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用新一代基因测序技术治疗传染病

Combating infectious diseases with next-generation sequencing

音乐
[music]
乔希·奥斯本14岁那年遭遇的事
What happened to Josh Osborn when he was 14 years old
完全算得上是一个恐怖故事
has all of the makings of a horror story.
在波多黎各度完假后 情况开始变得很糟
Things started to go wrong after a vacation to Puerto Rico.
在波多黎各
While in Puerto Rico,
乔希和他的家人在沙滩上看到了一条死狗
Josh and his family saw a dead dog lying on the beach.
回到美国后
Upon returning home to the United States,
乔西的朋友就因为发烧和尿血住院了
Josh’s friend was briefly hospitalized with fever and bloody urine.
乔希自己也开始出现发烧
Josh himself started to experience fever,
头痛 发冷 眼睛发炎等症状
headaches, chills, inflammation of his eyes,
被诊断出患有一种叫ITP的免疫系统疾病
and was eventually diagnosed with an autoimmune condition called ITP,
全称为特发性血小板减少性紫癜
idiopathic thrombocytopenic purpura,
皮肤下面会出现血点
in which he developed bleeding spots underneath his skin.
四个月内 乔希住了三次院
Over four months, Josh was admitted to the hospital three times,
在重症监护室待了44天
spent 44 days in the intensive care unit,
经历了100多次没有结果的诊断测试
underwent more than 100 inconclusive diagnostic tests.
脑部活检也没有结果
He underwent an invasive brain biopsy which was unrevealing.
而他的病情越来越严重
And ultimately, he became critically ill,
顽固性癫痫发作时甚至需要药物让他昏迷
and needed to be placed in a medically induced coma for intractable seizures.
但他的医生仍然查不出病因
But his doctor still couldn’t figure out what was going wrong,
到底怎么了?
what was wrong?
事实上 诊断了一年多都没结果
In fact, more than a year passed by without a diagnosis.
乔希的病例就像一个恐怖故事
Now, Josh’s case is indeed a horror story,
不幸的是这种情况并不少见
but sadly it’s not really that unusual.
20%到25%的情况下
Twenty to twenty-five percent of time,
我们诊断不出传染病 肺炎
we’re unable to diagnose infections, pneumonia,
等重症患者的病因
in intensive care unit patients,
虽然我们做了大量的常规检测
despite extensive conventional testing.
至于发热和血液感染
For fever and bloodstream infections,
也就是败血症 它的未诊断率达到30%
otherwise known as sepsis, it’s 30 percent.
而脑膜炎 脑炎的重病患者
And the percentage of the time that we’re unable to diagnose
的未诊断率
cases of meningitis and encephalitis in acutely ill hospitalized patients,
达到了惊人的70%到75%
a whopping 50 to 75 percent of the time.
我们再回到乔希
So let’s go back to Josh.
你现在看到的是乔希大脑的核磁扫描图
What you can see here is an MRI scan of Josh’s brain,
上面有箭头标记
and highlighted in arrows.
箭头指出了边缘增强的脑池
The arrows point to rim enhancement of the cisterns
也就是大脑里蓄存脊髓液的区域
or the fluid spaces in this brain that are bathed in spinal fluid.
脑池边缘增强是患脑膜炎的迹象
This enhancement is a telltale sign of meningitis,
但不幸的是这对诊断并没有什么帮助
but unfortunately it’s not very helpful making the diagnosis.
实际上放射科医生根据这张扫描图
In fact the radiologist read this particular scan was that
只能推断出传染病或炎症
these findings represent in an infectious or inflammatory process.
这已经不错了
So, good to know, good to know.
但是很不幸 仍然查不出病因
But unfortunately, it’s not giving you the diagnosis.
现在 这个未知的致命性感染
So at this point, Josh was critically ill,
已经让乔希病得很严重了
with a mysterious life-threatening infection.
他迫切需要进行打靶治疗
He desperately needed targeted treatment and he needed it fast.
很多人可能听说过精准医疗
Many of you may be aware of the promise of precision medicine,
它革新了我们诊断和治疗
and how it has revolutionized the way we now diagnose
癌症和遗传性疾病的方式
and treat cancer and hereditary diseases.
通过基因组测序
By sequencing the genome,
我们能为病人提供个性化治疗
we can provide personalized treatment for patients,
比如治疗病人的个体性肿瘤
for a patient’s individual tumor
或者个体性的基因突变
or for a patient’s individual genetic mutation.
我们想把这一技术运用到急性传染病上
I and we would like to do the same for acute infectious diseases
比如乔希这样的患者
in cases such as Josh’s.
我们用来精准诊断传染病的方法叫做
Our approach for precision diagnosis of infectious diseases is called
新一代宏基因组测序
metagenomic next-generation sequencing,
新一代宏基因组测序
metagenomic next-generation sequencing.
不像用带有浮漂的鱼杆
Instead of using a fishing pole attached to a bob
一个个地寻找
to look for individual infectious agents
事先假设的致病原
that have to be defined a priori.
我们的方法是投下一个巨大的网
Our approach is to cast a wide net,
探测并找到所有的病原体
to be able to capture and detect any and all pathogens,
不管它是病毒
no matter whether they’re viruses,
细菌 真菌或是寄生虫
bacteria, fungi or even parasites.
传统的临床检测是通过
Unlike conventional clinical testing such as culture
微生物培养来确定感染原因
in which you grow the organism to identify the cause of an infection.
这会耗费大量的人力
And unlike conventional clinical tests which often are quite laborious,
我们能用的样本量也是也限的
and also require you to use very limited amounts of sample,
并且要做大量的检测
and send test after test after test
因为很多寻找传染原的尝试都是徒劳的
in an often fruitless attempt to search for infectious agents.
新一代宏基因组测序能一步解决这些问题
Metagenomic next-generation sequencing encompasses all of this in a single test.
这个方法
And by doing so,
能为患者提供更精准更高效的治疗
we can provide timely targeted and effective therapy for patients
因为我们能更早更精确地诊断出病因
by virtue of earlier and more accurate diagnosis.
你可以把新一代宏基因组测序
Now you can think of metagenomic next-generation sequencing
当成一种大海捞针式的诊断方法
as a needle in a haystack approach to diagnosis.
我们要做的是采集临床标本
What we do is we take a clinical sample,
可以是血液 呼吸道分泌物
whether it’s blood, respiratory secretions,
脊髓液甚至是某些组织
spinal fluid, even tissue.
再运用高通量测序方法测得
And we generate hundreds to millions of sequence reads,
数以百万的DNA读长
DNA sequence reads on a high-throughput instrument.
接下来要分析这些读长
Next, we analyze these reads
找到与它们相对应的致病源
for any and all sequences corresponding to potential pathogens.
这就像大海捞针 我们要找到有效的方法
This is the needle in the haystack or finding the needle in the haystack approach.
为此 我的实验室发明了一个叫Surpi的计算流程
To do this, my laboratory has developed a computational pipeline called Surpi.
Surpi s-u-r-p-i
Surpi, s-u-r-p-i,
意思是 基于序列的致病原快速鉴定法
stands for sequence based ultra rapid pathogen identification.
Surpi计算流程可以在
The Surpi computational pipeline is able to analyze
3小时内分析3亿条序列
300 million sequences in under three hours.
现在它在服务器端
And it is now available on a server,
云端甚至是笔记本电脑上都可以使用
on the cloud and even on a laptop.
我们周五收到了乔希的样本
We receive Josh’s sample on a Friday,
48小时后就得出了诊断结果
and we had the diagnosis 48 hours later.
Surpi计算流程找到了病原体
The Surpi computational pipeline had identified a pathogen,
也就是乔希的病因
the cause of Josh’s illness,
所有的传统临床检测方法都没能做到这点
that had eluded all prior conventional clinical testing.
请看这张图
And this is the answer.
你们看到的是一张热图
What you’re seeing here is a heat map,
展示了计算流程得到的结果
showing the output of the therapy computational blackbox pipeline.
最左边的柱子代表的是
Shown in the leftmost column is
直接取自乔希脊髓液的DNA
Josh’s spinal fluid DNA, directly extracted from his spinal fluid.
你可以看见乔希感染的是一种钩端螺旋体属的罕见细菌
You can see at a glance that Josh was infected by a rare bacterium called Leptospira.
细螺旋体病源于细菌感染
Leptospirosis is a bacterial infection
这种感染可由接触被感染的水源引起
that’s acquired by a contact with infected water sources.
这些水源往往是被动物尿液污染了
And these are water sources, contaminate with animal urine.
乔希很可能在波多黎各被细菌感染了
What had happened is Josh probably got infected in Puerto Rico
他可能在湖里或小溪里玩过
where he had been playing in the lakes and the streams,
也可能在湖里或小溪里游过泳
or had been swimming in the lakes in the streams,
然后被这种微生物感染了
and had been affected by this particular organism.
而且 测序数据不仅能告诉你致病微生物
However the sequencing data not only gave you the identity of the cause of organism,
还能告诉你菌种
but you can even name the strain.
这个菌种很罕见 叫做圣地罗西钩端螺旋体
He had a rare strain called Leptospira santarosai,
事实上 人们只在
which is actually… Human cases of this bug
三个地方发现过这种菌
had only been found in three areas of the world:
台湾 南美 当然 还有波多黎各
Taiwan, South America, and yes, Frederico,
以及加勒比海的其他岛屿
and other islands of the Caribbean.
我们很庆幸在事情不可挽回之前找到了病因
Thankfully, we were made up to make the diagnosis before it was too late.
治疗乔希的最佳药物非得是盘尼西林?
The optimal treatment for Josh, why it actually was penicillin?
一定得是抗生素么?
Are all this antibiotic?
经过对症治疗 12小时后乔西的癫痫便停止发作
With appropriate treatment, Josh’s seizures resolved in 12 hours.
4周后 他健健康康地出院了
And he was actually out of the hospital in good condition within four weeks.
我想给你们听一段乔希说的话
What I’d like to show you is actually hearing from Josh
这是他在康复几个月后说的
a few months after his recovery and his diagnosis.
与家人健健康康地生活在一起
Being, have my home with my family alive
大概是一个小男孩最大的幸福了
is probably one of the most amazing feelings a boy can get.
乔希的病例 我刚说过 并不少见
Well, Josh’s case, as I said before, is by no means unusual.
我们希望能减少甚至消灭这种病例
However, we would like to make it rare or even non-existent,
我们要怎么做呢?
and how are we going to do that?
在2016年6月
Well, in 2016 of June, June of 2016,
我们发起了”急性传染病精准诊断”研究计划
we launched a study called precision diagnosis of acute infectious diseases.
这是一项涵盖了多家医院的全国性研究
This is a multi-hospital nationwide study
计划每年采集300份病例进行
that aims to involve 300 patients over one year,
新一代宏基因组测序测试
and directly compare the metagenomic next-generation sequencing test,
该技术已在旧金山加州大学
which has now been licensed in a clinical laboratory,
临床微生物实验室获得批准
the UCSF clinical micro lab,
做为传统临床测试的对照
against conventional clinical testing.
类似于致力于服务癌症病人的肿瘤委员会
Akin to a tumor board which is commonly used for cancer patients.
我们成立了一个临床微生物测序委员会
We have established a clinical microbial sequencing board,
很多专家参与进来
consisting of a number of individuals,
有病理学家 传染病医生 神经病学家
pathologists, infectious disease physicians, neurologists,
初级护理医生 生物信息学家等等
primary care doctors, bioinformaticists and others,
来研究病例并将测序数据
to review cases and to integrate the sequencing data
和临床实验数据结合起来
with the clinical laboratory data,
为急性传染病患者提供
to provide personalized diagnosis and recommendations
个性化的诊断和治疗
from managing patients with acute infectious diseases.
我们希望通过这些
It is our hope that by doing so,
能为患者提供更早更及时的诊断
that we may be able to provide more timely and earlier diagnosis for these patients
让他们得到更及时的治疗
and be able to get them treatment before it’s too late.
我们的努力正当其时
Our efforts are particularly timely,
就在今年五月份 美国食药监管局
given that the FDA, just this year in May,
发布了诊断测序仪器的管理指导草案
issued draft guidance for regulation of diagnostic sequencing devices,
比如我们这个
such as this one.
我们希望新一代宏基因组测序技术
And it is our hope that tests such as the metagenomic next generation sequencing assay
能够得到认可
that we’ve developed can be approved,
让它尽早惠及更多患者
and made available to benefit patients as soon as possible.
但是这项技术只能应用于发达国家么?
But is this technology only available in the developed world,
它们能在资源配置较低的贫困国家应用么?
or is it also going to be available in low resource settings in poor countries?
我口袋里的这个纳米孔测序仪器MinION
Well, the MinION nanopore sequencer which I actually have in my pocket,
可能会改变这一切
is a potential game changer in this regard.
这是一个能放进口袋的小测序仪
This is a pocket-sized, small portable sequencing device.
可以用笔记本电脑的USB口充电
And it’s powered by the USB port in your laptop.
当DNA通过半透膜上的小孔时
As DNA is guided through small pores in a semipermeable membrane,
电导的改变能让你
electrical conduction changes can enable you to do,
实时获取测序数据
to generate sequencing data in a real time.
我们正在设计协议和软件
We have been developing protocols and developing software
来进行即时临床样本的实时纳米孔测序分析
to do real-time nanopore sequencing analysis of clinical samples in point-of-care settings.
你们现在看到的是一个动画
What you can see here is a movie,
展示了经过3个小时的样品制备和协议分析
showing after a 3-hour sample preparation protocol
HIV 1病毒和寨卡病毒被检测出
analysis of a patient sample containing HIV 1 and Zika virus.
这个病人被这些病毒感染
This is a patient infected with these viruses.
你可以看到在测序开始后的3分钟内我们就检测出了HIV病毒
You can see that after starting sequencing we could detect HIV in under three minutes,
13分钟内检测出了较低浓度的寨卡病毒
and lower concentration Zika virus in under 13 minutes.
在与国内外的合作伙伴的共同努力下
In collaboration with a number of national international collaborators,
我们正在全球的很多地方试用这个设备
what we are doing is we have actually placed these devices in numerous areas
包括刚果民主共和国 巴巴多斯 巴西
around the world, including Democratic Republic of the Congo, Barbados, Brazil.
我们的目标不仅仅是利用这个
And the goal is not only to be able to use this
快速地诊断出患者的致病原
to diagnose patient infections in point-of-care settings,
还要做新生传染病的公共健康监督员
but also to search and kill,
搜索并杀死这些微生物
do public health surveillance for emerging infections
包括埃博拉病毒 寨卡病毒
including Ebola virus, Zika virus and
和会引发莱姆病的伯氏疏螺旋体
Borrelia burgdorferi, the cause of Lyme disease.
但是还不止这些
But it doesn’t really stop there.
正如这张幻灯片展示的 我们还在太空进行测序
We’re actually also doing as you can see in this slide, sequencing in space
经过多方的努力合作 实现太空测序
and collaborating on efforts to sequence in space.
在今年的8月份 宇航员凯特·鲁宾首次宣告
And in August of this year, astronaut Kate Rubin’s reported for the first time
在国际空间站进行的纳米孔测序获得成功
successful sequencing, nanopore sequencing in, on the international space station.
你可能会问 为什么要在太空测序?
Now you may ask why would be, be interest in sequencing in space.
原因是多方面的
Well, for several reasons,
一 我们能够对宇航员的感染进行诊断
one is that we might be able to diagnose infections in astronauts.
他们不用返回地球
So they don’t have to return to ground
就能进行诊断和治疗
to receive that we get diagnosed and receive treatment.
二是在国际宇宙空间站上进行环境监测
One is also for environmental surveillance aboard the International Space Station.
当然 或许
And yes, perhaps,
我们能够通过太空测序识别并定性外星生命
we can also sequence in space to be able to identify and characterize extraterrestrial life.
所有的战斗都有一个核心宗旨
One of the core truths of any battle,
无论是拳击场上的拳击手
no matter whether you’re two boxers fighting in a ring
还是想要对病人实施诊断治疗的医生团队
or a group of physicians trying to diagnose and cure a patient,
你都无法打败你看不见的敌人
is that quote, you can’t hit what you can’t see.
一个我们能比从前看得
Well, the time is soon coming
更远 更快 更清晰的时代就要到来
when we will be able to see much farther, much faster and much better than ever before.
所以 当家长走进急诊室询问我的孩子怎么了
So when a parent walks into the emergency room, asking what is wrong with my child.
是什么让我的孩子生病了
What is making my child sick?
我们可以给出答案了
We’ll have an answer.
我们能够快速准确地给出答案
We’ll be able to get it quickly and will able to get it right.
我们很快就能看到
The time is soon coming when we will be able to see
在日常诊治中实现精准医疗
the promise of precision medicine being fulfilled on a daily basis.
治好急性传染病患者
As we will be able to save patients routinely
将变成一件平常的事
from the scourge of acute infectious diseases.
谢谢
Thank you!

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视频概述

新一代基因测序技术能够帮助我们快速准确地找到传染病的致病原。

听录译者

【MED】清泉

翻译译者

研究僧

审核员

审核员E

视频来源

https://www.youtube.com/watch?v=_YOEq7mHsw4

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