2026生物医学研究前沿与其引领的生命科学革命

生物医学研究前沿与其引领的生命科学革命2026提要历史——HGP的由来和进程过程——生命科学新范式方向——生命科学前沿的预判大道至简大象无形悟者觅器信者至成每个核苷酸每一个基因簇每一个特征序列（比如CpG序列）每个基因组变异每个染色质DNA的共价修饰每个染色质组份的共价修饰每个基因产物和共价修饰每个基因表达的调控网络和机制………..每个氨基酸每一个肽链每一个蛋白质机构与变化每一个蛋白质复合体每一个细胞器………..每个化学分子每一个小分子与大分子的相互作用•每一个细胞每一个器官10/24/24BIG20242每一个胚胎每一个个体每一种生命………..Source:

NSF

Funding

Survey;

OMB

deflatorIf

you

want

to

curecancers,

try

to

knowgene

first!"

In

1971,

President

Richard

Nixondeclared

a

“War

on

Cancer”

withthe

hope

to

find

a

cure.If

you

want

to

curecancers,

support

drugdiscovery?"If

you

think

research

isexpensive,

try

disease!"The

Lasker

Legacy:NIH’s

Postwar

Growthator310/24/24BIG2024Why

HGP:

A

Matter

of

Great

Vision“We

have

two

options:

either

try

to

discover

thegenes

important in

malignancy

by

a

piecemealapproach, or

to

sequence

the

whole

genome

ofselected

animal

species”.From

Renato

Dulbecco:

A

Turning

Point

in

Cancer

Research:Sequencing

the

Human

Genome“我们只有两个选择：要么零敲碎打地去发现一个个重要基因，要么就有选择地测定数个动物（包括人类）的全基因组序列。”——杜贝克《癌症研究的转折点:测定人类基因组的序列》1964

Lasker1975

NobelDied

2012

at

age

984410/24/24BIG2024ImprovingHealthcareScience

of

MedicineBiology

ofDiseaseBiology

ofGenomeStructure

ofGenome基因组学发展不同阶段需要强调不同研究对象和研究目标19885510/24/24BIG20242011《人类基因组计划》对经济和社会的影响持续数十年BIG20246

科学意义与重要性

项目目标

主要创新点

技术路线

研究基础与条件十年投资回报率近210倍十年投资的累计回报率逾260倍10/24/247For

the

First

time:

Whole-Genome

SequencingDelivers

New

Treatment

Options

for

Twins

withRare

Genetic

Movement

Disorder10/24/24

BIG2024Whole-GenomeSequencing

forOptimized

PatientManagement.Bainbridge

et

al.

2011.Sci

Transl.

Med3:87re3.国家生物信息中心China

National

Center

for

BioinformationCauses

and

risk

factorsAutism

has

a

strong

genetic

component

asdemonstrated

by

twin

studiesA

child

has

an

approximately

19%

higher

riskofautism

if

an

older

sibling

is

on

the

spectrumA

growing

body

of

evidenceinvestigating

maternal

infection,

drug

use,

and

age

(there

is

also

evidence

linkingadvanced

paternal

age

to

an

increased

risk)

aspotential

causes

of

autismHealth

complications

during

pregnancy

and

inchildbirth

may

raise

a

child’s

autism

risksignificantly,

a

baby

experiencing

complicationsboth

during

and

before

birth

may

have

a44%increased

risk

of

autismToxins

in

the

environment,

especially

heavymetals

like

mercury

and

lead,

have

also

beenassociated

with

an

increased

risk,

but

most

ofthese

studies

have

various

methodologicallimitations8启动“全民基因组测序工程”——初衷、使命、终极目标10/24/24BIG20249科学项目与工程：三代人的“甲子之梦”（1980～2040）初心：癌症的预防、诊断和治疗（“War

On

Cancer”）“人类基因组计划”/DNA测序技术——承上启下起点和落脚点：从“基因身份证”——每个人的基因组序列，到“三数体系”——数字基因、数字医疗、数字健康社会化工程与产业迭代：“三数体系”是进入数字经济的“金钥匙”（2000～2040）产业重点转移：数据积累、互动路径、交流渠道、市场反馈元宇宙“三圈”：虚拟健康圈、虚拟社交圈、虚拟生活圈国家生物信息中心China

National

Center

for

Bioinformation通活学理念：“四新一体”!ã#(N&w

()*+h&-i-/01234567897:1<632=>?@!AB(CD3/!EF

(N&w

GHIHJiKL/0123MN6OPãQ1<6R!ãSTU(VWXYCZ[\C]^/!_`(N&w

abIicb*/0123MNde9fg1<6hR!ijklmn6!op(qrsEtSuvwij?ijvw/!xy(N&w

{|b}bK)/0123~6ÄÅÇÉ9ÑÖÜá1<632?àâäã(å~çé23èÜ[é23f89!ëxíìuîïñf8?!óíòôö/102011出炉精准学计划The

PMP

Reportpublished“人类基因组计划”完成二十年后：人人基因组工程20

years

after

the

Human

Genome

Project宣布启动精准学计划机构取样法规5千人先导项目参与人数启动全民计划数以百万计10/24/24BIG20241121世纪健康保障法2022数据查询电子病历共享资金接力：政府投入与制药产业的互动聚集人才10/24/24BIG202412经费加倍HGP时代（10x）后HGP时代（2x）中国制药业的R&D投入相当于美国产业界1990年时的投入中国制药业的R&D投入相当于美国NIH1960年时的投入China

has

a

lot

of

roomto

catch

up:

60

years

and30

years

lagged

behind

the

US“30年河东，30年河西”：

1960

to

199010/24/24R&D

expenditure

of

the

pharmaceutical

industry

in

China(billion

yuan).

Data

resource:

China

National

Bureau

ofStatistics,.Omics2024

1314打通信息交流障碍改变管理模式启动应用型项目国家生物信息中心China

National

Center

for

Bioinformation15二十一世纪治愈法案10/24/24BIG20241621世纪医疗信息资源共享法（2016-2020制定）21st

Century

Cures

Act

timelineKey

21st

Century

Cures

Act

milestones

through

2023.网络信息安全保障10/24/24BIG202417电子健康档案定义的拓展电子健康档案整合为联邦核心数据实现电子健保信息输出共享快速健保内部资源共享On

March

9,

2020,

the

Office

of

the

National

Coordinator

for

Health

InformationTechnology

(ONC)

released

its

final

interoperability

rule

thataims

to

provide

patients

with

more

control

of

their

health

data

and

restrict

information

blocking

by

health

care

providers,

developers

ofcertified

health

information

technology,

health

information

exchanges

and

networks

(called

“actors”

throughout

the

rule).

ONC’s

final

ruleimplements

the

information

blocking

provisions

of

the

21st

Century

Cures

Act,

which

prohibit

any

practice

that

is

likely

to

interfere

with,prevent

or

materially

discourage

access,

exchange

or

use

of

electronic

health

information,

except

as

required

by

law,

or

if

the

practice

meetsan

exception.Telemedicine

works

throughElectronic

Health

Records

(EHRs)10/24/24BIG202418国家生物信息中心China

National

Center

for

BioinformationImagine

if

doctors

could

tell

you

what

diseases

you're

mostsusceptible

to

before

you

get

sick--

and

if

scientists

could

createmedicines

to

fit

your

personal

genetics.

George

Church

sees

thatday

dawning.Church,

54,

a

big,

bearded

man

with

an

intense

curiosity

and

friendly

demeanor,

helped

launch

the

Human

Genome

Project

in

theearly

1980s.

Now,he

wants

to

dramatically

scale

down

the

technology—from

a

national

effort

on

the

order

of

a

moon

landing

tosomething

as

routine

as

a

cholesterol

check.

Church's

goal:

to

be

able

to

decode

an

individual's

DNA

for

about

the

cost

of

apersonal

computer,

$1,000.

And

to

do

it

by

2008.19庆祝发送1千五百万人的个性化基因组报告！2C市场早已突破数千万人10/24/24BIG202420国家生物信息中心China

National

Center

for

BioinformationAlphaFoldDeepmind

releases

AlphaMissense:

an

AImodel

that

can

classify

the

effects

of

71million

possible

genetic

mutations

onhuman

proteins

and

help

pinpoint

thecauses

of

diseases.2110/24/24BIG202422国家生物信息中心China

National

Center

for

Bioinformation23兰迪·谢克曼（RandyW.Schekman，1948年12月30日-），男，生于美国明尼苏达州圣保罗市，先后就读于加州大学洛

杉矶分校和斯坦福大学，1974年获得博士学位。导师是著名的阿瑟·科恩伯格教授（1959年获得诺贝尔奖）。1976年，谢克曼任职于加利福尼亚大学伯克利分校，他是该大学分子和细胞生物学系教授，并兼任霍华德·休斯医学研究所研究员。曾任《美国国家科学院院刊》主编。1992年当选美国国家科

学院院士。2002年与詹姆斯·罗思曼因对细胞膜传输的研究获拉斯克基础医学奖。2013获得诺贝尔生理学或医学奖。国家生物信息中心China

National

Center

for

Bioinformation24Bernard

Henbest

himself

was

nota

man

for

awards.

He

refusedanomination

for

Fellowship

of

the

RoyalSociety,

the

highest

honour

that

Britaincan

pay

a

scientist,

when

it

was

offeredto

him

at

the

age

of

43.

He

believed

thatscientists

spent

too

much

effort

chasingawards,

and

not

enough

educating

theirstudents.国家生物信息中心China

National

Center

for

Bioinformation252012202020132019201520142016201720182011《“健康中国2030”规划纲要》《中华人民共和国人类遗传资源管理条例》《中华人民共和国基本医疗卫生与健康促进法》202220232029

20302025202420262027

20282021《中华人民共和国生物安全法》《健康中国行动（2019—2030年）》国家生物信息中心国家生物安全证据基地PM

Report

PublishedAdvancingAccess

toPM

Act（19-20）AdvancingAccess

toPM

Act

（2016）PM

Initiative21st

CenturyCures

Act

（16-20）《国家“十四五”《中华人民共和国数据安全法》《中华人民共和国网络安全法》《中华人民共和国食品安全法实施条例》《中华人民共和国动物防疫法》国家科技资源共享服务平台国家对我国人类遗传资源和生物资源享有主权。摘自《中华人民共和国生物安全法》10/24/24生物经济发展规划》BIG20242610/24/24BIG20242710/24/24BIG202428医生资源短缺个人支付高产业结构不成熟人均投入偏低10/24/24BIG202429“精准医学研究”重点研发计划(2016-2020)30集成整合存储汇交数据安全标准规范技术规范体系生命周期管理分级分类管理数据精准医学大数据的资源整合、存储、利用与共享平台建设疾病研究和精准医学知识库构建精准数据库群生物医学语义和本体自然人群国家大型健康队列和重大疾病专病队列!"#$%&'()*+,!"-./0123045167&'*+,基线数据临床数据样本数据组学数据…….呼吸系统、心脑血管、罕见病等精准医疗临床决策系统队列大数据规范应用标准体系资源目录体系大数据规范化应用安全体系精准医学大数据处理和利用的标准化技术体系建设标准 应用示范平台知识库数据方向东老师制10/24/24BIG202431基于群体遗传和疾病的关联研究基于群体遗传

和症状的关联研究以疾病为核心的研究以机制为核心的研究抑郁症 肥胖与代谢失调 糖尿病数字基因组(DigitalGenomeSystems)数字医疗体系

(DigitalHealthcareSystem)全生命周期数字孪生体系(TheLife-spanDT

System)青春期

皮肤综合征（如痤疮）骨质疏松更年期综合征心脑血管疾病各类癌症体能与心智锻炼膳食健康神经退行性疾病罕见遗传疾病自闭症与广泛性发育障碍全基因组关联研究的意义学习障碍专家为主体的基因解读体系大众为主体的10/24/24BIG202432基因注释系统围棋成就了AlphaGO蛋白质结构解析成就了AlphaFold基因编辑将成就AlphaGene&Cell1990202020002010Web

4.0IntelligentPurposivePragmatic智能化目的性语用性SocialSemantic社交化语义性Web

1.0机器＋信息数据＋信息

Web

3.0＋知识创联网络人联网络机联通联化网络connectivity数字化

Digitalization物联

移动化网络

Mobility认知化

Cognition数字经济人＋数据平台经济人＋机器人＋智慧＋目的代币经济虚拟经济Web

2.0数字化句法性10/24/24BIG202433从虚拟到现实的反馈家园一体化虚拟健康圈物质世界虚拟生活圈精神世界虚拟社交圈元宇宙元宇宙元宇宙元宇宙从现实到虚拟的实现精准健康智能医院智能诊断智能康复算力算法数据10/24/24BIG202434制药业Pharmas（1423

blnUSD）电视产业TV

Industry游戏业Games(145blnUSD)电影业

Movie

Industry(136blnUSD)出版业PublishingIndustry（112.5bln10/24/24BIG20243510/24/24BIG20243610/24/24BIG20243710/24/24BIG20243813B09IG/240/2244国家生物信息中心China

National

Center

for

Bioinformation通活学理念：“四新一体”!ã#(N&w

()*+h&-i-/01234567897:1<632=>?@!AB(CD3/!EF

(N&w

GHIHJiKL/0123MN6OPãQ1<6R!ãSTU(VWXYCZ[\C]^/!_`(N&w

abIicb*/0123MNde9fg1<6hR!ijklmn6!op(qrsEtSuvwij?ijvw/!xy(N&w

{|b}bK)/0123~6ÄÅÇÉ9ÑÖÜá1<632?àâäã(å~çé23èÜ[é23f89!ëxíìuîïñf8?!óíòôö/40斯德尼・波兰讷尔科学进步依赖于这三个依次发生的要素——新技术、新发现、新思路We

cannot

solve

ourproblems

with

the

same

thinkingwe

used

when

we

created

them.（只有新思考才能解决老问题。）——

Albert

Einstein.41Logic

will

get

you

from

A

to

B.Imagination

will

take

youeverywhere.——Albert

Einstein.BIG202410/24/24国家生物信息中心China

National

Center

for

BioinformationDomains

under

heaven,

after

a

longperiod

of

division,

tends

to

unite;

aftera

long

period

of

union,

tends

to

divide.This

has

been

so

since

antiquity.”42从2003年说起……GPBGenomicsProteomics&

BioinformaticsReconciling

Mendel

with

Darwin

(1860s

–1940s)random

driftand

selectionmutation

andrecombinationMendeliangeneticsDarwinianselectionfrequencyof

allelesmodernsynthesis!"#$%&'(ø—+)(Th@

Fir4t

M

d@rn

Synth@4i4

f

Bi

l

gy)!•#$%&•'(A(Jean–Bapti4tePierreAntoinedeMonet,ChevalierdeLamar×k,1744I8K1I—18N9I1NK18I>,1RRTU,yR#W˚YZ[\]^_`$,bcd]ef`gh-˚1809I“lmn€_p`q(Philo4ophie

zoologique>-v,wx“ã{m'(A`|˚vQ¼m)eÅÇÉÑÖÜáàeäYã,åçDèêë1_í1ìª]ïñ,óëòôöõ]úù˚10/24/24BIG202443达尔文于1859年出版了《物种起源》molecular

biologysingle

genes

andproteinsinteracting

moleculesand

their

networkssystems

biologyvariance

inpopulationsobservationalbiology½"#$%&'(ø=+)The Molecular

Synthesis

of

Biology+

Cue-

Cue10/24/24BIG202444国家生物信息中心China

National

Center

for

Bioinformation45LDEEEEE2005年½"#$%ø三()*+(-.A012

19807–20107)A

Uni

n

f

Lęmęrckięn7

ęnd

Dęrwinięn7

M@@t

in

th@

RNA

W

rld,

ęt

th@H

lviv

7ph@r@,

ęnd

High@r

Dim@n7i

n7半个多世纪以来，RNA在生命系统中的核心作用被逐渐认识10/24/24

BIG202446分子生物学“中心法则”DNA复制RNA转录蛋白质翻译RNAProteinDNA“RNA世界”假说Altman

&

Cech,

ope-RNA,1989Watson

&

Crick,

1962SidneyBrenner,2002鲁棒性（Robustness）易变性（Variability）多样性（Diversification）复杂性（Complexity）国家生物信息中心China

National

Center

for

Bioinformation47GenotypePhenotypeInformational

TrackOperational

TrackHomeostatic

TrackCompartmental

TrackPlastic

TrackMolecular

SciencesObservatory

SciencesMechanochemical

ParametersCompatibility

ParametersInheritability

ParametersConnectivity

ParametersSpatiotemporal

ParametersDigital

Sciences2012年现代生物学的第四次思考——通活学The

Forth

Synthesis—Holovivology:Stratification,

Prioritization,

Reconciliation

&

UnificationBIG202448分⼦细胞板块

Molecular

Cell

Plates⽣理解剖板块

Anatomy-physiologyPlates通活学板块

Holovivology

Plates基因型与表型板块

Genotype-phenotypePlates由“多板块”知识构成的一个知识“新大陆”10/24/24!¾($%>1()*+(Macro-biosphere,

1800-19r0>:34¾6789:71;<=>?@¾($%>1()*+(Micro-biosphere,

19r0-2000>:DE1(>7FG1(>71(H>7IJ1(>71(K0>?M¾($%>1()*+(Holovivosphere,

2000->:NOH7IJH7M¾H(PQJR>1(>ST——QV>(Holovivology>Biology

has

evolved

into

new

integrated

stage

—

namely

holovivology(holo-,

通；vivo-，活；通活学)—

where

research

activities

are

being

carriedout

systematically

and

quantitatively

in

chemical

and

physical

parameterswithin

real

space

and

time,

and

hypotheses

are

tested

in

model

organismsand

artificial

biological

systems

that

are

so

close

to

in

vivo

situations

where

invivo

validations

become

necessary

only

for

clinical

application.近现代生命科学发展的理论技术轨迹和最后的瓶颈“三世界”“四思考”“五流通悟”“双单四定多维智能”4B9IG2024基因组生物学之“五行”==通活学的五流同（通）悟•••1.

信息流：遗传学与变演论The

Informational

Track:Genetics

and

Evolution基因组结构与变演

Genomics

and

Comparative

Genomics基因型与表型界定

Genotype

-phenotype

Relationship物种变演

Lineage-specific

Genomics

and

EvolutionThe

OperationalTrackTheOperational

Track-I:

EpigenomicsTheOperational

Track-II:

RibogenomicsTheOperational

Track-III:

Proteomics•••2.

操作流：细胞生物学与分子生物学操作流之一：表观组学操作流之二：核酸组学

操作流之三：蛋白质组学3.

平衡流：生物化学、生理学与药理学The

Homeostatic

TrackThe

Homeostatic

Track-I:

EnergyThe

Homeostatic

Track-II:

Matter平衡流之一：能源流平衡流之二：物质流•平衡流之三：信导流The

Homeostatic

Track-III:

SignalingThe

Compartmental

Track••4.

分室流：生命的起源、系统发育和发生分室流之一：生命起源分室流之二：生命发生formsThe

Compartmental

Track-I：

Origin

of

lifeThe

Compartmental

Track-II:

Development

of

diverse

lifeThe

Compartmental

Track-III

:

Organelles操作流之三：亚细胞器 功能分室流之四：细胞分化

The

Compartmental

Track-IV：Differentiation

and

Heterogeneityof

cells•5.

可塑流：表型可塑性与神经生物学The

Plasticity

Track可塑流之一：表型可塑性

The

Plasticity

Track-I:

Environmental

Influence

and

PhenotypicPlasticity可塑流之二：行为与认知的可塑性

The

Plasticity

Track-II:

The

Plasticity

of

Affect,Behavior,

and

Cognition5B0IG2024Five-track

Biology:Holovivology

（通活学）10/24/2451PCSurvivalBIG2024HomeostasisConnectivityMaterialEnergySignalingInformationInheritability

Trans-generationVariability信息流PHOPlasticity:Compatibility

for

adaptation

&

fitnessGrowthICompartmentSelf-organization

DevelopmentDifferentiation分室流OperationSelf-assembly

Mechanochemical

constraintsSpatiotemporal

constraints操作流Reproduction

可塑流平衡流GenotypePhenotype52国家生B物IG2信024息中心Informational

TrackOperational

TrackHomeostatic

TrackCompartmental

TrackPlastic

TrackEPIGENETICSEpigenomicsRibogenomicsProteomicsGENETICSBiology

=GenomicsHolovivology+Environment∑

Lj

=∑

Ii

+∑

Ok

+∑

H

m+

∑

Cn

+∑

Pz∑

Pz

=

∑

Ok

+∑

H

m+

∑

Cn+

Ii∑

Cn

=∑

Ii

+∑

Ok

+∑

H

m

+

PzChina

National

Center

for

Bioinformation国家生物信息中心关于生命起源的推理：“别异同，明是非”（墨子语）China

National

Center

for

Bioinformation生于平衡（属水、形藏；）——生命起源于海洋，其先发性本质是化学（细胞内的自组装），后发性本质是细胞生物学（细胞间的自组织）和生态学（生命群体的自适应），再发性本质是认知行为和社会学（认知与社会形态的自管理）始于操作（属木、善随）——生命开始于操作，其物理化学背景是分子机制、细胞过程等传于信息（属金、聚敛）——细胞生命稳定传承的物质基础是DNA，其功能单元是基因（完整的操作单元，即“OPERON”），基因（组）的保守性通过自组织能力造就了生命的谱系的各种起源物种，信息的结构也在不断优化、分化、变演衍于分室（属火、隔分）——细胞生命造就了生命的可变、易变、多变、渐变，造就物种多样性的新力度、新维度、新程度（新边缘）存于可塑（属土、优胤）——渐进中生存可能性的可控繁衍、不断适应、重组重建、选择应对，并不一定是简单的生存竞争和弱肉强食53Waddington的表观遗传学地貌Conrad

Hal

Waddington (8

November

1905

–

26

September

1975)

asa

British

developmental

biologist,

paleontologist,

geneticist,

embryologist

and

philosopher

who

laidthe

foundations

for

systems

biology,

epigenetics,andevolutionary

deBvIG2e02l4opmental

biology5410/24/24Vodnala

et

al.,

Science

363,

1417

(2019)10/24/24BIG202455信息流I-Track操作流O-Track平衡流H-Track分室流C-Track可塑流P-Track10/24/24BIG202456Life

startsso

does

thsimple,e

brain.It

gets

more

complexover

time

……What

does

the

brain

do

for

“spare”

parts?What

if

the

brain

has

done

something

wrong

in

theprocess?If

time

becomes

a

limiting

factor,

and

life

is

in

ahurry

to

grow?10/24/24BIG202457国家生物信息中心China

National

Center

for

Bioinformation58BIG202459Birdsong

Front

Psychol

2018发音差异词汇分型音系分类语⾔形成语10/素24/2差4

异国家生物信息中心China

National

Center

for

Bioinformation6020

Years

After

HGP:What

is

the

Next?

What

After

?198820112024Information-TIntegrationintoSocialProgramsProjects:PMICancer

MoonshotBRAINStem

CellOperation-T2035Homeostasis-TIntegrationintoIndustrialPrograms10/24/24BIG202461Compartmentalization-TPlasticity-T20452055国家生物信息中心China

National

Center

for

Bioinformation202462“Concerted

efforts

to

deepen

understanding

of

RNAs

andTheir

modifications

and

their

role

in

living

systems

hold

thepotential

to

advance

human

health,

improve

crop

yields,

andaddress

other

pressing

societal

challenges.

”突破遗传学“信息流”瓶颈的“操作流”策略RNA世界DNA世界从DNA到RNA和蛋白质：编码功能（Informational

Track）从DNA到修饰的RNA：操作功能（Operational

Track）DNA也加入到操作流之中：甲基化和DNA的其他修饰DNA甲基化和去甲基化酶Up

to

1000sRibo-nucleotidesRNA聚合酶蛋白质合成体系200n4

NucleotidesDNA聚合酶4n100s

nucleotides依赖于DNA的RNA聚合酶＋RNA修饰酶50n生命起源于操作流生命延续于信息流63On

the

informational

track:

AUGCOn

the

operational

track:

>200

nucleotides

identified1B0IG/240/224465The

limitation

of

DNA

sequencingInitial

RNA：GAUXCGAYCGGCZAATDUEU…

...Reverse

transcriptioncDNA：GATGCGATCGGCCAATGTTT…

...cDNA

sequencingRNA

sequences：GATGCGATCGGCCAATGTTT

…

...Error

rate:

5/20

＝

25%X,Y,Z,D,E:

non-canonical

or

chemically

modified

nucleotides10/24/24Du,

Dan,

et

al.

"METTL1-mediated

tRNA

m7G

methylation

and

tBraIGns2la0t2io4naldysfunction

restricts

breast

cancertumorigenesis

by

fueling

cell

cycle66blockade."

Journal

of

Experimental

&

Clinical

Cancer

Research

43.1

(2024):

1-18.“…

...to

develop

novel

technologies

that

will

enable

at

least

one

order

of

magnitude

improvement

in

DNA

sequencing,

and

practical

methods

for

direct

RNA

sequencing.

Advances

in

genomics

and

more

broadly

inbiomedical

research

have

been

greatly

facilitated

by

significant

andsustained

DNA

sequencing

throughput

increases

and

cost

decreases.The

goal

now

is

to

improve

the

quality

and

efficiency

of

DNA

sequencingand

enable

direct

RNA

sequencing

(e.g.,

longer

read

lengths,

fasterturn-around

time,

greater

accuracy,

and

higher-throughput

etc.)

atreasonable

costs

...

...”2008年以来：RNA直测技术的竞争The

RevolutionaryApproachesand

Devices

for

Nucleic

Acid

Analysis

(READNA)

consortium

includes

projects

to

accelerate

newbreakthrough

deoxyribonucleic

(DNA)

sequencing

technologies

and

methods

to

enhance

existing

analysismethods.

The

ultimate

aim

is

to

advance

DNA

sequencing

technologies

(combining

RNA

and

DNA

analysis

in

a

single

analytical

device)

to

a

level

where

a

human

genome

can

be

analyzed

at

high

resolution

for

less

than€1,000

in

less

than

oneday.READNA

is

afour-year

project

running

from

June

1,

2008,

until

May

31,

2012,

and

is

funded

through

a

€12million

grant

from

the

European

Commission

under

the

Seventh

Framework

Programme

for

Research

andTechnological

Development,

the

European

Union’s

main

instrument

for

funding

research

in

EuropeFrom

NHGRI

website:/grants/guide/rfa-files/RFA-HG-15-032.htmlBIG202410/24/24BIG202468“This

project

will

combine

cutting-edge

molecularcellular

ribogenomics

approaches,

mouse

genetics,and

developmental

neurobiology

to

understand

themechanisms

of

NMD

regulating

cortical

neuralprogenitor

cells,”

Zheng

said.The

effort,

supported

by

a

new

$2.3

million

grant

from

TheWarren

Alpert

Foundation,

aims

to

lay

the

groundwork

for

acomprehensive

“human

RNome”

project,

similar

to

the

HumanGenome

Project

completed

in

2003.10/24/24国家生物信息中心69China

National

Center

for

Bioinformation新一代分子检测技术的变演Evolution

of

IVD

Technology7010/24/24新思考202国0

家生物信息中心试管时代Test

Tube

Era96孔板时代96-well

Era表面吸附时代Surface

Array

Era表面加工时代Surface

fabrication

Era“双单四定”与“多维度智能化”时代4D

Single-Cell

&

-Molecule

Era10

–102

–104

–106

–“四定”技术定性（物理结构、机化功能等）：分子克隆、基因编辑、基因敲除、化学发光、冷冻电镜、X光等定位（细胞、亚细胞结构；器官组织结构）：原位杂交、荧光标记、超分辨、原子力显微镜定时（时空测量）：纳米孔、超分辨、质谱定量（数量与实际功能调控不一定成正比）：数字PCR、RNA测序、

DNA测序China

National

Center

for

BioinformationRNA

direct

sequencing

system712004～20132013～20182018～2023A:

2G:

2C:

1U:

1m6A:

15mC:

1matrixExonucleaseNanoporeSERSbasisLaserRamanSpectrometerNanopore

single-moleculesensingCaptureSERS

finger

printingRNA

SequencingCompositiondeciphering5'-GGCAUAAC-3’•

•1B0IG/240/2244

An

example

of

nanopore-based

direct

RNA

sequencingCross-validation国家生物信息中心China

National

Center

for

Bioinformation73通生学对生命时空世界的认知实观世界＝（宏观＋微观）^时间74/art/human-life-cycle-180795004http://www.earthcyclecalendars.c10/24/24昼夜节律-IXCircadian

rhythmLife

Span

（寿长周期-VII）季节周期-XSeasonal

cycle细胞分裂周期-III（Cell

cycle）物种系统发生-XI（Ontology）基因表达调控周期-IICircadian

time细胞内自组装Self-assembling生殖周期-VI（Reproduction

Cycle）/faculty/yong_wan/Zhu

BK

et

al.

2018

doi:

10.1210/js.2018-00113Self-organizingSelf-adapting分室流操作流可塑流平衡流信息流分室流可塑流信息流平衡流分室流平衡流分室流操作流早期发育周期-IV&V基因组复制+甲基化周期-I环境与微生态-VIII谱系系统发生-XII）BIG2024细胞间自组织细胞内外稳态生命时间轴：基因征数分离、分子组装、细胞组织、个体发育、谱系发生10/24/24BIG202475信息优化重组（Ia、Ib、Ic、Id等）基因的内含外显结构分工的发生（O）基因转录本的长度与时限（P）基因的功能集成——谱系变演的四个模式（P）基因簇——基因结构和功能的操作性简并、同步优化（P）染色质（体）时空分隔（P）分子自组装（II、III、IV）：分子机制（O）：DNA复制+甲基化、转录+翻译+PTM个体自适应（IX、X、XI、XII）：个体寿长模式（P）个体微环境（P）个体生态环境（P）物种自适应（XIV、XV）：物种发生（ALL）谱系发生（ALL）细胞过程（O+H）：细胞周期物质稳态（H）：能量平衡、氧化还原、Heme（能量+氧化还原）、信号传导细胞自组织（V、VI、VII、VIII）：个体早期发育-器官形成（C）个体早期发育-系统形成（C+P）发育周期遗传系统发生（I+C+P）生殖周期形成与竭结（I+C+P）国家生物信息中心China

National

Center

for

Bioinformation时间轴上的生命——Chronobiology生命是时间的函数：∑Life

∝∑Timei

；L（t）=t1

+t2

+……tn复杂生命周期可分为不同的时段：Life

=∑Timeij时间轴上的变化主要是可塑流的表述，包括物质和能量的稳态、实现稳态的时间和两者表现出来的周期性规律：∑

P

=

（全身）∑

H

w+（局部）∑OL

+（细胞）∑CN+（遗传）∑II

（

∑H>>∑O+C+I）生命时间轴上的规律性变化——节律——就表征而言是可塑流，就物质基础而言是平衡流76国家生物信息中China

National

Center

for

Bioinformat心ion77Tracing

back

the

chemicalpathways

tothe

origins

of

life透明度——平衡流：生物化学、生理学与药理学The

Homeostatic

Track平衡流之一（I、II）：物质流（TheHomeostatic

Track-II:Matter）平衡流之二（III、IV）：能源流（TheHomeostatic

Track-I:Energy）平衡流之三（V、VII）：信导流（TheHomeostatic

Track-III:Signaling）Leverhulme

Centre

for

Life

in

the

Universe：https://www.lclu.cam.ac.uk/about无机小分子-H有机大分子-H分子自组装-O信息自复制-I细胞自组织-C生态共生-P“潮汐”=可塑性（平衡流+操作流+分室流）国家生物信息中心China

National

Center

for

Bioinformation78“水”——血红素与其衍生物，游离状态“球”——广义血红素结合蛋白，结合态与分离态、合成与清除“水”与“球”亲和力——血红素与结合蛋白的解离动态与常数“潮汐”——“水”的涨落“太阳”——血液球蛋白“月球”——血红蛋白、血清白蛋白“黑洞”——凝血酶（hemopexin）、亲血球蛋白（Haptoglobin）“地貌”——中枢与外周（大脑、脏器、体液等）生命周期：《上古天真论——素问》国家生物信息中心China

National

Center

for

Bioinformation79女子七岁，肾气盛，齿更发长；二七而天癸至，任脉通，太冲脉盛，月事以时

下，故有子；三七，肾气平均，故真牙生而长极；四七，筋骨坚，发长极，身体盛壮；五七，阳明脉衰，面始焦，发始堕；六七，三阳脉衰于上，面皆焦，发始白；七七，任脉虚，太冲脉衰少，天癸竭，地道不通，故形坏而无子也。丈夫八岁，肾气实，发长齿更；二八，肾气盛，天癸至，精气溢泻，阴阳和，故能有子；三八，肾气平均，筋骨劲强，故真牙生而长极；四八，筋骨隆盛，肌肉满壮；五八，肾气衰，发堕齿槁；六八，阳气衰竭于上，面焦，发鬓颁白；七八，肝气衰，筋不能动，天癸竭，精少，肾脏衰，形体皆极；八八，则齿发去。昼夜与季节周期春生，夏长，秋收，冬藏，

是气之常也，人亦应之，以一日分为四时，朝则为春，日中为夏，日入为秋，夜半为冬。朝则人气始生，病气衰，故旦慧；日中人气长，长则胜邪，故安；夕则人气始衰，邪气始生，故加；夜半人气入脏，邪气独居于身，故甚也。《黄帝内经》国家生物信息中心China

National

Center

for

Bioinformation80可塑流HumanMicrobiomeCircadian

rhythms

and

the

gut

microbiota:from

the

metabolic

syndrome

to

cancer,Bishehsari

et

al.

Nat

Endocrinol,

2020春气者病在头，

夏气者病在脏，秋气者病在肩Re，冬气者病在四肢。——《素问·金匮真言论》10/24/24BIG202481黄道：太阳在天空中的路径国家生物信息中心

82China

National

Center

for

Bioinformation时间轴上的现代之问——节律的物质基础是什么？The

word

“tide”

has

two

different

meaningsThe

variation

of

sea

level

at

coastal

locations,which

depend

strongly

on

shoreline

topography,and

on

ocean

currents

near

shore.

These

can

bequite

complicated

in

detail,

primarily

due

tocoastal

topography.The

deformation

of

land

and

water

of

the

earthdue

to

the

gravitational

forces

of

the

moon

andsun

acting

on

every

part

of

the

earth.

Thisdeformation

results

in

two

"tidal

bulges"

one

onthe

side

of

the

earth

nearest

the

moon,

and

one

onthe

opposite

side.

These

"drive"

all

of

the

tidalphenomena

with

a

periodicity

synchronized

withthe

moon's

position

in

the

sky.初一、十五国家生物信息中心China

National

Center

for

Bioinformation83初七、二十二The

circadian

clock

relates

to

four

b