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Sunday, September 11, 2011

Mitigated Speech

Every case of scientific misconduct involves a powerful scientist and dishonest or disgruntled underlings. In the case of Silvia Bulfone-Paus, two rogue post docs were assigned the blame for fraud. In the Baltimore Case a disgruntled post doc outed her P.I. Speaking truth to power is never easy, even when the powerful are scientists. They expect certain outcomes. If the truth differs from the expected outcome, you have a choice. Do you stick with the truth or do you tell the leader what they want to hear?

Telling the truth will require mitigated speech. You have to decide how to tell the powerful scientist something they don't want to hear. In a recent post I talked about a situation where the CEO of a biotechnology company would tell the white lab coat scientists what they were suppose to do in order to find drug delivering molecules. Point A, (do this) did not lead to point B (and you will have a drug delivering molecule). What was doable was point A. We could make a peptide library. Point B was scientific analysis of point A. To this date, no one has said to the leaders of the biotech company, "this isn't going to work".

The first question that really needed to be addressed was the logic behind the drug delivering holy grail research. The leadership had decided how the holy grail would be found. A peptide or protein would bind to certain cellular proteins and the binding would lead to all sorts of wonderful effects. But how did they know? We hadn't found the molecules that bind yet. Do you ask questions or do you do what you can and hope that things will work out? How do you deal with the research when you find a molecule that binds to it's intended target but the desired effect does not happen?

The term 'mitigated speech' was recently popularized by Malcolm Gladwell in his book, Outliers. He defines mitigated speech as "any attempt to downplay or sugarcoat the meaning of what is being said". He continues with reference to Fischer and Orasanu, to describe 6 degrees of mitigation with which we make suggestions to authority:

1. Command – “Strategy X is going to be implemented”

2. Team Obligation Statement – “We need to try strategy X”

3. Team Suggestion – “Why don’t we try strategy X?”

4. Query – “Do you think strategy X would help us in this situation?”

5. Preference – “Perhaps we should take a look at one of these Y alternatives”

6. Hint – “I wonder if we could run into any roadblocks on our current course”

Gladwell brings up the concept in the context of how crews relate to each other in the cockpit of a commercial airliner, graphically illustrating the degree to which mitigated speech can be detrimental in high risk situations which require clear communication. Gladwell also talks about different cultures and how they use mitigated speech.

What then can we make of the culture of science? It has been shown to be, at times, the art of deception. It is self correcting, but those who possess power work against the self correcting, as exhibited in the Baltimore Case. It pits the P.I. against the underlings, the office versus the lab. There is no way to correct a superior when they are wrong, other than to hope they are open to such a discussion. When a paper needs to be retracted everyone, scientists and journal editors, are embarrassed. They mitigate the need for the retraction or worse, they brush it under the rug.

A new way of communicating science is needed, Does mitigated speech stifle innovation?

9 comments:

Anonymous said...

New Bulfone-Paus retraction.

http://journals.lww.com/transplantjournal/Citation/2011/12270/An_Interleukin_2_IgG_Fas_Ligand_Fusion_Protein.19.aspx

Brought to our attention by:

http://abnormalscienceblog.wordpress.com/2011/06/06/blowing-the-whistle-on-transplantation-2000-69-1386/

The retraction is for this original publication.
I do not see the names of Elena Bulanova or Vadim Budagian on the original publication. These are the people blamed by Bulfone-Paus for the manipulations.
Transplantation. 2000 Apr 15;69(7):1386-91.
An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.
Bulfone-Paus S, Rückert R, Krause H, von Bernuth H, Notter M, Pohl T, Tran TH, Paus R, Kunzendorf U.
Source
Institute of Immunology and Department of Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Abstract
BACKGROUND:
Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation.
METHODS:
The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo.
RESULTS:
In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response.
CONCLUSION:
The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.
PMID: 10798759

Anonymous said...

New Bulfone-Paus retraction.

http://journals.lww.com/transplantjournal/Citation/2011/12270/An_Interleukin_2_IgG_Fas_Ligand_Fusion_Protein.19.aspx

Brought to our attention by:

http://abnormalscienceblog.wordpress.com/2011/06/06/blowing-the-whistle-on-transplantation-2000-69-1386/

The retraction is for this original publication.
I do not see the names of Elena Bulanova or Vadim Budagian on the original publication. These are the people blamed by Bulfone-Paus for the manipulations.
Transplantation. 2000 Apr 15;69(7):1386-91.
An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.
Bulfone-Paus S, Rückert R, Krause H, von Bernuth H, Notter M, Pohl T, Tran TH, Paus R, Kunzendorf U.
Source
Institute of Immunology and Department of Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Abstract
BACKGROUND:
Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation.
METHODS:
The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo.
RESULTS:
In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response.
CONCLUSION:
The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.
PMID: 10798759

Anonymous said...

New Bulfone-Paus retraction.

http://journals.lww.com/transplantjournal/Citation/2011/12270/An_Interleukin_2_IgG_Fas_Ligand_Fusion_Protein.19.aspx

Brought to our attention by:

http://abnormalscienceblog.wordpress.com/2011/06/06/blowing-the-whistle-on-transplantation-2000-69-1386/

The retraction is for this original publication.
I do not see the names of Elena Bulanova or Vadim Budagian on the original publication. These are the people blamed by Bulfone-Paus for the manipulations.
Transplantation. 2000 Apr 15;69(7):1386-91.
An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.
Bulfone-Paus S, Rückert R, Krause H, von Bernuth H, Notter M, Pohl T, Tran TH, Paus R, Kunzendorf U.
Source
Institute of Immunology and Department of Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Abstract
BACKGROUND:
Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation.
METHODS:
The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo.
RESULTS:
In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response.
CONCLUSION:
The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.
PMID: 10798759

Anonymous said...

New Bulfone-Paus retraction.

http://journals.lww.com/transplantjournal/Citation/2011/12270/An_Interleukin_2_IgG_Fas_Ligand_Fusion_Protein.19.aspx

Brought to our attention by:

http://abnormalscienceblog.wordpress.com/2011/06/06/blowing-the-whistle-on-transplantation-2000-69-1386/

The retraction is for this original publication.
I do not see the names of Elena Bulanova or Vadim Budagian on the original publication. These are the people blamed by Bulfone-Paus for the manipulations.
Transplantation. 2000 Apr 15;69(7):1386-91.
An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.
Bulfone-Paus S, Rückert R, Krause H, von Bernuth H, Notter M, Pohl T, Tran TH, Paus R, Kunzendorf U.
Source
Institute of Immunology and Department of Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Abstract
BACKGROUND:
Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation.
METHODS:
The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo.
RESULTS:
In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response.
CONCLUSION:
The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.
PMID: 10798759

Anonymous said...

New Bulfone-Paus retraction.

http://journals.lww.com/transplantjournal/Citation/2011/12270/An_Interleukin_2_IgG_Fas_Ligand_Fusion_Protein.19.aspx

Brought to our attention by:

http://abnormalscienceblog.wordpress.com/2011/06/06/blowing-the-whistle-on-transplantation-2000-69-1386/

The retraction is for this original publication.
I do not see the names of Elena Bulanova or Vadim Budagian on the original publication. These are the people blamed by Bulfone-Paus for the manipulations.
Transplantation. 2000 Apr 15;69(7):1386-91.
An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.
Bulfone-Paus S, Rückert R, Krause H, von Bernuth H, Notter M, Pohl T, Tran TH, Paus R, Kunzendorf U.
Source
Institute of Immunology and Department of Urology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Abstract
BACKGROUND:
Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation.
METHODS:
The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo.
RESULTS:
In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response.
CONCLUSION:
The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.
PMID: 10798759

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