Search This Blog

Wednesday, November 30, 2011

A Tale of Two Janets

Janet had an important job. Unfortunately, just as she was about to wrap up the show, her boob fell out. The exposure was an embarrassment to those who placed their confidence in her. The exposure of that one boob led to a Congressional investigation!

Of course I'm talking about Janet Jackson, not Janet Allen the director of research at the Biotechnology and Biological Sciences Research Council. Janet Allen had an important job as well, director of research for the Biotechnology and Biological Sciences Research Council. She finished her career there with a boob exposed in the form of a former PhD student and world class Cargo Cult Scientist Alirio Melendez. There was no federal government investigation into her culpability in this boob incident however. She let this boob out into society. This boob should have turned her face red and sent her scrambling to find a solution to reversing the damage that was done. Instead:
Douglas Kell, chief executive of the BBSRC, publicly thanked Professor Allen for her work at the research council. He said her "leadership and personal drive" had led to "noteworthy" contributions to the delivery of every aspect of the organisation's strategic plan, including multipartner programmes and the move to longer, larger grants.

Contrast this praise with the fallout from Janet Jackson boob falling out. The NFL Commissioner Paul Tagliabue was apologetic before Congress! How much control would he have over such an incident? How much warning did he have that this boob would be exposed? Perhaps we need science commissioners to apologize and help make sense of our own boobs.

What Janet Allen did was have a successful career. She did increase her organizations grants and their duration. Who could ask for more? Well... I could. Did the planes land? What was the outcome of those longer more expensive grants? Who benefited most? I would have to say that it was the brass at the BBSRC.

Those of us who watched Janet Jacksons boob falling out at halftime of the superbowl on national tv had something to talk about the next day. It was funny to me and I knew there would be outrage amongst our conservative branch of society. Yet in science, we are not seeing that branch who are outraged by people who direct bogus research. We don't think they have any responsibility controlling rogue scientists who blatantly manipulate data and spin yarns in scientific journals.

And so we continue on with another saga in the Cargo Cults of Biotechnology. A director of scientific misconduct offers no apology. Janet Allen stepped down as director citing personal and private reasons. Her relationship to Melendez and the research they did together is not something she wants to revisit. Another unsatisfactory ending to a possible learning experience. I'm guessing we will see many more cases of scientific misconduct before we see another female breast on mainstream TV.

Thursday, November 24, 2011

Geron Research

What is research? Wiki says, "Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method."

Geron conducted research into the use of human stem cells for use in spinal cord injuries. What we at the CCS would like to spend our days doing is conducting research into research. Measuring the measurements. We would love to learn everything we could about stem cell research. That is to say, we want to research the research. A prime target of our research would be the Roslin Institue and Geron.

The curiosity of Keith Campbells departure prior to the Roslin Institute selling their cloning technology to Geron followed by the failure of Geron to reproduce the work needs to be understood. Why couldn't Geron scientists do what Campbell could do? Campbell left the Roslin Institue in 1997. In 1998 Campbell in collaboration with PPL (Pharmaceutical Proteins Limited) created another sheep named 'Polly'. She was made from genetically altered skin cells containing a human gene. In 2000, after joining PPL Ltd, Campbell and his PPL team (based in North America) were successful in producing the world's first piglets by somatic cell nuclear transfer (SCNT), the cloning technique. The PPL teams based in Roslin, Scotland and Blacksburg (USA) also used the technique to produce the first gene targeted domestic animals as well as a range of animals producing human therapeutic proteins in their milk.

Geron finally called it quits last month. What went wrong? That is the research question is ask. What were there success stories and how did it all lead to nothing? My hypothesis is that scientists and businessmen do not think the same way. Both groups of thinkers wish to hold the title of scientist. The former adopt the title to help others identify their chosen profession. The latter want to make others think they are like the former.

Ultimately I am trying to get at the understanding of the thinking that separates a scientist from the rest of the human race. An example of scientific thinking comes from a comment given on the link to Gerons decision to hang up the stem cell research.
This company would not walk away from this trial in the absence of an unexpected complication or safety concern, if there was any evidence that it was working," said Dr. Daniel Salomon, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute in San Diego. "The assumption has to be that they designed a study with a purposeful plan to complete it to a certain benchmark of efficacy and that they had the funds for that effort in hand.

Then comes a concept straight out of the Cargo Cult Science speech.
Without seeing the data, one cannot be certain that there was not a clinical reason for stopping the trial," said Dr. Robertson Parkman, professor of pediatrics at the University of Southern California.

Indeed in the research of the research, the data must be seen. We must present all of the data, not just the stuff we want people to see. How could a researcher of research gain access to the data? Who would pay such a person to conduct such research?

The data is piled high but in that pile is Dr. Campbell and his successes. Geron scientists couldn't pull out what was necessary to reproduce the work. The executives steered the research into a profit driven R&D project that failed. The connection between cloning an animal and using stem cells for regenerating human tissue, organs and whole beings is there. That is a separate research project. What I am interested in is how we miss that connection and veer off into the cargo cults.

Like Poldermans 500 papers, the quantity of research is great. The quality is suspect. Stem cell research was and is overhyped. "Embryonic stem cells are not ready for 'prime-time,'" said Dr. Bryon Petersen, professor in the Institute for Regenerative Medicine at Wake Forest Baptist Medical Center. "There are too many variables about these cells that we just don't know about." How do we get to "know about" the variables? Certainly not by starting a biotech company and hoping to make drugs out of the cells. Science conducted honestly will eventually spit out a useful medical application. Pursuing a useful (profitable) medical application will most often not produce anything resembling science.

Sunday, November 20, 2011

Avastin Oh Avastin

"Sometimes, despite the hopes of investigators, patients, industry and even the FDA itself, the results of rigorous testing can be disappointing." FDA Commissioner Margaret A. Hamburg

Hamburg said the choice was difficult because so many women and their doctors have put their faith in the drug and lobbied hard on its behalf.

"It does not improve survival," said Dr. Joanne Mortimer, director of the Women's Cancers Program at City of Hope in Duarte, who served on two of the three FDA advisory panels that debated Avastin's use for breast cancer. "Yes, it keeps your cancer under control longer. But … the risks are pretty huge."

They claim that Avastin will keep your cancer under control but you will have a higher risk of death from stroke or heart attack. The medication raised blood pressure and increased the risk of congestive heart failure. The risk of serious bleeding was five times higher among users of Avastin than it was for those on chemotherapy only. What about survival?

Hopes that Avastin could prolong life for patients with advanced breast cancer rested on a 2007 study in the New England Journal of Medicine. Researchers found that patients who took the drug in combination with the chemotherapy agent paclitaxel experienced an 11.8-month window, on average, during which their cancer was not growing. That compared with an average of 5.9 months of progression-free survival in patients receiving standard chemotherapy alone.

But even in that study, patients on Avastin did not live longer, said Dr. Kerin Adelson, a medical oncologist at Mount Sinai School of Medicine in New York.

A later study confirmed Avastin's failure to extend survival, and brought the drug's risks into better focus, Adelson said. (One of her own breast cancer patients who took Avastin had a massive stroke, she said.)

"Many drugs will improve the amount of time it takes for a cancer to grow but don't improve the amount of time a patient lives," she said.

Alas you would think that an interesting cancer research project would be born. Using tumor growth as an end point to a cancer drug development program is flawed. What could be a better approach? Avastin generated about $3.5 billion in sales in the United States in 2010. Sales have dropped since the FDA made it known that they were concerned about the risks and the lack of efficacy on survival.

That plane did not land. People still want to take it. At $5oK per year, that cargo plane should land and bring with it plenty of health and happiness for those running short due to breast cancer. Since it doesn't, we have to say good by. The choice should not be difficult for the FDA boss. Ah but how reluctantly the mind consents to reality!

Friday, November 18, 2011

500 Papers

Retraction Watch posted the story yesterday of Dr. Don Polderman who was fired from Erasmus University in Rotterdam for scientific misconduct. He studied the risk of complications during cardio-vascular surgery. According to the DutchNews website, "In particular, he failed to obtain patient consent for carrying out research and recorded results ‘which cannot be resolved to patient information."

Having a forum like Retraction Watch allows for a conversation that doesn't always take place among people interested in science. We know people cheat. We know all of us are prone to fooling ourselves. What a forum such as Retraction Watch does is provide a journalistic approach to the fallout of being wrong. You might be purposely wrong or accidentally wrong. Being wrong however is nothing to be ashamed of. In fact finding out that you were wrong is how some of us learn. The greater our concern over right and wrong, the greater our desire is to understand why something is true or false. Retraction Watch opens up room for a conversation on the way in which scientists communicate (publish their work) and how flawed the system can be.

Our analogy of the Cargo Cults provides another way of looking at modern science. We like the philosophy of right and wrong and how subjective the two can be among mere mortals. Let's take two of the four comments currently up on Retraction Watch's story on Dr. Polderman.

Polderman has “some 500 publications to his name”; does that number, 500, alone incite incredulity? A vast undertaking would be to review all of those publications to determine just how unique and how reliable was each study. Conrad Seitz M.D.

It’s a culture in clinical medicine to just look at the quantity, not the quality. You need to get more than 15 publication/year in order to reach 500 in a 30 year career span and this is a theoretically impossible task if you’re doing real science. Jey

These two concerned scientific people seem to be at odds in their philosophy. Dr. Seitz suggests that the quantity of publications is not important. He suggests reviewing each paper. Jey suggests that 500 papers in 30 years is too good to be true. Looking at the quantity of publications versus the quality of them seems to be a part of the culture of success in clinical medicine.

When I was a boy in Boy Scouts we had a contest of who could hold their breath the longest. The winner went about 4 minutes. Of course the winner and everyone who made it past the first minute were cheating. We didn't really need to follow each boy scout to see when they took in a fresh lung full of air. We didn't need to hold a mirror under every kids nose to see if they were breathing. We knew that the max of holding ones breath lasts about a minute. Jey is very astute in his observation regarding the number of papers Dr. Polderman has his name on. Jey goes on to say "Only possibility I can think of is that everyone in the building have been putting his name as a co-author. It’s even difficult to make up over 15 papers/year".

It is very difficult to take a single paper and reproduce the entire set of experiments and come to the same conclusion as the lead author. The list of authors on a paper haven't even taken the time to verify (in the lab) what is being reported. Therefore Dr. Seitz has proposed a far more difficult way of resolving this situation. Rather it would be of some value to assess the main thrust of what Dr. Polderman has put forth for the medical profession and to first look into the papers that support those ideas. Along the way perhaps a pattern will emerge that will lead us to pull out other papers that may contain false information.

The fact of the matter remains, a successful doctor/scientist has been caught cheating once again. As Jey pointed out, one would have to publish 15 papers a year. In 2001 Jan Hendrik Schon of the infamous Schon Scandal was listed as an author on an average of one newly published research paper every eight days. A pattern is thus already apparent for scientists. The quantity of ones publications may be inversely correlated to the quality.

I have my name, as an author, on a paper that was "published" in the Journal of Biological Chemistry. In fact, that paper is listed as a paid advertisement.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Other than that paragraph, the paper looks like a normal peer reviewed article. It is listed on the authors resumes. I did the work, my supervisor wrote the paper, our CSO signed off on it and a couple others got their names on it as well. And of course it is part of the art of deception.

Those who work inside the laboratories are usually too young, scared and otherwise unfit to take on the likes of a powerful doctor such as Dr. Polderman. It takes a lot to correct someone who has captured the attention of the scientific community. My thanks go out to Retraction Watch for the valuable service they are providing to help shine a light on the dark side of science. We, who have worked or currently work inside the laboratories know all about the pressure to obtain publishable results. It is the Cargo Cult Culture. It is not important whether or not the planes land. Our careers present a conflict of interest in the pursuit of the truth.