复旦大学新视野系列研究生课程：科研论文的构思、撰写和发表
复旦大学讲座教授
复旦大学发育生物学研究所所长
科罗拉多大学教授,HHMI研究员
韩 珉
主讲人
下一讲,10月 24日 马兰教授
1982年北京大学毕业后入选 CUSBEA留美项目, 1983年赴美
国加州大学洛山矶分校攻读博士学位 。 1988年获博士学位后在
加州理工学院从事博士后研究 。 1991年到卡罗拉多大学执教,
先后任助理教授, 副教授, 教授 。 97年被遴选为著名的休斯医
学研究所研究员 。 发现 Ras途径在发育中的作用, 所领导的研
究组在细胞信号转导和发育方面有诸多重要贡献, 在 Cell,
Nature,Science等刊物上发表了多篇论文并获专利 2项 。 1999
年以来在复旦大学讲授细胞信号转导和发育课程, 2000年获国
家杰出青年科学基金, 2001年与许田, 庄原教授一起创建了复
旦大学发育生物学研究所 。
韩珉教授简介
训练成为独立思考的科学家
- 共识与,偏见,
韩珉
Why do give such a talk?
- As an over-achiever,I appreciate more about
the good training I have received,
- Getting old,and on the down slope in the career,
I am more interested in talking,
-A class at Fudan Medical School
训练自己尽早成为一个全面的科学家
- 读研究生时做学问的方法决定了你将来科学生涯的基调
- 正确的训练将帮助你在竞争好的博士后或者其他职位时
优势更加明显
- 只有以正确的方式进行研究才能感到科学的乐趣
训练的目标是什么？
- 正确的科学道德
- 思考科学问题和解决方法的能力
- 合理利用时间高效完成各种任务的能力
- 阅读和分析文献的能力
- 口头表达和确立观点的能力
- 撰写研究论文和综述的能力
- 与他人交流合作的能力
- 和同事愉快相处的能力
如何评价学生
- 推荐信和电话交谈
- 发表的论文
- 对科研兴趣的自我表述／面试
How do NIH panels evaluate
postdoctoral fellowship applicants?
Confidential letters by the advisor and other professors
Ranking following aspects (1-5),
- Research Ability and Potential
- Write and Verbal Communications
- Perseverance in Pursuing Goals
- Self-reliance and Independence
- Laboratory Skills and techniques
- Originality
- Accuracy
- Scientific Background
- Familiarity with Research Literature
- Ability to Organize Scientific Data
Example of the evaluation of a good student
Example of the evaluation of a weaker student
Q u i c k T i m e? a n d a T I F F (U n c o mp r e s s e d ) d e c o m p re s s o r a r e n e e d e d t o s e e t h i s p i c t u re,
What are the pre-requisites to be a
successful graduate student?
? High GPA?
? Great GRE score?
? Wealth of your family?
? Type of undergraduate college?
– Fudan vs others?
– Rao Yi’s argument
More about your college grades
? Good grades in high school and college are
far from sufficient,In fact,they are not even
necessary,There are other important traits.
Tom Cech,
1989 Noble Prize in Chemistry
President of Howard Hughes Medical Inst
Professor at the University of Colorado
Q u ic kT ime? a n d a
T I F F (U n co m p re s se d ) d e co m p re ss o r
a r e n e e d e d to se e th i s p ict u re,
"It isn't always true that the people who are the brilliant
high school students,who get the highest grades on
the exam,are the ones who do well as practicing,
experimental scientists,There are a lot of skills in
doing experimental science that can't be tested on
standardized exams" Cech says,B students often "are
the ones who end up doing the really great work in
research."
Example,
Graig Hunter- Professor at Harvard
Undergraduate GPA
Oregon State University (80-81),3.3
University of Oregon (81-84),3.1
Graduate Student
University of Colorado super star
Postdoctoral training
UCSF super star
Professorship
Harvard (main campus) One of the best young guys
What besides the grades for him?
Recommendation letters from the advisor,
Craig has had complete freedom in designing his own
experiments and deciding overall strategy in the
research he has conducted in my lab,His
understanding and mastery of the techniques of
molecular biology and his sound scientific judgment
compares very favorably with that of some of our best
graduate students,I have the utmost confidence that
Craig Hunter would be extremely successful as a
graduate student in any….
More about grades
-Difference between US and China
- Changes in US high school
What are the pre-requisites to have the
potential to be trained into a good scientist?
2,Being hard-working is essential,but not sufficient
3,Loving what you do is important,
- Motivated,but for the right reason
- Good scientists often sacrifice other aspects of life.
1,Need to be smart,Yes,But,...
5,Ethical
4,Having the potential to be initiative and independent
Graduate school is not for everyone
? How to make sure that is what your want?
? Have some research experience first.
Learn to address good scientific questions
This is a major objective of your training in
graduate school.
- Easy to say,hard to do,
- Many researchers are not good at it,
“small science” often demands more on this,
- This is THE most important thing I learned from my
thesis advisor,
Learn to address good scientific questions
Big question 1,leading the field
# o
f p
ap
er
s/y
ea
r
time
A
B
C
D
A,ground breaker
B,leading the trend
C,working in a hot field
D,catching the tail
What is your work?
Level of the fields
A major field
e.g,Developmental genetics
A specific area
e.g,Wnt signaling in development
A very focused field
e.g,function of wnt receptors
What can we learn from its tradition?
The,MRC”
The Medical Research Council
In 1947 the Medical Research Council set up a Unit
for,Research on the Molecular Structure of Biological
Systems” to enable Max Perutz and John Kendrew to
develop their work using X-ray diffraction to study
proteins,
The,Laboratory of Molecular Biology” became
known simply as the“LMB”...
The independence of the researchers
Francis Crick
2nd student
Jim Watson
1st PostdocMax Perutz
John Kendrew
1st student
All four won the Noble Prize
? Max Perutz
? John Kendrew
? Francis Crick
? James Watson
? Fred Sanger
? Cesar Milstein
? Sydney Brenner
? John Sulston
? Many others were trained there,Sydney
Altman,Bob Horvitz,Andy Fire …..
The,Culture” created by Perutz at MRC
- Students and Postdocs were independent,PIs did not
take credit for their work,
- They addressed big time questions.
- The funding mechanism encouraged risk taking,
- It was an extremely stimulating environment,
- Eating,drinking,and talking
- Many very smart and devoted people around
Brenner & Benzer’s,ridiculous” exploratory vision
Sydney Brenner Seymour BenzerPhage geneticists
C,elegans Drosophila
MRC Caltech
What was Brenner’s thought?
In a letter to Max Perutz,June 1963…
,...It is now widelyrealized that nearly all the,classical”
problems of molecular biology have either been solved or
will be solved in the next decade…because of this,I have
long felt that the future of molecular biology lies in the
extension of research to other fields…”
“The new major problem in molecular biology is the
genetics and biochemistry of control mechanisms in
cellular development”
“...The great difficulty of these fields is that the nature
of the problem has not been clearly defined,and
hence the right experimental approach is not
known…” (= very risky)
What did Brenner do?
In 1965,Sydney Brenner chose a nematode
Caenorhabditis elegans,as a promising model animal
He published his first paper in Genetics in 1974.
Since then,knowledge has accumulated to the extent that
C,elegans is now probably the most completely
understood metazoan in terms of anatomy,genetics,
development,and behavior.
Sydney Brenner Bob Horvitz John Sulston
Big Question Example 2
Apply technology to study important
problems
Using temperature sensitive mutations to study how a phage
is assembled step by step
Functional map of T4 assembly genes
Bob Edgar addressed the question and isolated temperature sensitive
mutants that disrupt each step of the assembly process in 1960s,
Bob Edgar and Bill Wood collaborated on the
project at Caltech,early 1970s
Lee Hartwell was a student at Caltech
He heard about Bob Edgar’ Ts mutants,
Harwell asked another big question,
How is the cell division cycle regulated?
He isolated TS mutants that disrupt various steps of the cell division
cycle,Cdc mutants (1970s UC Irvine and UW)
2001 Noble prize,A great genetic tool was used to attack a big time
question.
Q u ic k T im e? a n d a
T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e,
Common, unattractive” projects
- Wanting to do gene knockout,but does not address a good
scientific problem.
- Doing two-hybrid screen on a protein of which function is
unknown and there is no vision about what is going to happen.
- Repeating studies on proteins that have been well-characterized in
another organism and do not have a good idea about what are the
new things to be learned,
- Applying an advanced technique to something for the sake of
applying the technique,
- Making interesting observations,but not sure how to study the
mechanism or develop the story,
Practice:
- When reading research papers,question the
questions addressed by the papers.
- When listening the seminars,question the questions
addressed by the speakers,
- Write a proposal on your research plan,
“BIG” or,small”,the questions should be
significant,interesting,and solvable
重要的,你喜欢的,实际的
Writing a research proposal
C,Experimental designs
Describe in detail how you would experimentally address the
questions,You often need to justify what you would do,You need
to consider possible problems and alternative methods,
A,Specific Aims
1,A short paragraph to summarize the goal of the proposal
2,List 2-3 specific aims,Clearly address the specific questions
and state the approaches used to attack the problems.
B,Background and Significance
Where the questions come from,why the questions are important,
and the rationale of the approach suggested,
Science 1987 Oct 23;238(4826):542-5
A cytoplasmic protein stimulates normal N-ras p21 GTPase,but does
not affect oncogenic mutants.
Trahey M,McCormick F.
The role of guanine nucleotides in ras p21 function was determined by using the ability of p21
protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity,Two
oncogenic mutant human N-ras p21 proteins,Asp12 and Val12,actively induced maturation,
whereas normal Gly12 p21 was relatively inactive in this assay,Both mutant proteins were found to
be associated with guanosine triphosphate (GTP) in vivo,In contrast,Gly12 p21 was predominantly
guanosine diphosphate (GDP)-bound because of a dramatic stimulation of Gly12 p21-associated
guanosine triphosphatase (GTPase) activity,A cytoplasmic protein was shown to be responsible for
this increase in activity,This protein stimulated GTP hydrolysis by purified Gly12 p21 more than
200-fold in vitro,but had no effect on Asp12 or Val12 mutants,A similar factor could be detected in
extracts from mammalian cells,It thus appears that,in Xenopus oocytes,this protein maintains
normal p21 in a biologically inactive,GDP-bound state through its effect on GTPase activity,
Furthermore,it appears that the major effect of position 12 mutations is to prevent this protein from
stimulating p21 GTPase activity,thereby allowing these mutants to remain in the active GTP-bound
state.
Cited 1000 times
Example 3,A more specific question
RAS
GDP
RAS
GTP
Pi
GTPGDP
target
ActiveInactive
Discovery of GTPase activating protein (GAP)
Observing or reading the literature
GTPase of Ras
体外 weak t 1/2 > 30 min
体内 strong t 1/2 < 1 min
Specific question,What is it in cells that stimulates the GTPase activity?
oncogene
X
Frog eggs
In vitro Gly12 (wt) 3 hours
Val12 (oncogene) 3 hours
+ extract Gly12 2-3 min
Val12 >3 hours,1000X
Question,
What is it in cells that stimulates the GTPase activity?
RAS
GDP
RAS
GTP
Pi
GTPGDP
target
ActiveInactive
X
oncogene
GAP was discovered
GAP
- Read a lot about the subjects to gain good sense
-Have good discussion with your advisor - make him think
hard,Do not always trust your boss’s initial thoughts.
- Talk to other senior students (or postdocs) in the lab.
Picture this:
If all the experiments worked without any problems,would a
paper resulting from the work be good enough to be published in a
significant journal?
In reality,only a limited percent of projects will get the most
desirable results,
However,if you know from the very beginning that the best
results of your work would have no chance,don’t even start!
Learn to judge the significance of a problem
Your major work should be published in a journal with
a rigorous review process that warrants respect
-Do not take the impact factor too seriously.
-Great papers are not always published in the big journals.
- Not all papers in big journals are good ones,
At the same time:
Great papers in non-top journals
- S,Brenner's first worm genetics paper,
Genetics (1974,>2500X) Nobel Prize 2002
-Sulston's worm lineage papers,
-Dev,Biol,(1983,>1200X; 1977,>1100X)
-Nobel prize 2002
-Jack Dixon,PTEN is a lipid phosphatase,
JBC (1998,>500X)
About secondary citations,
Question yourself
Why are we working so hard in the lab?
1,We will contribute to the science of China and world
2,We are getting the training for our future.
Without addressing good questions,you will accomplish
neither.
And you might have …..
Push your advisor?
PIs need to constantly learn (read,listen,
discuss,etc) to improve themselves so that they
can address important questions in their current
research programs,
Three factors in choosing a lab/advisor
- Advisor,fame,reputation,personality,training philosophy
- Laboratory,other people in the laboratory,funding
- Projects,questions addressed,potential project for you
At your university,how do students choose their labs?
In US,a decision is made by both students and PIs after
rotations
How did I select my thesis laboratory
Choices:
Michael Grunstein,genetics on histone functions
Nice guy but unpopular lab
Histones were considered extremely boring
Steve Clark,Protein methylation
- Super nice and smart
- Pure biochemistry
- Significance of the work was not clear then.
Arnold Berk,Mechanism of transcription regulation
- the most popular professor at UCLA
- Super nice and brilliant
- All three invited me to join their labs,I was the first
Chinese student that ever worked in these labs.
Went with the questions on histones
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s s o r
a re n e e d e d t o s e e t h is p i c t u re,
Michael Grunstein had good
questions but was still in the stage
to find effective genetic
approaches
1,What are the fundamental cellular functions of
histones and nucleosomes?
2,Are histones and their modifications relevant to
transcription regulation?
Why should we do genetics on histones?
- Biochemical roles already well known
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p re s s o r a r e n e e d e d to s e e t h is p ic t u re,
- Giants in the
transcription field did not
believe that histones or
nucleosomes have
anything to do with
transcription regulation
Specific Question,
What are the cellular consequences if you conditionally shut down the
production of a histone gene and disrupt nucleosome formation?
Gal10 promoter
Histone H2B or H4
Galactose,promoter on
Glucose,promoter off 1000x
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a re n e e d e d to s e e th i s p i c tu r e,
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a r e n e e d e d t o s e e th i s p i c tu r e,
Simple Results
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a re n e e d e d to s e e th is p i c tu r e,
G2 arrest,
chromosome segregation
disrupted,
Dramatic transcription de-repression even without the enhancer
Q u i c k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a r e n e e d e d t o s e e th i s p i c tu r e,
UAS
Gal Glu
Publications
Yoshinaga,S.,Dean,N.,Han,M,and Berk,A,J,(1986),Adenovirus stimulation of transcription by
RNA polymerase III,evidence for an E1A-dependent increase in transcription factor IIC
concentration,EMBO J,5,343-353.
Schuster,T.,Han,M,and Grunstein M,(1986) Yeast histone H2A and H2B amino termini have
interchangeable functions,Cell 45,445-451.
Han,M,Chang,M,Kim,U,and Grunstein M,(1987),Histone H2B repression causes cell cycle
specific arrest in yeast,effects on chromosomal segregation,replication and transcription,Cell
48,589-597.
Han,M.,Kim,U.,Kayne,P,and Grunstein,M,(1988),Depletion of histone H4 and nucleosomes
activates the PHO5 gene in S,cerevisiae,EMBO J.,7,2221-2228.
Kim,U.,Han,M.,Kayne,P,and Grunstein,M,(1988),Effects of H4 depletion on the cell cycle and
transcription of Saccharomyces cerevisiae,EMBO,J,7,2211-2219.
Kayne,P.,Kim,U.,Han,M,and Grunstein,M,(1988),Extremely conserved histone H4 N-terminus in
dispensable for growth but essential for repressing silent mating type genes in yeast,Cell 55,
27-39.
Han,M,and Grunstein,M,(1988),Nucleosome loss activates yeast downstream promoters in vivo
in the absence of UAS elements,Cell 55,1137-1145.
Grunstein,M.,Han,M.,Kim,U.,Schuster,T,and Kayne,P,(1989),Histone and nucleosome function
in yeast,In Molecular Biology of Chromosome Function,Ed,K.W,Adolph,Springer-Verlag,
New York.
Role of histones and chromatin in transcription
# o
f p
eo
pl
e /
$/
pa
pe
rs
/ye
ar
time
About taking risk
Max Perutz
On Seeking an interesting
scientific problem
“Look for the important problem and don’t be
detoured if it turns out to be difficult because the important ones
always are difficult,And young people now are under great
pressure to produce publications,to produce results,So,they
are really pushed to take on only problems which are safe,which
you can answer within the time of a grant of three years,And,I
think that’s a sad thing,You shouldn’t worry too much about
how long it might take and whether it will be possible to solve
the problem,Just the same as in other walks of life,in science,
if you want to win,you have to take risks.”
About taking a risk
-"Risky" projects may not always be that risky,
Be brave and exploratory.
Things will most likely work out,
- To be exploratory and safe,do at least two projects,
- Is the risk factor is often proportional to the significance
of the discovery?
Well,not always,
It depends on the questions addressed,
Conflict with our system and society
- We are not in an ideal world to do science; we are
making discoveries and we are not allowed to take risk,
- We need to the quality control of Ph.Ds; everyone got
to have the paper; so there is the risk,
- The granting agencies and institutions are counting
beans (paper #) to determine you funding,salary and
promotion…
HHMI push its investigators the other way
- High risk,high reward
- Gerry Rubin’s deletion test
- five papers are the key for renewal,
CELL 84, 843-851 1996,(and others from David Allis)
Tetrahymena histone acetyltransferase A,A homolog to yeast Gcn5p linking
histone acetylation to gene activation
Brownell JE,Zhou JX,Ranalli T,Kobayashi R,Edmondson DG,Roth SY,Allis
CD
“Discovery of histone acetyltransferase and its role
in gene activation”
Histone modification and chromosome remodeling by
HAT and HDAC have been the most significant
advancement in the past 10 years in the transcription
field.
I chickened out the project because of the risk
- Grunstein lab started to idenentify HAT in 1981
- My first thesis topic,identifying and cloning HAT
- Tried a novel method for 6 months
- Felt too risky and started on second project to
back it up,As soon as the second project seemed
promising,I chickened out on the first one.
- Had I stayed with the project …,you never know,
David Allis
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e ss o r
a re n e e d e d t o s e e t h i s p ic t u re,
2004 Wiley Prize Winner
2005,US National Academy Member
Major player in Chromatin functions
Joy and Jack Fishman Professor at Rockefeller
High risk,high reward,Linda Buck’s 8 year struggle
“I had tried so many things and had been working so hard for
years,with nothing to show for it,So when I finally found the
genes in 1991,I couldn't believe it! …,That was very satisfying.”
Richard Axel and
Linda Buck.
1991 Cell paper
brought them
fames and 2004
Noble Prize
Should we always focus our effort on one subject?
Linda Buck,Yes,but not until you know you are
working on an important program
Buck L,Stein R,Palazzolo M,Anderson DJ,Axel R,Gene expression and the
diversity of identified neurons,CSH Symposia On Quant Biol,48 2,485-92,1983.
Buck LB,Bigelow JM,Axel R,Alternative splicing in individual Aplysia neurons
generates neuropeptide diversity,Cell,51,127-33,1987.
Hynes MA,Gitt M,Barondes SH,Jessell TM,Buck LB,Selective expression of an
endogenous lactose-binding lectin gene in subsets of central and peripheral
neurons,The J,of Neuroscience, 10,1004-13.1990,
Buck L,Axel R,A novel multigene family may encode odorant receptors,a
molecular basis for odor recognition,Cell,65(1),175-87,April 1991,
Did postdoc twice with the same person,Axel
Philosophy of Rich Axel
In an era in which we have seen the steady encroachment of
numerical and statistical accounting procedures as proxies for
evaluating scientific contributions at all levels of careers,the Buck
and Axel paper serves as a bracing counterexample,We are
increasingly inundated with the idea that science is a team sport,
requiring the integration of disparate skills to make important new
discoveries,The dual authorship of the Buck and Axel paper
shows that great discoveries have at their core the genius and
motivation of exceptional individuals with the confidence,courage,
and conviction to venture into uncharted territory.
David Julius and Lawrence Katz
“A Noble for Smell” Cell,119,747-752,2004
Philosophy of Rich Axel
In the face of all the pressures to produces short-term,tangible
evidence of ongoing accomplishments,a laboratory environment
that genuinely encourages the, high risk,high payoff” approach to
scientific discovery remains a rarity,…an atmosphere of
intellectual excitement mixed with an element of creative chaos,
one in which we were given the freedom and support (intellectual,
philosophical,and financial) to take leaps of faith and develop
innovative approaches to cloning and characterizing genes of
significance to nervous and immune system function,
David Julius and Lawrence Katz
“A Noble for Smell” Cell,119,747-752,2004
许田, take the risk
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p re s s o r
a re n e e d e d t o s e e t h i s p ic t u r e,
Professor at Yale
Investigator at HHMI
Director and Professor at IDM of Fudan
博士后工作 (1993)
Development 1993 Apr;117(4):1223-37
Analysis of genetic mosaics in
developing and adult Drosophila
tissues.
Xu T and Rubin GM.
Howard Hughes Medical Institute,
University of California,Berkeley
How can we effectively identify gene
functions in specific tissues?
The genomes:
- the number of genes
- yeast 6,400
- worm 20,000
- fly 14,000
- Rice >32,000
- Human >20,000
There are too few genes
Most genes act in multiple developmental processes,
making it difficult to isolate mutations for a specific
role,
Many human diseases are caused by somatic
mutations that lead to genetic mosaics,
>90% of the cancers are caused by sporadic mutations
in somatic cells,
Traditional germline mutations are often not good
disease models and often prevent us from examining
the functions in specific tissues
#1 obstacle for genetics,Pleiotropism
Most cancers are caused by somatic mutations
Somatic Recombination
*
**
* * **
*
*
*
FRT screen
*
X-ray
P(FRT)
*
FRT,target for yeast FLP recombinase
雄 X
P(FRT)
雌
Genetic Mosaic Screens
*
*
wild type mutant
Induction of mitotic
recombination at the FRT site,
e.g,HS-drive FLP in flies
镶嵌遗传筛选获得的果蝇生长失调突变
Lats 突变
Tsc1 突变
畸肢过度生长
肿瘤
Potter,Turenchalk & Xu,Trends Genet,2000
PB insertion in mouse,take the risk
- Why it is an important problem to attack
- background of fly and worm geneticists
- Xu Tian’s,aggressive” thinking,
- About Ding Sheng and his project
学习成为独立的科研人员
研究生学习的主要目标
独立性
- 独立思考和独立工作是成为一个优秀科学家的必要条件。
-问：我会选择以下两位博士后候选人中哪一个？
学生 A,发表一篇, Cell,第一作者论文。但是导师提供的实验题目，设
计了所有的实验过程，帮助学生做了一些实验，同时撰写了文章。
学生 B,在, Development,或甚至, Genetics,发表一篇第一作者论文。
他提供了自己的想法，与导师和其他同事讨论下自己设计并完成了所有的实
验，最后在导师的帮助下自己写了论文。
-答：答案是显然的。
Actually,I just practiced this in my recent recruit in Beijing
- Hands-off 教授,
Have enough discussion with PI and hope he or she is always
thinking about science,
关于训练独立工作能力的几点建议
- Hands-on 教授,
Demand some space between you and him to gain some
“independence",Do not let him or her tell you what to do everyday,
Write your own paper,
-独立性并不代表不交流。恰恰相反。
-独立性并不代表不合作。恰恰相反。
-有良好的研究环境是培养独立工作能力的至关因素。
马俊
(学生 )
袁钧瑛
(博士后 )
王晓东
(导师 )
Ma J and Ptashne M,(1987) Deletion analysis of GAL4 defines two transcriptional
activating segments,Cell,48:847-53
Ma J and Ptashne M,(1987) The carboxy-terminal 30 amino acids of GAL4 are
recognized by GAL80,Cell,50:137-42
Ma J and Ptashne M,(1987) A new class of yeast transcriptional activators,Cell,
51:113-9.
Ma J,Przibilla E,Hu J,Bogorad L,Ptashne (1988) Yeast activators stimulate plant
gene expression,Nature,334:631-3.
Ma J and Ptashne M,(1988) Converting a eukaryotic transcriptional inhibitor into an
activator,Cell,55:443-6.
Sadowski I,Ma J,Triezenberg S,Ptashne M,(1988) GAL4-VP16 is an unusually potent
transcriptional activator,Nature,335:563-4.
Driever W,Ma J,Nusslein-Volhard C,Ptashne M,(1989) Rescue of bicoid mutant
Drosophila embryos by…,Nature,342:149-54.
Ruden DM,Ma J,Ptashne M,(1988) No strict alignment is required between a
transcriptional activator binding site and the "TATA box" of a yeast gene,PNAS
85:4262-6.
….
马骏的超重量级研究生论文 1984-1988
马骏 - 独立思考工作的成功例子
The more impressive part,How the work was done.
Mark Ptashne’s life was,easy”.
Harvard junior fellow 1988
Professor
Cincinnati Children’s
Hospital Medical Center
邓兴旺,买,来,自主
权,去,冒 险,
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s so r
a re n e e d e d to s e e t h i s p ic tu re,
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s so r
a re n e e d e d t o s e e t h i s p ic t u re,
复旦大学发育生物学 研究所 (IDM)
许田，韩珉,庄原 共同指导
目标：
建立高水平的教育机构
培养未来的科学领头人
建立第一流的科研机构
产生对科学有真正重要意义的贡献
http://life.fudan.edu.cn/idm/
指导方针
? 培养学生是研究所的第一任务
? 给学生最大的发展空间
? 培养学生多方面的能力
创新与实践
? 轮训, 双向选择
? 每一个学生都有他 /她自己独立的研究课题
? 每一个学生都有多个在不同领域研究的导师
? 一个学生可以在多种模式生物中进行研究或者应用多种
研究技术
? 研究有重要意义的又有意思的课题
? 英语是工作语言
学生指导方式
三位导师
每个学生
多位青年教师
多种模式生物
多种现代
生物学技术
2004,休斯医学研究院
对我们的研究项目非常感兴趣
David Clayton,Chief Scientific Officer and
Vice President visited IDM twice
复旦－休斯研究生联合培养计划
? 休斯－复旦研究生培养项目 (亚洲 )
? 休斯－剑桥大学研究生培养项目 (欧洲 )
? 联合招生
? 联合开课
? 联合提供研究培训
? 复旦学者可去休斯参加学术会议和使用仪器
? 每周休斯学术报告传至复旦
Janelia 研究园的地点
? Washington D.C.
休斯医学研究院 Janelia 研究园
投资６亿美元建成
Sharp-Hughes Rollin Bit
Major ambitions:
- Film making
- Aviation
- Business
Howard Hughes 1905-1976
Took control of the Hughes Tool
Company at 18
Howard Hughes was a powerful film maker in Hollywood
-Directed and produced many f films,
Hell’s Angels (1930) was the most successful film made by then.
Howard Hughes broke world aviation speed record in 1935
Designed and constructed planes
Made TWA a premier international airline
Become the first billionaire in the world in 1960s
Started and built the Hughes Aircraft Company
into one of the country's largest and most
important defense contractors.
Gave it to HHMI as gift in 1954.
It was sold in 1985 to GE for $5.5 Billion
History of HHMI
1954 Hughes announces the creation of the institution.
1985 Trustees decide to sell the Hughes Aircraft Company
(5.5 B).
1994 HHMI adds investigators selected through the first
national competition.
1997 Second national competition are appointed (Wang,
Xu,Han and Wu)
2000 Tom Cech became the President of HHMI
2002 Start to build Janelia research campus,
Thank you
Questions?
复旦大学讲座教授
复旦大学发育生物学研究所所长
科罗拉多大学教授,HHMI研究员
韩 珉
主讲人
下一讲,10月 24日 马兰教授
1982年北京大学毕业后入选 CUSBEA留美项目, 1983年赴美
国加州大学洛山矶分校攻读博士学位 。 1988年获博士学位后在
加州理工学院从事博士后研究 。 1991年到卡罗拉多大学执教,
先后任助理教授, 副教授, 教授 。 97年被遴选为著名的休斯医
学研究所研究员 。 发现 Ras途径在发育中的作用, 所领导的研
究组在细胞信号转导和发育方面有诸多重要贡献, 在 Cell,
Nature,Science等刊物上发表了多篇论文并获专利 2项 。 1999
年以来在复旦大学讲授细胞信号转导和发育课程, 2000年获国
家杰出青年科学基金, 2001年与许田, 庄原教授一起创建了复
旦大学发育生物学研究所 。
韩珉教授简介
训练成为独立思考的科学家
- 共识与,偏见,
韩珉
Why do give such a talk?
- As an over-achiever,I appreciate more about
the good training I have received,
- Getting old,and on the down slope in the career,
I am more interested in talking,
-A class at Fudan Medical School
训练自己尽早成为一个全面的科学家
- 读研究生时做学问的方法决定了你将来科学生涯的基调
- 正确的训练将帮助你在竞争好的博士后或者其他职位时
优势更加明显
- 只有以正确的方式进行研究才能感到科学的乐趣
训练的目标是什么？
- 正确的科学道德
- 思考科学问题和解决方法的能力
- 合理利用时间高效完成各种任务的能力
- 阅读和分析文献的能力
- 口头表达和确立观点的能力
- 撰写研究论文和综述的能力
- 与他人交流合作的能力
- 和同事愉快相处的能力
如何评价学生
- 推荐信和电话交谈
- 发表的论文
- 对科研兴趣的自我表述／面试
How do NIH panels evaluate
postdoctoral fellowship applicants?
Confidential letters by the advisor and other professors
Ranking following aspects (1-5),
- Research Ability and Potential
- Write and Verbal Communications
- Perseverance in Pursuing Goals
- Self-reliance and Independence
- Laboratory Skills and techniques
- Originality
- Accuracy
- Scientific Background
- Familiarity with Research Literature
- Ability to Organize Scientific Data
Example of the evaluation of a good student
Example of the evaluation of a weaker student
Q u i c k T i m e? a n d a T I F F (U n c o mp r e s s e d ) d e c o m p re s s o r a r e n e e d e d t o s e e t h i s p i c t u re,
What are the pre-requisites to be a
successful graduate student?
? High GPA?
? Great GRE score?
? Wealth of your family?
? Type of undergraduate college?
– Fudan vs others?
– Rao Yi’s argument
More about your college grades
? Good grades in high school and college are
far from sufficient,In fact,they are not even
necessary,There are other important traits.
Tom Cech,
1989 Noble Prize in Chemistry
President of Howard Hughes Medical Inst
Professor at the University of Colorado
Q u ic kT ime? a n d a
T I F F (U n co m p re s se d ) d e co m p re ss o r
a r e n e e d e d to se e th i s p ict u re,
"It isn't always true that the people who are the brilliant
high school students,who get the highest grades on
the exam,are the ones who do well as practicing,
experimental scientists,There are a lot of skills in
doing experimental science that can't be tested on
standardized exams" Cech says,B students often "are
the ones who end up doing the really great work in
research."
Example,
Graig Hunter- Professor at Harvard
Undergraduate GPA
Oregon State University (80-81),3.3
University of Oregon (81-84),3.1
Graduate Student
University of Colorado super star
Postdoctoral training
UCSF super star
Professorship
Harvard (main campus) One of the best young guys
What besides the grades for him?
Recommendation letters from the advisor,
Craig has had complete freedom in designing his own
experiments and deciding overall strategy in the
research he has conducted in my lab,His
understanding and mastery of the techniques of
molecular biology and his sound scientific judgment
compares very favorably with that of some of our best
graduate students,I have the utmost confidence that
Craig Hunter would be extremely successful as a
graduate student in any….
More about grades
-Difference between US and China
- Changes in US high school
What are the pre-requisites to have the
potential to be trained into a good scientist?
2,Being hard-working is essential,but not sufficient
3,Loving what you do is important,
- Motivated,but for the right reason
- Good scientists often sacrifice other aspects of life.
1,Need to be smart,Yes,But,...
5,Ethical
4,Having the potential to be initiative and independent
Graduate school is not for everyone
? How to make sure that is what your want?
? Have some research experience first.
Learn to address good scientific questions
This is a major objective of your training in
graduate school.
- Easy to say,hard to do,
- Many researchers are not good at it,
“small science” often demands more on this,
- This is THE most important thing I learned from my
thesis advisor,
Learn to address good scientific questions
Big question 1,leading the field
# o
f p
ap
er
s/y
ea
r
time
A
B
C
D
A,ground breaker
B,leading the trend
C,working in a hot field
D,catching the tail
What is your work?
Level of the fields
A major field
e.g,Developmental genetics
A specific area
e.g,Wnt signaling in development
A very focused field
e.g,function of wnt receptors
What can we learn from its tradition?
The,MRC”
The Medical Research Council
In 1947 the Medical Research Council set up a Unit
for,Research on the Molecular Structure of Biological
Systems” to enable Max Perutz and John Kendrew to
develop their work using X-ray diffraction to study
proteins,
The,Laboratory of Molecular Biology” became
known simply as the“LMB”...
The independence of the researchers
Francis Crick
2nd student
Jim Watson
1st PostdocMax Perutz
John Kendrew
1st student
All four won the Noble Prize
? Max Perutz
? John Kendrew
? Francis Crick
? James Watson
? Fred Sanger
? Cesar Milstein
? Sydney Brenner
? John Sulston
? Many others were trained there,Sydney
Altman,Bob Horvitz,Andy Fire …..
The,Culture” created by Perutz at MRC
- Students and Postdocs were independent,PIs did not
take credit for their work,
- They addressed big time questions.
- The funding mechanism encouraged risk taking,
- It was an extremely stimulating environment,
- Eating,drinking,and talking
- Many very smart and devoted people around
Brenner & Benzer’s,ridiculous” exploratory vision
Sydney Brenner Seymour BenzerPhage geneticists
C,elegans Drosophila
MRC Caltech
What was Brenner’s thought?
In a letter to Max Perutz,June 1963…
,...It is now widelyrealized that nearly all the,classical”
problems of molecular biology have either been solved or
will be solved in the next decade…because of this,I have
long felt that the future of molecular biology lies in the
extension of research to other fields…”
“The new major problem in molecular biology is the
genetics and biochemistry of control mechanisms in
cellular development”
“...The great difficulty of these fields is that the nature
of the problem has not been clearly defined,and
hence the right experimental approach is not
known…” (= very risky)
What did Brenner do?
In 1965,Sydney Brenner chose a nematode
Caenorhabditis elegans,as a promising model animal
He published his first paper in Genetics in 1974.
Since then,knowledge has accumulated to the extent that
C,elegans is now probably the most completely
understood metazoan in terms of anatomy,genetics,
development,and behavior.
Sydney Brenner Bob Horvitz John Sulston
Big Question Example 2
Apply technology to study important
problems
Using temperature sensitive mutations to study how a phage
is assembled step by step
Functional map of T4 assembly genes
Bob Edgar addressed the question and isolated temperature sensitive
mutants that disrupt each step of the assembly process in 1960s,
Bob Edgar and Bill Wood collaborated on the
project at Caltech,early 1970s
Lee Hartwell was a student at Caltech
He heard about Bob Edgar’ Ts mutants,
Harwell asked another big question,
How is the cell division cycle regulated?
He isolated TS mutants that disrupt various steps of the cell division
cycle,Cdc mutants (1970s UC Irvine and UW)
2001 Noble prize,A great genetic tool was used to attack a big time
question.
Q u ic k T im e? a n d a
T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e,
Common, unattractive” projects
- Wanting to do gene knockout,but does not address a good
scientific problem.
- Doing two-hybrid screen on a protein of which function is
unknown and there is no vision about what is going to happen.
- Repeating studies on proteins that have been well-characterized in
another organism and do not have a good idea about what are the
new things to be learned,
- Applying an advanced technique to something for the sake of
applying the technique,
- Making interesting observations,but not sure how to study the
mechanism or develop the story,
Practice:
- When reading research papers,question the
questions addressed by the papers.
- When listening the seminars,question the questions
addressed by the speakers,
- Write a proposal on your research plan,
“BIG” or,small”,the questions should be
significant,interesting,and solvable
重要的,你喜欢的,实际的
Writing a research proposal
C,Experimental designs
Describe in detail how you would experimentally address the
questions,You often need to justify what you would do,You need
to consider possible problems and alternative methods,
A,Specific Aims
1,A short paragraph to summarize the goal of the proposal
2,List 2-3 specific aims,Clearly address the specific questions
and state the approaches used to attack the problems.
B,Background and Significance
Where the questions come from,why the questions are important,
and the rationale of the approach suggested,
Science 1987 Oct 23;238(4826):542-5
A cytoplasmic protein stimulates normal N-ras p21 GTPase,but does
not affect oncogenic mutants.
Trahey M,McCormick F.
The role of guanine nucleotides in ras p21 function was determined by using the ability of p21
protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity,Two
oncogenic mutant human N-ras p21 proteins,Asp12 and Val12,actively induced maturation,
whereas normal Gly12 p21 was relatively inactive in this assay,Both mutant proteins were found to
be associated with guanosine triphosphate (GTP) in vivo,In contrast,Gly12 p21 was predominantly
guanosine diphosphate (GDP)-bound because of a dramatic stimulation of Gly12 p21-associated
guanosine triphosphatase (GTPase) activity,A cytoplasmic protein was shown to be responsible for
this increase in activity,This protein stimulated GTP hydrolysis by purified Gly12 p21 more than
200-fold in vitro,but had no effect on Asp12 or Val12 mutants,A similar factor could be detected in
extracts from mammalian cells,It thus appears that,in Xenopus oocytes,this protein maintains
normal p21 in a biologically inactive,GDP-bound state through its effect on GTPase activity,
Furthermore,it appears that the major effect of position 12 mutations is to prevent this protein from
stimulating p21 GTPase activity,thereby allowing these mutants to remain in the active GTP-bound
state.
Cited 1000 times
Example 3,A more specific question
RAS
GDP
RAS
GTP
Pi
GTPGDP
target
ActiveInactive
Discovery of GTPase activating protein (GAP)
Observing or reading the literature
GTPase of Ras
体外 weak t 1/2 > 30 min
体内 strong t 1/2 < 1 min
Specific question,What is it in cells that stimulates the GTPase activity?
oncogene
X
Frog eggs
In vitro Gly12 (wt) 3 hours
Val12 (oncogene) 3 hours
+ extract Gly12 2-3 min
Val12 >3 hours,1000X
Question,
What is it in cells that stimulates the GTPase activity?
RAS
GDP
RAS
GTP
Pi
GTPGDP
target
ActiveInactive
X
oncogene
GAP was discovered
GAP
- Read a lot about the subjects to gain good sense
-Have good discussion with your advisor - make him think
hard,Do not always trust your boss’s initial thoughts.
- Talk to other senior students (or postdocs) in the lab.
Picture this:
If all the experiments worked without any problems,would a
paper resulting from the work be good enough to be published in a
significant journal?
In reality,only a limited percent of projects will get the most
desirable results,
However,if you know from the very beginning that the best
results of your work would have no chance,don’t even start!
Learn to judge the significance of a problem
Your major work should be published in a journal with
a rigorous review process that warrants respect
-Do not take the impact factor too seriously.
-Great papers are not always published in the big journals.
- Not all papers in big journals are good ones,
At the same time:
Great papers in non-top journals
- S,Brenner's first worm genetics paper,
Genetics (1974,>2500X) Nobel Prize 2002
-Sulston's worm lineage papers,
-Dev,Biol,(1983,>1200X; 1977,>1100X)
-Nobel prize 2002
-Jack Dixon,PTEN is a lipid phosphatase,
JBC (1998,>500X)
About secondary citations,
Question yourself
Why are we working so hard in the lab?
1,We will contribute to the science of China and world
2,We are getting the training for our future.
Without addressing good questions,you will accomplish
neither.
And you might have …..
Push your advisor?
PIs need to constantly learn (read,listen,
discuss,etc) to improve themselves so that they
can address important questions in their current
research programs,
Three factors in choosing a lab/advisor
- Advisor,fame,reputation,personality,training philosophy
- Laboratory,other people in the laboratory,funding
- Projects,questions addressed,potential project for you
At your university,how do students choose their labs?
In US,a decision is made by both students and PIs after
rotations
How did I select my thesis laboratory
Choices:
Michael Grunstein,genetics on histone functions
Nice guy but unpopular lab
Histones were considered extremely boring
Steve Clark,Protein methylation
- Super nice and smart
- Pure biochemistry
- Significance of the work was not clear then.
Arnold Berk,Mechanism of transcription regulation
- the most popular professor at UCLA
- Super nice and brilliant
- All three invited me to join their labs,I was the first
Chinese student that ever worked in these labs.
Went with the questions on histones
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s s o r
a re n e e d e d t o s e e t h is p i c t u re,
Michael Grunstein had good
questions but was still in the stage
to find effective genetic
approaches
1,What are the fundamental cellular functions of
histones and nucleosomes?
2,Are histones and their modifications relevant to
transcription regulation?
Why should we do genetics on histones?
- Biochemical roles already well known
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p re s s o r a r e n e e d e d to s e e t h is p ic t u re,
- Giants in the
transcription field did not
believe that histones or
nucleosomes have
anything to do with
transcription regulation
Specific Question,
What are the cellular consequences if you conditionally shut down the
production of a histone gene and disrupt nucleosome formation?
Gal10 promoter
Histone H2B or H4
Galactose,promoter on
Glucose,promoter off 1000x
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a re n e e d e d to s e e th i s p i c tu r e,
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a r e n e e d e d t o s e e th i s p i c tu r e,
Simple Results
Q u ic k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a re n e e d e d to s e e th is p i c tu r e,
G2 arrest,
chromosome segregation
disrupted,
Dramatic transcription de-repression even without the enhancer
Q u i c k T i m e? a n d a T I F F ( U n c o m p r e s s e d ) d e c o m p r e s s o r a r e n e e d e d t o s e e th i s p i c tu r e,
UAS
Gal Glu
Publications
Yoshinaga,S.,Dean,N.,Han,M,and Berk,A,J,(1986),Adenovirus stimulation of transcription by
RNA polymerase III,evidence for an E1A-dependent increase in transcription factor IIC
concentration,EMBO J,5,343-353.
Schuster,T.,Han,M,and Grunstein M,(1986) Yeast histone H2A and H2B amino termini have
interchangeable functions,Cell 45,445-451.
Han,M,Chang,M,Kim,U,and Grunstein M,(1987),Histone H2B repression causes cell cycle
specific arrest in yeast,effects on chromosomal segregation,replication and transcription,Cell
48,589-597.
Han,M.,Kim,U.,Kayne,P,and Grunstein,M,(1988),Depletion of histone H4 and nucleosomes
activates the PHO5 gene in S,cerevisiae,EMBO J.,7,2221-2228.
Kim,U.,Han,M.,Kayne,P,and Grunstein,M,(1988),Effects of H4 depletion on the cell cycle and
transcription of Saccharomyces cerevisiae,EMBO,J,7,2211-2219.
Kayne,P.,Kim,U.,Han,M,and Grunstein,M,(1988),Extremely conserved histone H4 N-terminus in
dispensable for growth but essential for repressing silent mating type genes in yeast,Cell 55,
27-39.
Han,M,and Grunstein,M,(1988),Nucleosome loss activates yeast downstream promoters in vivo
in the absence of UAS elements,Cell 55,1137-1145.
Grunstein,M.,Han,M.,Kim,U.,Schuster,T,and Kayne,P,(1989),Histone and nucleosome function
in yeast,In Molecular Biology of Chromosome Function,Ed,K.W,Adolph,Springer-Verlag,
New York.
Role of histones and chromatin in transcription
# o
f p
eo
pl
e /
$/
pa
pe
rs
/ye
ar
time
About taking risk
Max Perutz
On Seeking an interesting
scientific problem
“Look for the important problem and don’t be
detoured if it turns out to be difficult because the important ones
always are difficult,And young people now are under great
pressure to produce publications,to produce results,So,they
are really pushed to take on only problems which are safe,which
you can answer within the time of a grant of three years,And,I
think that’s a sad thing,You shouldn’t worry too much about
how long it might take and whether it will be possible to solve
the problem,Just the same as in other walks of life,in science,
if you want to win,you have to take risks.”
About taking a risk
-"Risky" projects may not always be that risky,
Be brave and exploratory.
Things will most likely work out,
- To be exploratory and safe,do at least two projects,
- Is the risk factor is often proportional to the significance
of the discovery?
Well,not always,
It depends on the questions addressed,
Conflict with our system and society
- We are not in an ideal world to do science; we are
making discoveries and we are not allowed to take risk,
- We need to the quality control of Ph.Ds; everyone got
to have the paper; so there is the risk,
- The granting agencies and institutions are counting
beans (paper #) to determine you funding,salary and
promotion…
HHMI push its investigators the other way
- High risk,high reward
- Gerry Rubin’s deletion test
- five papers are the key for renewal,
CELL 84, 843-851 1996,(and others from David Allis)
Tetrahymena histone acetyltransferase A,A homolog to yeast Gcn5p linking
histone acetylation to gene activation
Brownell JE,Zhou JX,Ranalli T,Kobayashi R,Edmondson DG,Roth SY,Allis
CD
“Discovery of histone acetyltransferase and its role
in gene activation”
Histone modification and chromosome remodeling by
HAT and HDAC have been the most significant
advancement in the past 10 years in the transcription
field.
I chickened out the project because of the risk
- Grunstein lab started to idenentify HAT in 1981
- My first thesis topic,identifying and cloning HAT
- Tried a novel method for 6 months
- Felt too risky and started on second project to
back it up,As soon as the second project seemed
promising,I chickened out on the first one.
- Had I stayed with the project …,you never know,
David Allis
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e ss o r
a re n e e d e d t o s e e t h i s p ic t u re,
2004 Wiley Prize Winner
2005,US National Academy Member
Major player in Chromatin functions
Joy and Jack Fishman Professor at Rockefeller
High risk,high reward,Linda Buck’s 8 year struggle
“I had tried so many things and had been working so hard for
years,with nothing to show for it,So when I finally found the
genes in 1991,I couldn't believe it! …,That was very satisfying.”
Richard Axel and
Linda Buck.
1991 Cell paper
brought them
fames and 2004
Noble Prize
Should we always focus our effort on one subject?
Linda Buck,Yes,but not until you know you are
working on an important program
Buck L,Stein R,Palazzolo M,Anderson DJ,Axel R,Gene expression and the
diversity of identified neurons,CSH Symposia On Quant Biol,48 2,485-92,1983.
Buck LB,Bigelow JM,Axel R,Alternative splicing in individual Aplysia neurons
generates neuropeptide diversity,Cell,51,127-33,1987.
Hynes MA,Gitt M,Barondes SH,Jessell TM,Buck LB,Selective expression of an
endogenous lactose-binding lectin gene in subsets of central and peripheral
neurons,The J,of Neuroscience, 10,1004-13.1990,
Buck L,Axel R,A novel multigene family may encode odorant receptors,a
molecular basis for odor recognition,Cell,65(1),175-87,April 1991,
Did postdoc twice with the same person,Axel
Philosophy of Rich Axel
In an era in which we have seen the steady encroachment of
numerical and statistical accounting procedures as proxies for
evaluating scientific contributions at all levels of careers,the Buck
and Axel paper serves as a bracing counterexample,We are
increasingly inundated with the idea that science is a team sport,
requiring the integration of disparate skills to make important new
discoveries,The dual authorship of the Buck and Axel paper
shows that great discoveries have at their core the genius and
motivation of exceptional individuals with the confidence,courage,
and conviction to venture into uncharted territory.
David Julius and Lawrence Katz
“A Noble for Smell” Cell,119,747-752,2004
Philosophy of Rich Axel
In the face of all the pressures to produces short-term,tangible
evidence of ongoing accomplishments,a laboratory environment
that genuinely encourages the, high risk,high payoff” approach to
scientific discovery remains a rarity,…an atmosphere of
intellectual excitement mixed with an element of creative chaos,
one in which we were given the freedom and support (intellectual,
philosophical,and financial) to take leaps of faith and develop
innovative approaches to cloning and characterizing genes of
significance to nervous and immune system function,
David Julius and Lawrence Katz
“A Noble for Smell” Cell,119,747-752,2004
许田, take the risk
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p re s s o r
a re n e e d e d t o s e e t h i s p ic t u r e,
Professor at Yale
Investigator at HHMI
Director and Professor at IDM of Fudan
博士后工作 (1993)
Development 1993 Apr;117(4):1223-37
Analysis of genetic mosaics in
developing and adult Drosophila
tissues.
Xu T and Rubin GM.
Howard Hughes Medical Institute,
University of California,Berkeley
How can we effectively identify gene
functions in specific tissues?
The genomes:
- the number of genes
- yeast 6,400
- worm 20,000
- fly 14,000
- Rice >32,000
- Human >20,000
There are too few genes
Most genes act in multiple developmental processes,
making it difficult to isolate mutations for a specific
role,
Many human diseases are caused by somatic
mutations that lead to genetic mosaics,
>90% of the cancers are caused by sporadic mutations
in somatic cells,
Traditional germline mutations are often not good
disease models and often prevent us from examining
the functions in specific tissues
#1 obstacle for genetics,Pleiotropism
Most cancers are caused by somatic mutations
Somatic Recombination
*
**
* * **
*
*
*
FRT screen
*
X-ray
P(FRT)
*
FRT,target for yeast FLP recombinase
雄 X
P(FRT)
雌
Genetic Mosaic Screens
*
*
wild type mutant
Induction of mitotic
recombination at the FRT site,
e.g,HS-drive FLP in flies
镶嵌遗传筛选获得的果蝇生长失调突变
Lats 突变
Tsc1 突变
畸肢过度生长
肿瘤
Potter,Turenchalk & Xu,Trends Genet,2000
PB insertion in mouse,take the risk
- Why it is an important problem to attack
- background of fly and worm geneticists
- Xu Tian’s,aggressive” thinking,
- About Ding Sheng and his project
学习成为独立的科研人员
研究生学习的主要目标
独立性
- 独立思考和独立工作是成为一个优秀科学家的必要条件。
-问：我会选择以下两位博士后候选人中哪一个？
学生 A,发表一篇, Cell,第一作者论文。但是导师提供的实验题目，设
计了所有的实验过程，帮助学生做了一些实验，同时撰写了文章。
学生 B,在, Development,或甚至, Genetics,发表一篇第一作者论文。
他提供了自己的想法，与导师和其他同事讨论下自己设计并完成了所有的实
验，最后在导师的帮助下自己写了论文。
-答：答案是显然的。
Actually,I just practiced this in my recent recruit in Beijing
- Hands-off 教授,
Have enough discussion with PI and hope he or she is always
thinking about science,
关于训练独立工作能力的几点建议
- Hands-on 教授,
Demand some space between you and him to gain some
“independence",Do not let him or her tell you what to do everyday,
Write your own paper,
-独立性并不代表不交流。恰恰相反。
-独立性并不代表不合作。恰恰相反。
-有良好的研究环境是培养独立工作能力的至关因素。
马俊
(学生 )
袁钧瑛
(博士后 )
王晓东
(导师 )
Ma J and Ptashne M,(1987) Deletion analysis of GAL4 defines two transcriptional
activating segments,Cell,48:847-53
Ma J and Ptashne M,(1987) The carboxy-terminal 30 amino acids of GAL4 are
recognized by GAL80,Cell,50:137-42
Ma J and Ptashne M,(1987) A new class of yeast transcriptional activators,Cell,
51:113-9.
Ma J,Przibilla E,Hu J,Bogorad L,Ptashne (1988) Yeast activators stimulate plant
gene expression,Nature,334:631-3.
Ma J and Ptashne M,(1988) Converting a eukaryotic transcriptional inhibitor into an
activator,Cell,55:443-6.
Sadowski I,Ma J,Triezenberg S,Ptashne M,(1988) GAL4-VP16 is an unusually potent
transcriptional activator,Nature,335:563-4.
Driever W,Ma J,Nusslein-Volhard C,Ptashne M,(1989) Rescue of bicoid mutant
Drosophila embryos by…,Nature,342:149-54.
Ruden DM,Ma J,Ptashne M,(1988) No strict alignment is required between a
transcriptional activator binding site and the "TATA box" of a yeast gene,PNAS
85:4262-6.
….
马骏的超重量级研究生论文 1984-1988
马骏 - 独立思考工作的成功例子
The more impressive part,How the work was done.
Mark Ptashne’s life was,easy”.
Harvard junior fellow 1988
Professor
Cincinnati Children’s
Hospital Medical Center
邓兴旺,买,来,自主
权,去,冒 险,
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s so r
a re n e e d e d to s e e t h i s p ic tu re,
Q u ic kT i m e? a n d a
T IF F ( U n c o m p re s s e d ) d e c o m p r e s so r
a re n e e d e d t o s e e t h i s p ic t u re,
复旦大学发育生物学 研究所 (IDM)
许田，韩珉,庄原 共同指导
目标：
建立高水平的教育机构
培养未来的科学领头人
建立第一流的科研机构
产生对科学有真正重要意义的贡献
http://life.fudan.edu.cn/idm/
指导方针
? 培养学生是研究所的第一任务
? 给学生最大的发展空间
? 培养学生多方面的能力
创新与实践
? 轮训, 双向选择
? 每一个学生都有他 /她自己独立的研究课题
? 每一个学生都有多个在不同领域研究的导师
? 一个学生可以在多种模式生物中进行研究或者应用多种
研究技术
? 研究有重要意义的又有意思的课题
? 英语是工作语言
学生指导方式
三位导师
每个学生
多位青年教师
多种模式生物
多种现代
生物学技术
2004,休斯医学研究院
对我们的研究项目非常感兴趣
David Clayton,Chief Scientific Officer and
Vice President visited IDM twice
复旦－休斯研究生联合培养计划
? 休斯－复旦研究生培养项目 (亚洲 )
? 休斯－剑桥大学研究生培养项目 (欧洲 )
? 联合招生
? 联合开课
? 联合提供研究培训
? 复旦学者可去休斯参加学术会议和使用仪器
? 每周休斯学术报告传至复旦
Janelia 研究园的地点
? Washington D.C.
休斯医学研究院 Janelia 研究园
投资６亿美元建成
Sharp-Hughes Rollin Bit
Major ambitions:
- Film making
- Aviation
- Business
Howard Hughes 1905-1976
Took control of the Hughes Tool
Company at 18
Howard Hughes was a powerful film maker in Hollywood
-Directed and produced many f films,
Hell’s Angels (1930) was the most successful film made by then.
Howard Hughes broke world aviation speed record in 1935
Designed and constructed planes
Made TWA a premier international airline
Become the first billionaire in the world in 1960s
Started and built the Hughes Aircraft Company
into one of the country's largest and most
important defense contractors.
Gave it to HHMI as gift in 1954.
It was sold in 1985 to GE for $5.5 Billion
History of HHMI
1954 Hughes announces the creation of the institution.
1985 Trustees decide to sell the Hughes Aircraft Company
(5.5 B).
1994 HHMI adds investigators selected through the first
national competition.
1997 Second national competition are appointed (Wang,
Xu,Han and Wu)
2000 Tom Cech became the President of HHMI
2002 Start to build Janelia research campus,
Thank you
Questions?
