Developing a Research Plan:Part 1

10/6/06

Is it Publishable?

• Rule #1–Do good science and don’t worry about

publishing.

• Rule # 2–If you don’t publish, you will not succeed in

science (publish or perish).

• Rule # 3–See Rule #1.

Why do I want to publish my results?• To do something good for humanity?• To impress girls/boys/parents?• To improve my chances of getting into a good

college/grad school/med school/ motorcycle gang?

• Vanity, ego, and/or several other themes encapsulated by the seven deadly sins?

• To establish myself as a resource in an area in which I am genuinely interested, so I can become part of an ongoing scientific dialog with scientists around the world?

What does a good CV contain?

• A quality pedigree• First-author refereed journal publications• Grants• Awards• Teaching experience (with evaluations)• Reviewing experience• Intellectual property• A Research and Teaching Plan

–Most important!

Ethics in Science• The basic rules:

–Do not invent/distort data–Do not steal data or take credit for the work of

others–Do not hurt your research subjects/animals

• The Protégé’s Bill of Rights:–The right to an experienced and judicious mentor–The right to due process–The right to be treated with respect

Getting Credit for Your Work• Order of names in publications/ corresponding

author• Lead author, senior author, equal authorship• List your % contribution after negotiation with

your advisor and colleagues–Origination of idea–Design of experiment–Data collection–Data analysis–Writing the paper

• You need a first/equal author publication

Early Independence

• Choosing a field of study• Using your advisor (Society appointments, study sections, etc.)• Showing independence from your advisor• Professional society involvement

Planning for Leadership

• There is little formal education for• leadership• Six principles (Duda 2004)

–Develop a vision–Cultivate a plan–Focus–Seek counsel–Periodically reassess–Enjoy the journey

Useful Sources

• Making the Right Moves: Howard Hughes Medical Institute practical guide for post-docs and new faculty.–http://www.hhmi.org/labmanagement/

• Becoming a Scientist: HMI investigators give theirviews–http://www.hhmi.org/becoming/

For Next Time:1) Read Chapter 11 in RIP-ing through Scientific Inquiry

– Creation of a Research Study Design – Handout

2) Analyze “Word Recall” data– means and SDs– Analyze for significant difference by t test. 

• males vs females (overall)• males vs females on male terms• and males vs females on female terms

3) Make an “observation” which we will develop into a hypothesis– Be prepared to discuss a possible plan– This will NOT be your final research project so

DON’T PANIC!

Coming Up Soon:

• Handout “Great Papers in Biology” • Select one paper, read it and write an

(minimum one page, typed, double spaced) essay on WHY IT IS GREAT.–In most cases I have identified the web site

where the paper can be obtained for free.–Some papers are MUCH shorter than others,

but try not to use that as the criteria for selection

Why Doesn’t It Work?• Some very good ideas fail to give the

expected results because of unforseen circumstances or failure to take all the variables into consideration

• We will examine a logical idea that failed• HOWEVER:

–It failed for a very good reason–It taught the field something very important–It was responsible for the development of a

better design when it was repeated

• Cystic Fibrosis is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene

• 1 in 400 Caucasians are carriers

• Characterized by mucus in the lungs, chronic infection, pancreatic and gastrointestinal symptoms, infertility and early death

Logic of Gene TherapyRecessive disorder

CFTR gene defined

Airway epithelial CFTR deficiency

CFTR cDNA corrects in vitro

Vectors transfer CFTR cDNA in vivo

Cure CF?

Gene Therapy for the Respiratory Manifestations of Cystic Fibrosis

Transfer gene to airway epithelium

Express enough CFTR to correct CF disease

Safe

CFTR cDNA

Adenovirus as a Vehicle to Deliver the CFTR Gene

• High level, transient gene expression

• Efficiently infects airway epithelium

Ad vector

Adenovirus

Fiber

Pentonbase

Hexon

20 nm

20 nm

80 nm

Advantages: Can be produced in large amounts Can carry large genetic payload Can target to specific cells High efficiency

Disadvantages: Induces strong immunological reaction Transient expression

Adenovirus

Gene Transfer with a Marker Gene

Adenovirus coding for “blue” gene (-galactosidase)

Uninfected Ad.RSVgal

109

Vector-derived CFTR mRNA Expression (109 pfu)

100

10

1

0.1

Time (days)

CFT

R m

RN

A E

xpre

ssio

n

0.001

0.01

5%

Undetectable

Pre + 30+3cycle 1

108.5

108

Pre + 30+3cycle 2

Pre + 30+3cycle 3

1st 2nd 3rd

109

Host Defenses Against Adenovirus Gene Transfer Vectors

Time (wk)

Gen

e ex

pres

sion

100

101

102

103

104

0 1 2 3 4 8 9 10 11 12 24 25 26 27 28

Now what do we do?

• The failure of the Adenovirus cystic fibrosis clinical trial taught us:–Natural immunity is a major barrier to corrective

gene expression using Ad vectors–Other vectors, with longer expression times and

that evoke a less powerful immune reaction might work better

• These details have been used to improve gene therapy for CF–Details next time we meet

The Moral(s) of the Story• Research involves REPEATED analysis of a

system under different conditions to eventually come to a (more or less) full understanding of that system

• Analysis of a single parameter is an EXPERIMENT. A single experiment is NOT research.

• The lab is not a classroom, although you get a fantastic education there.–There are no answers in the back of the book in

research.