3月25日，在亚洲青年领袖论坛健康与医疗主题论坛上，哈药慈航制药股份有限公司董事长段燕文发表主旨演讲。
全文如下：
各位来宾、青年朋友们：
大家好！首先，感谢论坛组委会的邀请，在疫情放开后有机会与大家面对面地交流和分享。我今天分享的题目是“创新合作赢未来，开启合成生物学制药的新时代”，讲讲我们自己的故事。
大家一定还记得2015年诺贝尔生理医学奖颁给中美日三国的科学家。日本的学者大村智从土壤中分离了阿维菌产生有生物活性的阿维菌素，与美国学者坎贝尔合作通过半合成化学修饰的方法得到了活性更好的伊维菌素，来治疗河盲病和丝虫病。中国的学者屠呦呦从植物黄花蒿中发现了青蒿素，治疟疾。他们的成功经验挽救了全球无数人的生命，这是国际创新合作成功的典范。
2015年10月5号，诺贝尔基金会公布3位科学家获奖。16号，全球最顶级的刊物《Cell》杂志主编邀请我们为三位诺奖获奖得主写了评述文章。我们认为这是天然产物药物开发的新黄金时代，这个成功的案例开启合成生物制药的大门。合成生物学技术颠覆性改变了传统产业生产制造方式，以青蒿素为例，我们用合成生物学的方法构建人工细胞工厂，100立升的工业发酵罐就可以替代过去5万亩农业的种植。
下面开启我们合成生物学制药的经历。面对肿瘤和感染性疾病的重大威胁，人类急需加速原创新药的开发。小分子药物目前销售仍然占据全球药物市场的主导地位，天然产物是小分子药物和药物先导物的主要来源。其中，天然产物药物代表性分子带来了革命性的治疗，屡获诺贝尔奖。目前全球最热门的抗体偶联靶向药物，已经上升了到12个品种中，11个弹头分子都来自于天然产物。
尤其微生物天然产物，具有辉煌的成药纪录和高达0.7%的成药率。我们目前发现的天然产物，大概全球就是50万种，其中1300种成药。天然产物来源于动物来源、植物来源，其中以微生物来源的成药率是最高的。这是因为微生物基因组蕴含着巨大的天然产物新分子合成潜能。随着基因组测序能力大大提升和费用的降低，现在已经检测了34万多细菌基因组，单个细菌基因组平均含有30个生物合成基因簇，意味着一个细菌可以产生30种化合物的能力，但是现在不到0.25%的生物合成基因簇对应已知的天然产物。
以诺奖分子阿维菌素生产菌——阿维链霉菌为例，基因组中含有生物合成基因簇大概40个，但是只有其中17个生物合成基因簇是找到对应的天然产物，其他23个是未知的。所以，微生物天然产物新药面临的挑战就是新分子的发现、获得和规模化的制备。A线路是传统的线路活性导向的天然产物开发。它面临的挑战是如何避免已知产物的重复发生。我们采用和创建的是B线路，基因簇挖掘开发天然产物，它面临的挑战是如何有效激活大量沉默基因簇。
中美政府在改变人类未来的关键技术之一合成生物学积极发力。“十四五”已经把合成生物学列为中国“十四五”的生物经济发展规划的颠覆性技术。美国列入《2021创新与竞争法案》和《国家生物技术和生物制造计划》。最近几年，合成生物学的领域的融资额增速是十分惊人的。
我们的策略就是去围绕两个制高点、一个加速器建立国际一流团队进行破局。大家知道，新药的研发是1万个新分子经过14、15年的周期，最终只有一个分子获得上市，其中的研发费用要26亿美元，其中14亿美元的直接研发费用和12亿美元的分摊费用。所以，我们在两个制高点，就是合成生物学与分子库、药物靶标发现的确认，以及临床转化应用技术方案加速器方面来进行破局。
我们合作创建了全球最大菌种资源库，典藏了20万个菌种，意味着可以产生600万个新分子的能力，这是未来我们的重大新药发现的聚宝盆。
从基因组到天然产物药物发现关键科学问题的阐述，成就瞩目。我们在这几年在世界最顶级的刊物发表了一系列大概100多篇有关合成生物学方面的成果，同时构建了新药人工细胞工厂和高效生物合成关键技术平台，创立了以企业为主体新药创制产学研国际一体化的新模式，从基因的挖掘、筛选、工程化的验证，临床的转化性研究，智能化生产和专业化学术推广体系，建立了合成生物学驱动天然产物创新药物完整的技术链和产业链体系。
2007年开始，中美学者联合创办了合成生物学与创新药物中美圆桌会议，提升国际影响力和话语权，引领并推动合成生物学制药在中国的快速发展。同时，我们创办中南大学湘雅国际转化医学联合研究院和合成生物学与新药发现前沿交叉学科博士点。十年来，我们已经培养了一大批合成生物学的高端人才，获得了一大批具有自主知识产权的专利成果和承担了国家重大新药创制任务，十多个原创产品处于不同的开发阶段。
回顾三年疫情的感受，人类健康面对的挑战必须团结合作。在疫情第一时间，我们向国家建言受到重视，总书记有重要的批示。我们专家在武汉疫情第一时间培训了1.5万医务人员，为创造全国支援湖北医疗队员4.2万人无一感染的中国奇迹作出了卓越的贡献。同时，我们青年员工非常有担当，他们在肯尼亚出差，第一时间得到国内消息，跑遍内罗毕药店购买N95口罩，乘口罩专机回国及时捐赠南华医院。
Duan Yanwen talks about innovation and cooperation for the future and the new era of synthetic biopharmaceuticals
On 25 March, Duan Yanwen, chairperson of Hapharm Cihang Pharmaceuticals, delivered a keynote speech at the Health and Medical Care Forum of the Asia Youth Leaders Forum. Following is the full text of the speech.
Distinguished guests,
Dear young friends,
Greetings. First, I thank the organizing committee for the invitation. After COVID restrictions are lifted, we are now able to communicate face to face. Today, let me talk about innovation and cooperation for the future and the new era of synthetic biopharmaceuticals and tell our stories.
As you still remember, the Nobel Prize in Physiology or Medicine
was awarded to three scientists from China, US, and Japan in 2015.
Satoshi Ōmura, a Japanese scholar, isolated avermectin from soil, and produced bioactive ivermectin. He worked with Campbell, an American scholar, and, through chemical semi-synthetic modification, obtained more bioactive ivermectin, which can be used to treat river blindness and filariasis. Tu Youyou, a Chinese scholar, discovered from the plant Artemisia annua artemisinin, for malaria treatment. Their success has saved countless lives worldwide. These are all examples of successful international innovation and cooperation.
On 5 October 2015, the Nobel Foundation announced these three laureates. On 6 October, the editor of Cell, the world’s top journal, invited us to write a commentary for the three Nobel laureates. We believed that was a new golden age for developing drugs made from natural products. This successful case opened the door to synthetic biopharmaceuticals. Synthetic biology techniques have revolutionized the production and manufacturing of traditional industries. Take artemisinin as an example. If we use synthetic biology techniques. To build an artificial cell factory, the use of a fermentation tank of 100 liters is equivalent to 50,000 acres of farming in the past.
Next, I’ll share the experience of our synthetic biopharma. Faced with the great threats from tumors and infectious diseases, people are in urgent need to accelerate the development of original new drugs. Small molecule drugs still dominate the global drug market in sales. Natural products are the main sources of small molecule drugs and drug lead compounds. Representative molecules of natural product-based drugs have revolutionized medical treatment and won the Nobel Prize more than once. At present, the world’s most popular targeted antibody-drugs conjugate has evolved to 12 varieties, of which 11 warhead molecules come from natural products.
In particular, microbial natural products have a brilliant record in drug development and a success rate as high as 0.7%. Nowadays, we’ve discovered about 500,000 categories of natural products in the world, of which 1,300 categories have been developed into drugs. Natural products come from animals, plants, and microorganisms, the latter of which have the highest success rate in drug development, because microbial genomes have huge potential in new molecular synthesis of natural products. With the significant improvement of genome sequencing capability and the reduction of costs, we’ve sequenced over 340,000 bacterial genomes now. A single bacterial genome contains 30 biosynthetic gene clusters on average, meaning that one bacterium can produce 30 compounds, but less than 0.25% biosynthetic gene clusters can be attributed to known natural products.
Take the Nobel-wining molecule, the ivermectin-producing streptomyces avermitilis as an example. Its genome contains about 40 biosynthetic gene clusters, but only 17 of them is known to have corresponding natural products. The other 23 are unknown. So, the challenges faced by new drugs made from microbial natural products is the discovery, collection, and large-scale production of new molecules. Route A is the traditional activity-oriented natural product development, whose challenge is how to avoid the reproduction of known products. We developed and has been taking Route B, namely developing natural products from gene clusters. Its challenge is how to effectively activate a large number of silent gene clusters.
The Chinese and US governments are making active efforts on synthetic biology, a key technology that will change humanity’s future. China’s 14th Five-Year Plan has listed synthetic biology in its development plan during this period for bioeconomy as a disruptive technology. The US has also included it in its Innovation and Competition Act of 2021 and National Biotechnology and Biomanufacturing Initiative. In recent years, the financing for synthetic biology has increased at an amazing speed.
Our strategy is to focus on two fundamentals and one accelerator to build a world-class team to achieve breakthroughs. We know that in the R&D of new drugs, on average, after a 14-year or 15-year cycle, only one molecule could be brought to market among 10,000 new molecules. But its R&D costs 2.6 billion dollars,
including 1.4 billion dollars of direct research costs and 1.2 billion dollars of shared costs. Therefore, we focus on two fundamentals, namely, the library for the acquisition of biosynthetic molecules and the identification of drug targets, as well as the accelerator for clinical translation and verification technologies, to pursue breakthroughs.
We jointly created the world’s largest bacterial resource library, which collects 200,000 categories of bacteria, meaning the capability to generate 6 million new molecules. It’ll be a cornucopia of future new major drugs.
Speaking of the explanation of key scientific issues from genomes to natural product-based drugs, we’ve made great achievements. In recent years, we’ve published in the world’s top journals over 100 articles in a series about our findings in synthetic biology, built an artificial cell factory for new drugs and a key technology platform for efficient biosynthesis, and created a new enterprise-centered international industry-university-research model for new drug development. From gene discovery and screening to engineering verification, clinical translation study, intelligent production, and professional academic promotion, we have established a complete technical and industry chain system that allows for synthetic biology to advance innovative natural product-based drugs.
Since 2007, scholars from China and the US have been jointly organizing a round-table conference on synthetic biology and new drugs, enhancing the international influence and discourse power,
as well as leading and accelerating the rapid development of synthetic biopharma in China. In addition, we have established in partnership with Central South University Xiangya International Academy of Translational Medicine and advanced interdisciplinary doctoral program of synthetic biology and new drug discovery, which, for a decade, have cultivated a large number of talents in synthetic biology. We’ve also obtained lots of patents with independent intellectual property rights and undertaken the national task of developing new major drugs, with over ten original products in different development stages.
Looking back at the 3-year pandemic, tackling humanity’s health challenges entails solidarity and cooperation. During the first outbreak, the State paid attention to our proposals, and the president gave us important instructions. During the Wuhan outbreak, our experts immediately trained 15,000 medical professionals. Consequently, among the 42,000 medical personnel who went to Hubei, none of them were infected. We had a major role to play in that. Our young staff were very responsible. They were on a business trip in Kenya at the time. As soon as they learned of the outbreak in China, they went to all pharmacies in Nairobi for N95 masks and took a special plane for masks to promptly donate to Nanhua Hospital.
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