每天一篇经济学人 | Genetic disease 遗传性疾病（2022...

Full-genome screening for newborn babies is now on the cards

对新生儿进行全基因组筛查已成为可能

Genetic disease

基因疾病

【背景】新生儿全基因组检测通过筛查和诊断新生儿遗传病，可在其症状或早期干预，“早发现、早干预” ，有效避免或减少疾病对儿童及家庭的影响。 新生儿全基因组检测包括150多种遗传性疾病和儿童安全用药相关药物的基因组分析，实现对遗传性耳聋、地中海贫血、苯丙酮尿症、葡萄糖-6-磷酸脱氢酶缺乏症、杜氏肌营养不良、脊髓性肌萎缩等常见疾病的一站式筛查。通过筛查和遗传咨询，可以评估疾病复发的风险，为家庭生育提供指导。根据新生儿安全用药检测结果，指导新生儿生长发育期间合理安全用药，有效降低药物不良反应的影响。

Over the years, doctors have described more than 7,000 rare diseases, generally defined as those affecting fewer than one in 2,000 people. So, though individually unusual, such illnesses are collectively a serious problem—a long-tail of need which is hard to treat because patients are few in number and their symptoms often picked up too late. Three-quarters of rare diseases are genetic, and Global Genes, an American advocacy group, reckons 400m people around the world are affected by them. For medicine to do better, people with them need to be noticed earlier, preferably in the first days of their lives.

多年来，医生们描述了7000多种罕见疾病，这些疾病通常被定义为发病率低于两千分之一的疾病。因此，尽管这些疾病在个体中不常见，但总体而言这是一个严重的问题——需求的长尾效应很难治疗，因为患者数量很少，而且他们的症状往往发现得太晚。四分之三的罕见疾病是遗传性的，美国的一个倡导组织Global Genes估计全世界有4亿人受其影响。为了使药物发挥更好的作用，患者需要尽早发现这些疾病，最好是在他们出生后的前几天。

To that end, doctors in many places want to sequence and screen babies’ entire genomes at birth. In America there are projects to do just that at Boston Children’s Hospital, Columbia University and Rady Children’s Hospital in San Diego. A pioneering group at Harvard, known as BabySeq, has recently received money to expand its small-scale work to include 1,000 babies. In Europe, a five-year project called Screen4Care is starting. And efforts are also under way in Australia, China and Qatar. But the project to watch is in Britain. There, a government-owned company called Genomics England, originally set up to run a study called the 100,000 Genomes Project, which investigated genetic diseases and cancer in adults, will soon start a pilot project intended to sequence the genomes of 200,000 babies. That could presage a national programme.

【1】pioneering 有开拓精神的; 开拓性的 

【2】presage 预示

为此，许多地方的医生希望对婴儿出生时的全基因组进行测序和筛查。在美国，波士顿儿童医院、哥伦比亚大学和圣地亚哥的瑞迪儿童医院都有这样的项目。哈佛大学的一个名为BabySeq的开创性团队最近获得了一笔资金，将其小规模工作扩大到包括1000名婴儿在内。在欧洲，一个名为Screen4Care的五年项目正在启动。澳大利亚、中国和卡塔尔也在进行中。但值得关注的项目在英国。在那里，有一家名为Genomics England的政府部门所有的公司，其成立之初是为了开展一项名为“10万人基因组计划”的研究，该研究主要研究成人的遗传疾病以及癌症。该公司不久将启动一个试点项目，旨在对20万名婴儿的基因组进行测序。这可能预示着一项全国性的计划。

Screen saverScreening babies for genetic diseases is not a novel idea. Across North America, Europe and the Middle East, in particular, newborns are often checked at birth for a handful of common heritable illnesses, such as sickle-cell anaemia, thalassaemia and cystic fibrosis. But a whole-genome sequence offers the prospect of spotting thousands of disorders rather than the few which are currently searched for.

对婴儿进行遗传病筛查并不是一个新奇的想法。特别是在北美、欧洲和中东地区，在新生儿出生时经常需要检查是否患有一些常见的遗传性疾病，如镰状细胞性贫血、地中海贫血和囊性纤维化。不过，全基因组测序有望发现数千种疾病，而不是目前正在筛查的少数疾病。

Early diagnosis means earlier treatment. This, in turn, means that children’s lives will be improved and even saved. But the power of the technology also means it is possible, in theory, to screen for conditions that would occur later in life, or even to help parents avoid having other children with the same genetic mutation.

早诊断意味着早治疗。这反过来又意味着儿童的生活将得到改善，甚至得到拯救。但这项技术的力量也意味着，从理论上讲，它有可能筛查出今后可能出现的情况，甚至可以帮助父母避免生下其他有同样基因突变的孩子。

Just how many risk-associated variants it is appropriate to screen for is an open question. BabySeq, which was the first project of its kind, tested for about 1,000. It found that 11% of the 159 infants it looked at harboured at least one variant associated with a child-onset disorder.

究竟有多少与风险相关的变异适合筛查是一个悬而未决的问题。BabySeq是第一个此类项目，其测试了大约1000人。研究发现159名婴儿中有11%至少有一种与儿童期疾病相关的变异。

While techno-utopians might think it a good idea to test for everything, parents of newborns are more cautious. On May 4th, at a meeting held in London by Genomics England, Rick Scott, the organisation’s chief medical officer, said discussions with parents and doctors had led his team to conclude that people want any genomic-screening programme for newborns to look for a far narrower set of conditions than BabySeq sought. The most appealing tests were for variants associated with a high probability of childhood illness, and which would benefit from early treatment.

虽然技术乌托邦主义者可能认为对一切都进行检测是个好主意，但新生儿的父母则更加谨慎。5月4日，由Genomics England在伦敦举办的一次会议中，该组织的首席医疗官里克•斯科特表示，与父母和医生的讨论让他的团队得出结论，人们希望任何新生儿基因组测序计划可以涵盖的疾病范围远比BabySeq寻找的要少得多。最吸引人的测试是与儿童疾病高概率相关的变异，这将受益于早期治疗。

The set of variants Genomics England will seek is therefore being decided “cautiously”, says Dr Scott. At the moment, the proposed list has several hundred items on it. If implemented in toto, this would result in about one baby in 200 receiving a diagnosis of a rare genetic disorder. That list would be likely to grow as understanding improves and new treatments arrive.

因此，斯科特博士说，Genomics England将寻找的一组变异是“谨慎”决定的。目前，提议的清单上有几百项。如果全面实施，这将导致大约每200个婴儿中就会有一名会诊断患有一种罕见的遗传疾病。随着理解的提高和新的治疗方法的出现，这个清单可能会增加。

This public consultation has shown that some parents want to know everything possible about their child while others very definitely do not. One particular finding, according to David Bick, a clinical geneticist who advises Genomics England, is that parents want certainty. They feel it is no use being told that a child is “fairly likely” to have a condition. Rather, they want a pretty clear “yes” or “no”.

这次公众咨询表明，一些家长想要尽可能了解关于孩子的一切，而另一些家长显然不想。据Genomics England的临床遗传学家大卫·比克说，一个特别的发现是，父母想要的是确定性。他们认为，告诉一个孩子“相当有可能”患有某种疾病是没有用的。相反，他们想要一个非常明确的“有”或“没有”。

Many also do not want to know of adult-onset illnesses that their children may one day suffer. This means rejecting tests which might indicate a newborn’s risk, later in life, of contracting cancer, diabetes or Alzheimer’s disease. That information would bring with it the burden of deciding what to tell their child, and when. Rather, these parents feel, it should be up to the children themselves, if they so wish, to seek that information when they are older—which would be easy if their genomes were already on file.

许多人也不想知道他们的孩子有一天可能会患上成年发病的疾病。这意味着拒绝那些可能表明新生儿在以后的生活中有患癌症、糖尿病或阿尔茨海默病风险的检测。这些信息会带来负担，需要决定告诉孩子什么，什么时候告诉他们。相反，这些父母认为，应该由孩子自己来决定，如果他们愿意的话，在他们长大后找出这些信息——如果他们的基因组已经被存档，这将是很容易的。

There are, however, still some conundrums. For example, Pompe’s disease is a disorder in which a carbohydrate called glycogen builds up in the body's cells. The infant-onset form of this illness must be treated straight away. The adult-onset form can be left until those with it are in their 30s. The current genetic test cannot distinguish between these forms. The cost of prompt treatment for youngsters is therefore that some parents must carry the knowledge that their offspring will suffer eventually, though not immediately.

【1】conundrum 复杂难解的问题

 【背景：庞贝氏病】由于溶酶体内缺乏酸性α-葡萄糖苷酶（acidalpha-glucosidase, GAA），使糖原及麦芽糖不能转化为葡萄糖而被利用，以致体内大量糖原在骨骼肌、心肌和平滑肌等组织细胞内聚积而致病。 庞贝氏病是累及全身的系统性疾病，临床变异较大，但主要以肌病表现为主。有个别报道中枢神经系统和肾小管受累。 根据起病年龄症状严重程度和进展速度不同可分为三种类型： 婴儿型，症状比较严重，一般在出生1个月或3～4个月后发病。首发症状为进食后发绀，呼吸困难。全身肌肉无力，呈弛缓性瘫痪，且病情进展较快，常在1岁之内因心肺功能衰竭而死亡。检查可见巨舌，心脏扩大，少数病儿肝脏肿大，心律失常。 儿童型，病情进展较慢，除肌无力外，其他器官受累不一；常以动作发育迟滞或步态不稳为初起症状，继而肌力减退，吞咽困难，呼吸肌麻痹，可伴腓肠肌肥大；常因肺部感染致呼吸衰竭而死亡。但部分患者可生存20年以上。 成人型，因残留GAA酶活性较高，症状比较轻微，仅表现骨骼肌无力，缓慢进展性的四肢肌肉萎缩，近端较远端重；以躯干肌、骨盆带肌明显，半数以上病人影响呼吸肌。常被误诊为多发性肌炎或肌营养不良症。

 然而，仍然存在一些难题。例如，庞贝氏病是一种由一种叫做糖原的碳水化合物在身体细胞中积聚而成的疾病。这种疾病的婴儿发病型必须立即治疗。成人发病型可以保留到30多岁。目前的基因测试无法区分这些形式。因此，对青少年进行及时治疗的代价是，一些父母必须知道，他们的后代最终会遭受痛苦，尽管不是马上。

Tay-Sachs disease, an illness fatal in childhood, causes another dilemma. Some parents absolutely do not want to know about it, because that would spoil their experience of the early years they have with their child. Others feel knowledge is power, and so do wish to know. 

【背景】泰-萨克斯病是由于HEXA基因突变所致。基因突变意味着构成基因的DNA序列永久改变，进而导致身体内一个或多个程序出错。突变的HEXA基因导致人体不能合成己糖脱氨酶A（Hex-A），从而引起一种叫做GM2神经节苷脂的脂肪物质积聚在大脑和神经细胞，阻止大脑和神经正常工作，最终使其丧失功能。 

泰-萨克斯病，一种儿童时期的致命疾病，导致了另一个困境。有些父母决然不想知道这件事，因为这会破坏他们与孩子相处的早年经历。有些人认为知识就是力量，他们也希望知道。

One of the trickiest questions of all concerns Duchenne muscular dystrophy, a degenerative illness that starts in childhood. Screening for this would find it in six of every 100,000 children tested. But only a small number of these have forms of the disease that can currently be treated, and the drugs needed are not widely available. However, learning that one’s child has this disease could also allow children to join trials of new drugs. 

【背景】杜氏肌肉营养不良症会导致肌纤维无力、萎缩。主要是进行性的肌肉无力和萎缩。多数是在4岁以前发病，比如开始发现男孩走路摇摇摆摆，之后就发现他上台阶特别费劲，他起身也很困难，如果要是想起来，需要蹭着身起来。主要是肌肉无力，少部分还会连累心脏，还有的病人会影响智力，包括落后和低下。 

最棘手的问题之一与杜氏肌营养不良症有关，这是一种始于儿童时期的退化性疾病。对这种疾病进行筛查发现，每10万名接受检测的儿童中就有6名患有此病。但其中只有一小部分具有目前可以治疗的疾病形式，而且所需的药物也不是广泛可用。然而，知道自己的孩子患有这种疾病也可以让孩子参加新药的试验。

Over the coming year Genomics England, along with doctors, patients and the wider public, will wrangle with such questions, armed with a set of principles (which are themselves up for discussion) about what tests should be done. These principles include the idea that screening should lead to improved outcomes in those it is applied to; that this should not involve many invasive follow-up tests; and that there is strong evidence the genetic variant being tested for does indeed cause the condition in question.

在接下来的一年里，Genomics England将与医生、患者和更广泛的公众一道，围绕这些问题展开争论，并制定一套关于应该做哪些检测的原则(这些原则本身也有待讨论)。这些原则包括：筛查应能改善其应用对象的结果；这不应该包括很多有创的后续检查；而且，有强有力的证据表明，正在测试的基因变异确实导致了上述情况。

And there is one other thing. This is the tricky question of how to ensure that the data are kept safe for a lifetime. Properly informed consent for all the various uses such data might be put to is central to the British plan. Other places may not be so scrupulous. Moreover, things change. The temptation to crack open genetic databases for police investigations might prove irresistible. Insurance firms would surely be delighted to snoop as well, if they were allowed to.

还有一件事。这是一个棘手的问题，即如何确保数据终身安全。在英国的计划中，对这些数据可能用于的各种用途的适当知情同意是核心。其他地方可能不会这么谨慎。此外，事情会发生变化。为警方调查而“开放”基因数据库的诱惑可能无法抗拒。如果被允许，保险公司肯定也会乐于窥探。

Most important, such data are a veritable Aladdin’s cave for medical researchers—a cave to which only some parents will be prepared to add their children’s sequences. (Informed consent means data should not be used in this way unless parents have explicitly agreed to it.)

【1】Aladdin's cave 收藏珍奇物品之处；宝库

最重要的是，这些数据对医学研究人员来说是一个名副其实的阿拉丁宝库——一个只有一些父母准备把他们孩子的测序数据添加进去的宝库。(知情同意意味着，除非父母明确同意，否则不应以这种方式使用数据。)

Combining the fruits of future scientific advances with people’s full dna sequences, collected at birth, could bring huge medical benefits. But it might also be a double-edged sword. Current knowledge of how genomes work is primitive. There is also a lot of so-called dark genetic matter in them, which does things currently unknown. Genomes may conceal secrets of, say, potential mental illness, or of behavioural predispositions that a genome’s owner would rather stayed private. Current rules say that they should. But for those who have opened the door to doctors and scientists to look at their data, the question of whether those data will remain secure for a lifetime may be a gamble. 

【1】predisposition 易受感染的体质；倾向

将未来科学进步的成果与人类出生时收集的完整DNA序列相结合，可能会带来巨大的医疗效益。但这也可能是一把双刃剑。目前关于基因组如何工作的知识还很原始。其中也有很多所谓的“暗遗传物质”，它们的作用目前未知。基因组可能会隐藏一些秘密，比如潜在的精神疾病或基因组所有者宁愿保密的行为倾向。目前的规则表明他们应该这么做。但对于那些向医生和科学家敞开大门，让他们查看自己的数据的人来说，这些数据是否会终身安全的问题可能是一场冒险。