinical database targets at rare diseases and is particularly suitable for conducting multicenter, long-term follow-up studies involving complex data registration. The database has established multicenter research groups for researchers of different kinds of rare diseases, which are managed efficiently and subject to strict quality control throughout the disease-related information acquisition and sorting process.
The biobank has established a repository of living biological samples concerning intractable and rare diseases and related technology systems and conducted multi-omics research and data mining with rare kidney, bone and respiratory diseases as the pilots, forming a cognitive model featuring “genotype + phenotype + disease model + clinical validation”. The biobank provides strong support for rare disease science and technology innovation and new drug development.
NRDRS has facilitated the implementation of rare disease policies, accelerated the clinical trials of 18 new drugs for rare diseases, and promoted international exchanges in this field. President Zhang Shuyang was invited to share China’s protocols of rare disease diagnosis and treatment at a UN conference and introduce the rare disease status quo and orphan drug policies of China on “The Lancet”. NRDRS has become a member of the International Rare Diseases Research Consortium (IRDiRC) and has conducted strategic cooperation with the leading international rare disease collaborative network Orphanet.
The State Key Laboratory and the National Infrastructures for Translational Medicine: Supporting National Collaborative Research on Rare Diseases
President Zhang Shuyang pointed out: “The journey of PUMCH is a medical journey of working relentlessly to tame intractable and rare diseases as well as a scientific journey of marching into the unchartered territory of those diseases. PUMCHers generation after generation have adhered to the principle of combining basic research with clinical practices and conducted multidisciplinary collaborative research on etiological mechanisms and treatment methods. This is an exemplary approach for translational medicine as well as an important lever to pull for achieving precision medicine.” Putting into use the two national scientific research platforms, the National Infrastructures for Translational Medicine and the State Key Laboratory of Complex, Severe and Rare Diseases, is a strong boost to major innovation in science and technology, the R&D of major new drugs as well as frontier research.
The State Key Laboratory of Complex, Severe and Rare Diseases embodies the national strategies of “the four orientations” and “empowering the country through science and technology”. It is also an important platform for PUMCH to go from strength to strength through science and technology in its new centenary. The laboratory is tasked with conducting applied basic research and cutting-edge technology research around intractable and rare diseases, aiming to address the practical issues of limited diagnostic tools and insufficient care, drugs and research. Currently, PUMCH has conducted a series of key research on the commonality, characteristic mechanism and precision diagnosis and treatment technology for intractable and rare diseases listed in the Chinese rare disease catalog.
One of the important tasks of the National Infrastructures for Translational Medicine is to carry out translational medical research on intractable and rare diseases. The platform brings together top universities, research institutes, biomedical and related industries in China, therefore well-placed to leverage the synergy between them to promote fast clinical translation that leads to innovative drugs, new diagnostic reagents and materials, and devices and technologies with intellectual property rights. The clinical research ward that has been put into use helps researchers systematically carry out translational medical research at the molecular, cellular, tissue, individual and population levels, thus playing an important role in promoting innovative breakthroughs in cardiocerebral vascular diseases, geriatrics, brain science research, AI modules and medical big data mining.
On the basis of the National Rare Diseases Registry System of China, the State Key Laboratory for Complex, Severe and Rare Diseases, and the National Infrastructures for Translational Medicine, PUMCH researchers have developed 100-plus treatment guidelines and consensus concerning intractable and rare diseases, and registered more than 500 studies. Through the implementation of the central high-level special program of clinical research, PUMCH will establish a research system and management platform covering the whole process from “clinical research to translation and then application and promotion”, enhance the ability of seeking innovations and breakthroughs in the clinical diagnosis and treatment of rare diseases, establish a chain of translation and incubation of innovative outcomes in rare disease research, and build a network for the application and promotion of research outcomes. More importantly, it will seek to generate PUMCH solutions to intractable and rare diseases and world-leading scientific and technological accomplishments.
Fruitful Research at the Frontier
“In any specialty, China’s absolute number of rare disease cases is likely to rank first in the world,” said Professor Tian Zhuang of the Department of Cardiology, also Deputy Director of International Medical Services. He further explained that accelerating research on rare disease prevention and treatment would not only benefit patients with rare diseases in China, but also shed more light on common diseases in a way that provides fresh perspectives of medical care worldwide.
Professor Chen Limeng’s team in the Department of Nephrology presided over the preparation of the “Chinese Experts Consensus on the Treatment of Gitelman Syndrome (2021 Edition)”, which, based on the latest medical evidence, establishes consensus on the clinical manifestations and typing as well as standardized diagnosis, treatment and management of the Gitelman syndrome and specifies the standardized pathway.
The team of Academician Qiu Guixing from the Department of Orthopedics Surgery has built the first internationally leading genetic research system for skeletal deformities in China, revealed that TBX6 variants were the most important genetic cause of congenital scoliosis (CS), defined TACS as a new subtype of CS, proposed the concept of TACS type II, and shed light on the new genetic mechanism of “common variants in the same gene combining with rare mutations to cause a disease”. The team also led the establishment of the collaborative research group of “systematic analysis of spinal deformities and related comorbidities”, which was joined by more than 30 centers worldwide. The team established the first genetic counseling clinic for skeletal deformities in China and developed several guidelines and standards for screening and early diagnosis and treatment of spinal deformities, helping make the screening, prevention, diagnosis and treatment of spinal deformities more standardized and homogenized in China.
A multidisciplinary team including Professor Zhang Shuyang and Professor Tian Zhuang from the Department of Cardiology and Professor Huo Li from the Department of Nuclear Medicine was the first in China to apply the 99mTc-PYP imaging to the non-invasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), significantly increasing the diagnosis rate of this rare, progressive and lethal disease from less than 1%. Nearly 100 patients with ATTR-CM were diagnosed at PUMCH, including the first case of wild-type ATTR-CM in China. The team extended the 99mTc-PYP imaging to nearly 100 medical institutions nationwide, which completed the screening of more than 2,000 patients in less than two years. Zhang Shuyang and Tian Zhuang led the establishment of the ATTR-CM National Collaborative Group which penned the first “Chinese Experts Consensus on the Diagnosis and Treatment of Transthyretin Amyloid Cardiomyopathy” in China.
Professor Liu Juntao’s team in the Department of Obstetrics and Gynecology has presided over and completed several major national science and technology projects; established a complete set of prenatal screening and prenatal diagnosis system in line with China’s national conditions; established a technical platform of genetic testing of prenatal ultrasound abnormalities that mostly adopts karyotype analysis, CMA and WES; formulated the “Technical Standards for Prenatal Screening and Diagnosis of Common Fetal Chromosomal Abnormalities and Open Neural Tube Defects”; and participated in the formulation of expert consensus and technical standards in the field of obstetrics. With all these efforts, the team has made important contributions to the reduction of birth defects in China.
Professor Chen Xiaowei’s team in the Department of Otolaryngology discovered for the first time mutations in the causative genes of USher syndrome in China, completed the genetic analysis of more than 4,000 cases of hereditary retinal degeneration patients, and mapped the spectrum of genetic variants of Chinese USher patients. The team also collected data on nearly 100 cases of deafness-ear malformation syndrome, which provides a theoretical basis for genetic testing.
Professor Long Xiao’s team in plastic surgery has carried out measurement and analysis after 3D imaging of rare disease patients’ face. It has jointly published several papers with Associate Professor Feng Ming’s team in the Department of Neurosurgery on their joint research of special facial features such as “acromegaly”. The team has converted subjective descriptions of clinical examinations into comparable and easy-to-analyze quantitative values, thus providing an objective basis for accurate diagnosis and treatment of rare diseases. The “facial big data” of Chinese people that the team has garnered also provides data support for the next step, which is AI-powered diagnosis of rare diseases.
In 2022, the “Journal of Rare Diseases”, a magazine supervised by the National Health Commission and managed by PUMCH, was officially launched. PUMCH President Zhang Shuyang serves as its first editor-in-chief. As one of the authoritative academic exchange platforms in the field of rare disease research in China, the journal sets its sights on the frontier of international rare disease research and focuses on the urgent challenges in diagnosis and treatment. The Journal will earnestly promote domestic and international academic exchanges and cooperation in rare disease prevention, diagnosis and treatment and insurance coverage, and inform policy makers, scientists and medical professionals engaged in rare disease-related research.
Since 2016, with the support of the Party and the State, PUMCH has secured a series of promising results in its research of intractable and rare diseases. “Progresses in genetics and research of various molecular mechanisms will take rare disease diagnosis and treatment and scientific research to a new era. More and more drugs with only one therapeutic target will rapidly enter the market, helping us tame more and more intractable and rare diseases,” said Zhu Yicheng, Director of the Department of Neurology, PUMCH, whose sincere expectations of the future echo the shared wishes of the vast number of medical professionals at the hospital.
The hybrid operating room in the National Infrastrctures for Translational Medicine
Written by: Gan Dingzhu and Chen Mingyan
Picture courtesy: Sun Liang
Translator: Liu Haiyan
Editor: Wang Yao