原创 童国庆医生的试管婴儿治疗技术开发之路
2015年03月02日 【健康号】 童国庆

       试管婴儿技术首先是在兔的研究中取得成功的,后来在其他动物模型中先后取得了成功,如鼠、牛、羊、猪和猴等。其实在动物实验中取得试管婴儿成功已经有近百年时间,而且传代很多年并没有发现试管婴儿出生的动物在成年后与自然受孕的动物在体格和心智上有明显区别。

       人类的试管婴儿发展是在动物实验成功的基础上建立起来的。但是人类的试管婴儿出生比试管兔子出生晚了40多年。20世纪60年代开始,英国科学家Robert Edwards和英国医生Patric Stepto经过10多年的尝试,从100多个治疗失败中取得了成功。他们不但要忍受知识、设备和技能的限制,还经历了来之教会、政府、社团和民众的强烈反对和磨练。从第一例1978年在英国出生,该项技术很快在全球推广和发展。到目前为止,每年都有数以百万计的试管婴儿出生。在北欧的发达国家试管婴儿占了出生孩子的1-2%。试管婴儿技术使不孕症的概念发生了翻天覆地的改变,以前的绝对不孕变成了相对。千千万万的不孕夫妇通过该项技术生了孩子而完善了家庭建设。

       在我国试管婴儿技术是从1996年后开始快速发展,刚开始时候试管婴儿技术仅在省级市的部分议员开展,到现在全国的大部分二线城市和三线城市都已经开展。但是开展规模、服务能力和治疗方式差异很大。特别是临床医生的知识、治疗方案甚至在同一家医院里也存在巨大差异。
       童国庆医生在1996年步入人类辅助生育技术(人工授精和试管婴儿治疗)领域,早期培训是在广州的中山医科大学第一附属医院接受的。1997年在广东省佛山市建立了国内第一家二线城市的试管婴儿婴儿治疗中心,年完成试管婴儿治疗250例,平均临床妊娠率达到34%。同时建立了精子和胚胎的程序化能动技术。在那个年代,国内还没有专职的试管婴儿实验室技术人员,作为医生,不仅要接诊病人(男科和女科都服务)、促排卵、卵泡监测、取卵手术、胚胎移植,同时还要完成精液洗涤、卵子授精、胚胎培养和胚胎冷冻等实验室操作。多面手的工作打下了坚实的辅助生育技术基础。

       童国庆医生1999-2000年赴新加坡国立大学留学,完成了临床胚胎学硕士课程(高级试管婴儿临床和实验室培训课程),研究课题为“钙剂在显微操作下对小鼠卵子受精的作用和机制研究”,大大提高了试管婴儿的知识和技能,显著提高了外语技能,掌握了现代化的不孕症知识和技能,获得了生殖科学硕士学位。2001-2004年于新加坡国立大学完成了生殖科学博士课程,研究课题为“猪卵子细胞浆对小鼠体细胞克隆胚胎的重编程作用和机制研究”,参与了课题组在猕猴和山羊的体细胞克隆研究,获得了生殖科学博士学位。研究发现发表在了Journal of Animal Science, Development等国际刊物。2005-2006年间在新加坡基因组研究院做博士后研究工作,主要从事种植前胚胎和胚胎干细胞的基因表达和机制研究,研究发现两次发表在了Nature Cell Biology国际刊物。在这期间多次赴美国、日本、澳大利亚、香港、台湾等地交流学习,丰富了生殖医学知识,开拓了国际视野。

       2007年回国工作。2007年至2010年间,先后担任南京医科大学教授、博士生导师,南京市妇幼保健院生殖医学中心主任,上海第一妇婴保健院生殖医学中心主任。在这期间,在研究生和博士生的帮助下取得了优秀的研究成果,并应用到临床实践,取得了良好的临床效果:

       1. 率先发现了:玻璃花冷冻囊胚移植比新鲜囊胚移植获得更高的妊娠率。率先发现了促排卵的药物对华人妇女子宫内膜产生不良影响,造成新鲜囊胚移植妊娠率下降。科学论文发表在了Fertility and Sterility, Journal of Ovarian Research等国际刊物。作为非常有价值的科学发现,收到了国际媒体路通社的转载和推广。

       2. 率先建立和应用了玻璃化冷冻方法保存人类剩余的试管婴儿胚胎,率先在小鼠模型研究中发现了8细胞阶段和桑椹胚阶段胚胎玻璃化冷冻复苏后存活率和发育潜力比2-4细胞期胚胎更高。并双向应用到临床实践,提高了人类试管婴儿治疗中的冷冻胚胎移植效率。科学发现发表在了RBM Online, Journal of Reproduction and Genetics, Zygote等国际刊物。

       2011年至今,大力发展上海中医药大学附属曙光医院生殖医学中心的不孕症治疗。依据15年来在不孕症治疗中的从医经验和科学研究,对试管婴儿治疗的发展和局限性深有体会。虽然人类试管婴儿治疗取得了很大程度的发展,但是技术的局限性仍然存在:

       首先,治疗效率仍有待提高; 

       第二,传统的促排卵治疗方法增加了诸如卵巢过度刺激综合症和卵巢手术出血的风险,同时 大剂量的促性腺激素应用增加了女性对乳腺疾病、卵巢疾病和子宫疾病的担忧;

       第三,传统的治疗方案用药时间长给患者造成身体、心理和工作生活的负担;

       第四,传统的用药方案时间长花费增加对患者经济方面造成了一定的负担。

       所以,自2011年来在曙光医院生殖医学中心的工作重点是:建立更加有效、更加安全、更加简洁经济的试管婴儿用药方案。到目前为止,曙光生殖医学中心已经建立了以口服药物为主,以注射针剂为辅的试管婴儿治疗方案,同时建立了一套优化子宫内膜容受性的治疗方法,中药药物的筛选研究取得了明确进展,重要的应用能偶提高子宫内膜的容受性,明显提高试管婴儿的妊娠率。极大简便了治疗过程,几乎杜绝了患者担心的治疗副作用,显著降低了试管婴儿治疗的花费。曙光医院生殖医学中心的胚胎移植妊娠率平均达到55%,在小于35岁年龄组的妇女中胚胎移植妊娠率达到60%以上。每周期平均花费1.5万元人民币。每个治疗周期时间为10-14天。高效安全简洁平价的曙光试管婴儿治疗越来越受到了更多不孕夫妇的选择。

       科学发现论文发表:
Clinical outcome of fresh and vitrified-warmed blastocyst and cleavage-stage embryo transfers in ethnic Chinese ART patients. Journal of Ovarian Research 2012, 5:27

Vitrified-warmed blastocyst transfer cycles yield higher pregnancy and implantation rates compared with fresh blastocyst transfer cycles-time for a new embryo transfer strategy? Fertil Steril. 2011 Apr;95(5):1691-5.

Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev Cell. 2010 Apr 20;18(4):675-85.

Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reproductive BioMedicine Online (2010) 20, 510– 515.
 
Effect of cryotop vitrification on preimplantation developmental competence of murine morula and blastocyst stage embryos. Reproductive BioMedicine Online 2009 Vol. 19 No.5. 708–713

Vitrification of mouse embryos at 2-cell, 4-cell and 8-cell stages by cryotop method. J Assist Reprod Genet. 2009 Nov-Dec;26(11-12):621-8.

Cryotop玻璃化冻融人类囊胚79例报告,《生殖医学杂志》, 2009,Dec;18(6),516-519.
补救受精卵子的囊胚发育潜能演究《生殖医学杂志》2009, Nov;18(3):219-221.
 睾丸内不活动精子行卵细胞胞质内单精子注射结局《中华男科学杂志》2008,14(12):1135-1137.

Sall4 modulates embryonic stem cell pluripotency and early embryonic development  by the transcriptional regulation of Oct4. Nat Cell Biol. 2006 Oct;8(10):1114-23.

A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol. 2008 Mar;10(3):353-60.

Aberrant Gene Expression Profile of Cloned Mouse Embryos derived from Donor Cumulus Nuclei.  Cell Tissue Research 2006 Aug; 325(2):231-43. 

Effect of heat during slaughter on in vitro maturation of prepubertal pigs and sows’ oocytes and subsequent parthenogenetic Development. Biology of reproduction 2003  68: (Supplementary) 342.

Cumulus-specific genes are transcriptionally silent following somatic cell nuclear transfer in a mouse model. J Zhejiang Univ Sci B. 2007; 8(8):533-539.

Global transcriptional factor expression profiling in mouse preimplantation development.  Serono Symposia International: The First Seven Days – from gamete to blastocyst and stem cells. Tampa, Florida, USA (26-28 April 2006).

Exposure of mouse cumulus cell nuclei to porcine ooplasmic extract eliminates TATA box protein binding to chromatin, but has no effect on DNA methylation. J Assist Reprod Genet. 2006 Nov-Dec; 23(11-12):413-9.

Effects of elevated in-vivo temperature on the in vitro maturation and subsequent developmental competence of porcine germinal vesicle oocytes. J. Anim. Sci. 2004. 82:3175-3180.

The first cell cycle after transfer of somatic cell nuclei in a non-human primate  Development 2004 131: 2475-2484.

       有效的囊胚移植方案显著提高试管婴儿的成功率。该篇文章已在Fertility and Sterility 发表,也引起了国际媒体路通社的关注和称赞。如下是路通社多我们的报道。

Clinical
Vitrified-warmed blastocysts may boost pregnancy
Last Updated: 2011-03-01 15:49:24 -0400 (Reuters Health)
By David Douglas
NEW YORK (Reuters Health) - Vitrified-warmed blastocysts yield higher pregnancy and
implantation rates than fresh blastocysts and should be considered for routine use, according
to Chinese researchers "Combined application of vitrification and human blastocyst transfer does revolutionize human ART practice," senior author Dr. Guo Qing Tong told Reuters Health by email.Most patients (60-70%) achieve clinical pregnancy after one oocyte collection as long as they have extra blastocysts vitrified, Dr. Tong said. Dr. Tong of Shanghai First Maternity and Infant Hospital of Tongji University and colleagues say it's widely believed that results are better when fresh embryos are transferred instead of frozen-thawed or vitrified-warmed embryos. As they report in Fertility and Sterility online February 11th, the researchers compared
outcomes in 80 women who had intracytoplasmic sperm injection treatments: 48 who had 136
vitrified-warmed blastocyst transfer (BT) cycles and 32 who had 110 fresh BT cycles.
The implantation rate was 37.0% in the warmed group and 25.0% in the fresh group, a
significant difference. The difference in clinical pregnancy rate was also significant (55.1% vs 36.4%). Rates of multiple pregnancies were similar (40.0% vs 37.5%) as were abortion rates (12.0% vs 10.0%). In 14 patients who had both warmed and fresh transfers, the cumulative pregnancy rate rose as high as 86%. Even allowing for the fact that only 85.7% of the blastocysts survived the vitrification-warming process, "these results were comparable if not better than those obtained in fresh BT cycles,"
the authors write.
The results are better than in previous studies - but those used conventional slow-cooling
protocols rather than the more up-to-date and effective vitrification process.
In addition, the researchers suggest that the improvement "may arise from endometrial
receptivity and enhanced synchronization between embryo and endometrial development in
natural ovulatory versus stimulated cycles."
Also involved may be "the weeding out of poor quality embryos through the act of
cryopreservation itself."
Reuters Health Information (2011-03-01): Vitrified-warmed blastocys... href="http://legacy.reutershealth.com/archive/2011/03/01/professional/link">http://legacy.reutershealth.com/archive/2011/03/01/professional/link...
1 of 2 3/25/2011 10:50 AMIn fact, said Dr. Tong, "More attention should be paid to endometrium receptivity rather than embryo quality.
"Vitrification does not increase the cost at all," Dr. Tong concluded. "On the contrary, the cost is lower as the procedure does not require an expensive machine. For blastocyst culture, the cost is quite minimal."
SOURCE: href="http://bit.ly/hQlOKE">http://bit.ly/hQlOKE
Fertil Steril 2011.
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Reuters Health Information (2011-03-01): Vitrified-warmed blastocys... 

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