Misconduct Case Study

Our story so far:

Peter: 4th-year grad. student

makes mice lacking SLAM gene

several cell types have abnormal function

Sally: 4th-year grad. student

moved onto Peter’s project to speed up cell function analysis

1st experiment: SLAM affects blood-cell function

2nd experiment: reports possibly switched samples

recovers from error, same result as 1st experiment

Misconduct Case Study

What are the pressures on Peter?

What are the pressures on Sally?

What are the pressures on Dr. Larson?

Is there evidence of error, negligence or misconduct?

Should Peter use Sally’s data and write the manuscript?

What are Peter’s other options?

What are Peter’s obligations as first author of the manuscript? What are Sally’s obligations as second author?

What are Dr. Larson’s obligations? Did his actions contribute to this problem?

Misconduct Case Study – Part 2

In order to avoid creating conflict in the lab, Peter wrote up the manuscript using Sally’s graph. The manuscript was published in Nature, and created quite a stir in the scientific community.

However, in the next six months, Peter was dismayed to read several publications by competing labs that contradicted Sally’s data. It had even been suggested at a national conference that Dr. Larson’s lab had performed their experiments poorly or had misrepresented their data. Peter now felt certain that Sally had falsified her data.

Misconduct Case Study – Part 2

How is the situation different now?

How have Peter’s options changed?

What must be taken into consideration in making a decision at this point?

What should Peter do?

What should Dr. Larson do?

Influenza virus structure

Enveloped

• Hemagglutinin (HA)

• Neuraminidase (NA) RNA genome

• single-stranded

• 8 segments, 10 genes

• minus-sense NP protein associated with RNA Polymerase (PA, PB1, PB2) Matrix proteins (M1, M2)

Influenza virus replication

HA binds sialic acid

Sialic acid: usually terminal carbohydrate on glycoprotein or glycolipid, attached to galactose or GalNAc by a-2,3 or a-2,6 linkage

Influenza virus replication

HA binds sialic acid Endocytosis Acidification of endosome HA conformational change Fusion M2 proton channel Acidification of virion Uncoating

Influenza virus replication

Transported to nucleus Viral replicase makes (+)RNA: mRNA / template Cellular mRNA used for 5’ cap / primer

Influenza virus replication

Host machinery translates mRNAs HA, NA inserted into membrane M1, NP bind RNA

Assembly at membrane Release by budding

Influenza virus replication

Neuraminidase (NA) cleaves sialic acid to release progeny

sialicacid

HANA

Influenza

“Flu season” Concentrated indoors in winter Lower temperature favors replication Cycles of spread

Influenza Antigenic Drift

Pandemic Influenza

Appearance of significantly different virus Immunologically “naïve” population May also have enhanced pathogenicity (virulence)

1918 “Spanish flu”

• 500 million infected (1/3 pop)

• 50-100 million deaths

• 600,000 in 120 days in US

• Elevated fatality rate

• ½ of deaths 20-40

• Avian virus?

Influenza Antigenic Shift

Two viruses (e.g. avian and human) infect one cell (e.g. in pig) Reassortment of RNA segments during packaging Result could be human virus with very different Ag

Fighting the Flu

Killed, whole vaccine: 2 predicted prevalent A strains, 1 B strain FluMist: new live, attenuated vaccine Amantidine, rimantidine: M2 inhibitors; currently too much resistance Zanamivir, Oseltamivir: NA inhibitors