Modern technology has provided us with the ability to offer up our opinions. If you want to get into an argument online just offer up your opinion and wait. If you are on LinkedIn however, you are engaged in a professional conversation, you are not anonymous and you don't want future potential employers to see you offer up an honest but surly opinion. You end up with a Cargo Cult-like conversation.
The topic is phage display ELISAs. The worker used up his protein target panning for binding phage. Now he wants to use suspension cells expressing his target as his target in the ELISA. The first question one has to ask is whether or not it would be easier to find more of the pure protein than to develop an ELISA with suspension cells as the target.
There are many suggestions that are at the level of solving the problem stated. Those who wish to be leaders will accept that problem. It allows them to make suggestions but still leave the final decision to the worker. The probability of failure is high, but the accountability is not on the leader. A true scientific leader however, is the one who asks the questions. The scientist asks the questions because the scientist best knows what the problem is.
I've stated often that our education system selects for the best question answerers. The question askers often come across as the students. They seem naive, in need of a teacher to answer them. A scientist is someone who has the intellectual confidence to ask questions that many might consider to already have an adequate answer, and that answer has been placed into the heads of the educated. As is the case in the above problem, the intelligent response on this public forum would be to answer the question. Be the teacher to the student. Yet I think there is another approach which would have a higher probability of getting to the heart of the matter. Ask why the question has been posed. Question the question. The worker is trying to verify binding of phage to target. Has he set up the best experiment to answer his question.
Ultimately, this is not a phage display problem. It is an ELISA problem. There is no phage problem because we have a phage expert in our lab with all of the skills needed to do the job. He is missing a reagent and we need to get him a substitute. That is our job as leaders accountable for the successful completion of this task.
As leaders we must take into account time and resources. We must also ensure that we get the best answer to the question. The most important part of developing any ELISA is knowing the difference between signal and noise. Phage ELISAs have less separation between signal and noise than ELISAs with purified proteins and antibodies. With this new twist of using suspension cells in place of purified protein, one has to wonder what the signal and noise will be once you fully saturate the surface of your ELISA plate with your cells. Will you be able to distinguish the difference between noise and signal with this system?
Verification of binding is the forest. Attaching these cells to a plate is the trees. Make a list of your ideas and the suggestions you get from colleagues, use design of experiment to most efficiently run a set or series of tests and knock it all out at once. If nothing works, quickly move on to trying to get more pure protein.
Thursday, July 26, 2012
Tuesday, July 24, 2012
The Five Year Outlook
Outlook for the next 5 years in drug innovation
Abstract
The decade-long crisis in the productivity of pharmaceutical research and development (R&D) has been widely discussed1, 2. Indeed, expectations of reduced returns on R&D investment have led large companies to scale back their R&D substantially in recent years, and there have also been shifts in R&D investment and activity in particular therapeutic areas by the industry overall.
Nature Reviews Drug Discovery
Decade long crisis?
What is the value of any five year plan or outlook? No battle plan survives contact with the enemy. The intellectual firepower of this article, likewise, will have to do battle with the reality of an industry that operates randomly. Without control over the randomness of FDA approvals combined with the lack of systematic training and educations that create researchers and research leaders, there is no way to predict our future. Perhaps a better approach would be to look at the 90% false findings in published research and attempt to predict if that will change.
The original assumption in predicting where we will be in five years, is the assumption that we know where we are right now. The assumption that we are in the midst of a ten year crisis is conjecture. The assumption that we can predict the future is just silly. The most scientific thing we could do at this stage of the drug industry would be to define where we are, why we succeed and fail, and what we can do to weed out more of the Cargo Cult.
The original assumption in predicting where we will be in five years, is the assumption that we know where we are right now. The assumption that we are in the midst of a ten year crisis is conjecture. The assumption that we can predict the future is just silly. The most scientific thing we could do at this stage of the drug industry would be to define where we are, why we succeed and fail, and what we can do to weed out more of the Cargo Cult.
Monday, July 23, 2012
More Than a Bachelor Degree
I recently read that higher degrees in computer science are not all that desirable. The skills needed are learned during an undergrad education and mastered on the job.
I was talking with a couple Pfizer scientists. They had a task that they were going to hire a temp to tackle. They needed that person to develop a method to grow their virus in a particular cell line. They went on and on about the virus, the cell line and how the virus was going to be used. They had their narrative down to... a science. So much so that they got the okay to go out and find the temp to do this job. There was two things missing in their narrative regarding the temp. They failed to say "upstream process development" or "design of experiment".
During this talk the Pfizer scientists mentioned that they had very little written information. The new kid was suppose to show up, read their minds, and complete their project. Ultimately, his/her job would be to figure things out and train his/her superiors how to talk about his/her work. There would be a technology transfer, from the kid, to the people who need to know.
One of the reasons biotech/pharma and science in general has had such a dismal record lately is our faith. We have faith in the PhD. We have faith that the university is spitting out highly skilled minds. We have faith that a PhD is THE prerequisite for getting the job done. In the Pfizer example however, they have no intention of getting the job done. They will sit there like their advisory committee passing judgement, but not designing proper experiments.
What is the purpose of the PhD if they are not the ones designing the experiments? They certainly do not work in the laboratories. When a new biotech/pharma scientist is hired, is it assumed that they know about upstream versus downstream processes? Who trained them to be in the business? Who trained them to be leaders? Do they know how to put together a team? Can any of this be sussed out in a conversation or two that is had during the hiring process? I say no, and the only way to ensure that the PhD gets the additional training is to actually train them.
I give these Pfizer scientists little chance at creating an upstream process for their virus project. They plan on hiring a junior scientist to do all of the work. They have done a fine job of describing the Cargo that they hope for. They have pointed to the sky and explained that the Cargo will come from there. The only thing left is to find someone who knows the proper ceremony to perform. They'll know if he/she succeeds by staring at the sky and waiting.
I was talking with a couple Pfizer scientists. They had a task that they were going to hire a temp to tackle. They needed that person to develop a method to grow their virus in a particular cell line. They went on and on about the virus, the cell line and how the virus was going to be used. They had their narrative down to... a science. So much so that they got the okay to go out and find the temp to do this job. There was two things missing in their narrative regarding the temp. They failed to say "upstream process development" or "design of experiment".
During this talk the Pfizer scientists mentioned that they had very little written information. The new kid was suppose to show up, read their minds, and complete their project. Ultimately, his/her job would be to figure things out and train his/her superiors how to talk about his/her work. There would be a technology transfer, from the kid, to the people who need to know.
One of the reasons biotech/pharma and science in general has had such a dismal record lately is our faith. We have faith in the PhD. We have faith that the university is spitting out highly skilled minds. We have faith that a PhD is THE prerequisite for getting the job done. In the Pfizer example however, they have no intention of getting the job done. They will sit there like their advisory committee passing judgement, but not designing proper experiments.
What is the purpose of the PhD if they are not the ones designing the experiments? They certainly do not work in the laboratories. When a new biotech/pharma scientist is hired, is it assumed that they know about upstream versus downstream processes? Who trained them to be in the business? Who trained them to be leaders? Do they know how to put together a team? Can any of this be sussed out in a conversation or two that is had during the hiring process? I say no, and the only way to ensure that the PhD gets the additional training is to actually train them.
I give these Pfizer scientists little chance at creating an upstream process for their virus project. They plan on hiring a junior scientist to do all of the work. They have done a fine job of describing the Cargo that they hope for. They have pointed to the sky and explained that the Cargo will come from there. The only thing left is to find someone who knows the proper ceremony to perform. They'll know if he/she succeeds by staring at the sky and waiting.
Monday, June 11, 2012
The Context of Our Cult
Imagine you are doing a crossword puzzle. The only way to finish the puzzle is to be honest. Often times that one correct letter along with the clue pair up for an instant visualization of the missing word. Without the correct letter nothing clicks. Likewise, the wrong letter might block an otherwise easy word. To purposely fill in a word, knowing you are probably wrong, does not make sense.
Most of us think of science and math as very complicated information that only a handful of humans will ever be able to grasp. What if we looked at science as merely an enterprise that builds and organizes knowledge to help us understand the truth about our world. No matter what we are doing, we have to focus on getting it right. If we can do this we will have that clue that just might get us over the hump later on down the road. It will be that extra letter that combines with the crossword clue that makes the answer come to us. It will work like an enzyme, catalyzing our thought process.
When Dr. Iaonnidis published "Why Most Published Research Findings Are False" he was addressing the most serious issue facing modern science. The amount of bullshit in the journals has created a crossword puzzle with all of the letters filled in and they are 90% wrong. We might as well erase the letters and start anew. Unlike other ventures, science cannot function in this environment. There is no context for deviating from the truth in science. It is why we succeed.
Friday, June 08, 2012
Thursday, June 07, 2012
Yet Another Business Model
Venture capitalists that traditionally supported such biotech companies have given up.
That's a fact folks and the usual suspects are scrambling to reinvent themselves. We see right through the cracks however. Those at the top are remaining at the top. The labs are disappearing, the jobs are disappearing and the executives continue to make the big bucks. The ones who made the decisions that led to our state of affairs are still making the decisions. The only difference is that they are making... so we are told... better decisions.
Take Kineta. Yesterdays article in Xconomy states that this is a new business model. They began with $38 million of other peoples money. They spent $10 million so far, in three years, and they have yet to start a clinical trial. They have 25 employees, they collaborate with university types, and they promise to get money back into the hands of their investors. The model is to sell the single target drug candidates after phase I trails, before the shit hits the fan. One thing the usual suspects know by now is when they shit hits the fan. The only problem is that big pharma also knows this. There is nothing new here. Kineta only seeks to get out before the usual point of failure. They still hope to participate in the same path to drug approval, just not the hard part.
Compare Kineta's non-new business model with the genius, get-to-the-heart-of-the-matter, common sense ideas of the CCS. I see things quite differently.
We need to address:
We now have virtual companies, accelerator companies, incubators and other bloviators. Yet, if you look close, it's business as usual.
Kineta will fail because: 1) The have a poor grasp on simple, complicated, complex and chaotic. 2) 3) They do not train their staff to follow the Kineta method of discovery. There is no method! 4) The executives are coming from a failed venture. They raised over $23 million for Illumigen and sold it for $9 million to Cubist. Cubist paid too much! 5) It is a collection of individuals following a chaotic path to an unknown location where they hope to find a pot of gold.
Business as usual! Look to the skies and hope they got it right this time.
That's a fact folks and the usual suspects are scrambling to reinvent themselves. We see right through the cracks however. Those at the top are remaining at the top. The labs are disappearing, the jobs are disappearing and the executives continue to make the big bucks. The ones who made the decisions that led to our state of affairs are still making the decisions. The only difference is that they are making... so we are told... better decisions.
Take Kineta. Yesterdays article in Xconomy states that this is a new business model. They began with $38 million of other peoples money. They spent $10 million so far, in three years, and they have yet to start a clinical trial. They have 25 employees, they collaborate with university types, and they promise to get money back into the hands of their investors. The model is to sell the single target drug candidates after phase I trails, before the shit hits the fan. One thing the usual suspects know by now is when they shit hits the fan. The only problem is that big pharma also knows this. There is nothing new here. Kineta only seeks to get out before the usual point of failure. They still hope to participate in the same path to drug approval, just not the hard part.
Compare Kineta's non-new business model with the genius, get-to-the-heart-of-the-matter, common sense ideas of the CCS. I see things quite differently.
We need to address:
- Our industry consists of simple, complicated, complex and chaotic areas. The science is more complicated than the business, not the other way around.
- Biotechnology in general does not train it's people. We assume that people are trained for biotechnology careers at the Universities they attend.
- There is no method for discovery. Instead we hire PhDs and put world renowned scientists on our advisory boards. We assume this is the scientific method.
- When a company dies, it is a life unexamined. We assume that the executives who ran the company into the ground learned something along the way. They are now more experienced and more capable of running a successful business as a result of their failure.
- There are no well defined career paths in biotech. Highly educated people are expected to be smart enough to figure out what they need to be doing on a daily basis. As a result, our experts are self appointed gurus.
We now have virtual companies, accelerator companies, incubators and other bloviators. Yet, if you look close, it's business as usual.
Kineta will fail because: 1) The have a poor grasp on simple, complicated, complex and chaotic. 2) 3) They do not train their staff to follow the Kineta method of discovery. There is no method! 4) The executives are coming from a failed venture. They raised over $23 million for Illumigen and sold it for $9 million to Cubist. Cubist paid too much! 5) It is a collection of individuals following a chaotic path to an unknown location where they hope to find a pot of gold.
Business as usual! Look to the skies and hope they got it right this time.
Wednesday, June 06, 2012
Unemployment In Biotechnology
Have you ever received training at your biotech job? Did you show up, get your paperwork, fill it out, and start training? How long before you were on your own.
Biotech has a personality disorder where the science employees are very protective of their image. Without the uniformity that comes from official training, each individual develops their own way of doing things. Many will wait until it's quiet time in the lab to go in and do their work. I've seen some strange techniques. Some are detrimental to others, such as adding DTT to the entire tube of running buffer. It was assumed that the DTT would remain stable. When this worker, a supervisor of lab techs, was asked if he had put DTT in the buffer, he said, "oh, sorry, I meant to label it + DTT." He didn't know that the DTT is added to just the amount you will be needing, in a separate tube so as to not contaminate the running buffer with DTT. His embarrassment led to further isolation and unsanctioned detrimental techniques.
It is these tedious little things that cause people to work in solitude. If they rise up the ranks, (the few that do) their faulty techniques become the law of their silo. And I do mean silo. Each group, whether it is in biotech, big pharma, or academia, has a leader who has his own silo. The best methods can be done by anyone, anywhere, with just a protocol. The worst can only be done in the silo, by specific people.
The unemployment issue then becomes far more confounding for those in biotech looking for work. They didn't come from the silo they are trying to climb into? They weren't that specific person who was the only one trusted to get the required results. When interviewing you end up discussing the two silos, trying to see if the belief systems are compatible.
Some places however, have a great respect for training and the uniformity that it brings. The orthogonal approach to problem solving is also represented in training. Bring in someone else to train you to do what you think you already know. While working in my silo in Seattle, we had a very smart individual from GE Healthcare who offered free consultations. Obviously he wanted us to buy GE products but you could take his advice or leave it. If you took it, you had a real piece of advice that you could test. If he was wrong you would know it. He was also intimidating due to his rapid fire responses. His questions were upper level. You needed to know the lingo and you had to answer his questions in order to get good advice. As a result our leaders got the hell out of the building when he showed up. It was the equivalent of working in the lab when no one was around. They didn't want to talk about their work, logic and the progress. They took the silo with them so no one could look in.
The last time I saw our GE friend, before I left the biz, he was on his way to train scientists in Germany, some of whom had over 30 years of experience. The Germans were paying for the training. We were turning down free chat sessions because we were embarrassed by our ignorance.
What happens then when a company has such leadership and they want to hire a new member to their team? Do they seek individuals like the GE expert or do they screen for people who fit their silo? Will there be training? The biotech method, especially small biotech, is to hire someone who is ready to go. If they make it through the interview process, they have proven themselves to be work ready. If they fail, they can be blamed for not living up to their resume. But having an excuse or scapegoat does not lead to success.
This article tells it best:
In my utopian society, non PhD laboratory professionals would all enter the work for based on their degrees. Biochemistry grads would tackle different problems than cell biology grads. A career path would exist for both but they would be different, not simply biotech research associate. PhDs would use these professionals in the lab to conduct experiments that they would design. The measure of their minds would be in the results of their experiments. Even negative data should provide insight as to what to do next. There would be much cross training so that everyone would be able to understand what is going on. What we do is not rocket science. It's much easier than that at the lab level. At the living organism level it's much more complex than rocket science.
Once career paths become defined, clearly defined job descriptions will begin to exist. A recent post doc will be given a project. He will learn to communicate as a leader. He will learn the equipment and methods that will be at his disposal. The young lab staff will learn their trade then progress to supervisory roles. They will become liaisons with the PhD levels. A structure will emerge that will prevent both classes, lab and management, from the current state where the best bullshitters prevail.
We've lost the faith of the investment community. They've seen the dishonesty from researchers of all walks of life. It needs to be cleaned up. Ironically, creating more jobs that we train people to do could be the answer. If you hold the purse strings, wouldn't it make sense to change business as usual and begin to train the workforce? As Dr. Capelli says,
Biotech has a personality disorder where the science employees are very protective of their image. Without the uniformity that comes from official training, each individual develops their own way of doing things. Many will wait until it's quiet time in the lab to go in and do their work. I've seen some strange techniques. Some are detrimental to others, such as adding DTT to the entire tube of running buffer. It was assumed that the DTT would remain stable. When this worker, a supervisor of lab techs, was asked if he had put DTT in the buffer, he said, "oh, sorry, I meant to label it + DTT." He didn't know that the DTT is added to just the amount you will be needing, in a separate tube so as to not contaminate the running buffer with DTT. His embarrassment led to further isolation and unsanctioned detrimental techniques.
It is these tedious little things that cause people to work in solitude. If they rise up the ranks, (the few that do) their faulty techniques become the law of their silo. And I do mean silo. Each group, whether it is in biotech, big pharma, or academia, has a leader who has his own silo. The best methods can be done by anyone, anywhere, with just a protocol. The worst can only be done in the silo, by specific people.
The unemployment issue then becomes far more confounding for those in biotech looking for work. They didn't come from the silo they are trying to climb into? They weren't that specific person who was the only one trusted to get the required results. When interviewing you end up discussing the two silos, trying to see if the belief systems are compatible.
Some places however, have a great respect for training and the uniformity that it brings. The orthogonal approach to problem solving is also represented in training. Bring in someone else to train you to do what you think you already know. While working in my silo in Seattle, we had a very smart individual from GE Healthcare who offered free consultations. Obviously he wanted us to buy GE products but you could take his advice or leave it. If you took it, you had a real piece of advice that you could test. If he was wrong you would know it. He was also intimidating due to his rapid fire responses. His questions were upper level. You needed to know the lingo and you had to answer his questions in order to get good advice. As a result our leaders got the hell out of the building when he showed up. It was the equivalent of working in the lab when no one was around. They didn't want to talk about their work, logic and the progress. They took the silo with them so no one could look in.
The last time I saw our GE friend, before I left the biz, he was on his way to train scientists in Germany, some of whom had over 30 years of experience. The Germans were paying for the training. We were turning down free chat sessions because we were embarrassed by our ignorance.
What happens then when a company has such leadership and they want to hire a new member to their team? Do they seek individuals like the GE expert or do they screen for people who fit their silo? Will there be training? The biotech method, especially small biotech, is to hire someone who is ready to go. If they make it through the interview process, they have proven themselves to be work ready. If they fail, they can be blamed for not living up to their resume. But having an excuse or scapegoat does not lead to success.
This article tells it best:
Unfortunately, American companies don't seem to do training anymore. Data are hard to come by, but we know that apprenticeship programs have largely disappeared, along with management-training programs.Imagine a PhD coming out of a highly specific post-doc experience trying to get a paper published. The next thing he has to do is become a supervisor of the molecular biology group. Chances are molecular biology was only a small part of the post doc work. Furthermore it was just a means to an end. Now it's the entire job. Rather, a better supervisor would be someone with a strong grasp on Vectors NTI. If you understand the software, you understand molecular biology. Leave the dreaming and scheming up to the PhD who just finished his post doc.
In my utopian society, non PhD laboratory professionals would all enter the work for based on their degrees. Biochemistry grads would tackle different problems than cell biology grads. A career path would exist for both but they would be different, not simply biotech research associate. PhDs would use these professionals in the lab to conduct experiments that they would design. The measure of their minds would be in the results of their experiments. Even negative data should provide insight as to what to do next. There would be much cross training so that everyone would be able to understand what is going on. What we do is not rocket science. It's much easier than that at the lab level. At the living organism level it's much more complex than rocket science.
Once career paths become defined, clearly defined job descriptions will begin to exist. A recent post doc will be given a project. He will learn to communicate as a leader. He will learn the equipment and methods that will be at his disposal. The young lab staff will learn their trade then progress to supervisory roles. They will become liaisons with the PhD levels. A structure will emerge that will prevent both classes, lab and management, from the current state where the best bullshitters prevail.
We've lost the faith of the investment community. They've seen the dishonesty from researchers of all walks of life. It needs to be cleaned up. Ironically, creating more jobs that we train people to do could be the answer. If you hold the purse strings, wouldn't it make sense to change business as usual and begin to train the workforce? As Dr. Capelli says,
"It helps build the supply of human capital in the economy, as well as opening the pathway for more people to get jobs. It's an important instance where company self-interest and societal interest just happen to coincide."
Monday, June 04, 2012
The Beginnings
What happens when a biotech company goes out of business? Does someone write a book about it so others can learn from their successes and mistakes? Is the science put down in a text book so others can come along later with more money and the missing technological link to make it all work? Or does it just fade away?
With the demise of Marina Biotech I've been wondering about lost civilizations, old ghost towns, the science of the Mayans and all sorts of things that humans have gained and lost. We have written accounts like the Rise and Fall of the Roman Empire, written centuries after the facts. To me, Life and Letters On the Roman Frontier offers some of the best insight into ancient Rome. It's unintended insight but far better than a scholarly version of the facts. There is one letter where an old man criticizes the way the kids "nowadays" are dressing. Old people have always complained about the younger generation. Most of us will be young and old and we will behave in this manner. We learn these things from studying our history.
When archeologists study ancient civilizations they look for signs of everyday life. They look for things like tools, an interest in the stars, written language. Thus we begin to piece together the history of man. Why do we get so excited just to find a letter from an ancient Roman citizen talking about the mode of dress in his day? There is something about a simple thought put down for future generations.
Marina Biotech for the historians of the future.
Nastech, a nasal spray company, knew that they needed to get on the RNAi bandwagon. They hired some young scientists and began with the usual research project. Send the young people into the lab to figure this RNAi thing out, knock out TNF alpha (IL2, IL6, IL17, amyloid beta, VEGF... fill in your favorite target here) and move up the chain of R&D, animal studies then clinical trials. They soon found out that delivery was going to be an obstacle. The CEO dreamed up a solution in the form of a phage library. This was their first primitive attempt at dealing with the situation. The library was made, tested and nothing seemed to pop out. It was decided that the phage staff was unable to advance the concept set forth by the CEO and they were let go. A lab in Denmark was given the library and they allegedly succeeded.
At this point Marina had given up on being a world leader in nasal spray technology. They decided to be a world leader in RNAi. In our time that requires you only to make the claim on your website. They spruced up their RNAi ideas to become UsiRNAs with a DiLA(2) based liposome and peptide based nanoparticle delivery system. Notice the evolution of thinking with regards to the RNAi and the delivery problem. Usi and DiLA(2), legitimate or not, are more complicated. They are less simple. In order to give off the illusion of advancement, what we do next must be more complicated. The new idea must make the old idea seem simple. The narrative that the peptides be used in conjunction with Marina delivery systems remained the same. When the line between the preconceived outcome and the laboratory reality was impossible to draw, a new and more complicated reality needed to be developed.
At this point, future historians, you can see the mixing and matching of narratives. The CEO who dreamed up the library had a notion and it failed. Rather than accepting the fact that the idea failed, the failure was placed on the lab staff. Later the CEO and CSO were replaced but the idea remained. The lab work was handed over to someone else. The new execs adopted the narrative and used it to hedge their bets on the delivery problem.
With the demise of Marina Biotech I've been wondering about lost civilizations, old ghost towns, the science of the Mayans and all sorts of things that humans have gained and lost. We have written accounts like the Rise and Fall of the Roman Empire, written centuries after the facts. To me, Life and Letters On the Roman Frontier offers some of the best insight into ancient Rome. It's unintended insight but far better than a scholarly version of the facts. There is one letter where an old man criticizes the way the kids "nowadays" are dressing. Old people have always complained about the younger generation. Most of us will be young and old and we will behave in this manner. We learn these things from studying our history.
When archeologists study ancient civilizations they look for signs of everyday life. They look for things like tools, an interest in the stars, written language. Thus we begin to piece together the history of man. Why do we get so excited just to find a letter from an ancient Roman citizen talking about the mode of dress in his day? There is something about a simple thought put down for future generations.
Marina Biotech for the historians of the future.
Nastech, a nasal spray company, knew that they needed to get on the RNAi bandwagon. They hired some young scientists and began with the usual research project. Send the young people into the lab to figure this RNAi thing out, knock out TNF alpha (IL2, IL6, IL17, amyloid beta, VEGF... fill in your favorite target here) and move up the chain of R&D, animal studies then clinical trials. They soon found out that delivery was going to be an obstacle. The CEO dreamed up a solution in the form of a phage library. This was their first primitive attempt at dealing with the situation. The library was made, tested and nothing seemed to pop out. It was decided that the phage staff was unable to advance the concept set forth by the CEO and they were let go. A lab in Denmark was given the library and they allegedly succeeded.
The collaboration will utilize Marina's patented phage display library and Dr. Laakkonen's unique expertise with phage display libraries and experience in the evaluation of peptides for preferential homing. Such peptides are expected to be used in conjunction with Marina's delivery systems, including DiLA(2)-based liposomes and peptide-based nanoparticles, to further enhance the uptake of Marina's proprietary UsiRNAs in targeted tissues and improve overall performance of RNAi therapeutic drug candidates.
This agreement expands on a successful collaboration between Marina and Dr. Laakkonen's lab in which screening in the library using in vitro/in vivo "biopanning" methods has already identified candidate peptides with high specificity for homing to prostate cancer cells.
At this point Marina had given up on being a world leader in nasal spray technology. They decided to be a world leader in RNAi. In our time that requires you only to make the claim on your website. They spruced up their RNAi ideas to become UsiRNAs with a DiLA(2) based liposome and peptide based nanoparticle delivery system. Notice the evolution of thinking with regards to the RNAi and the delivery problem. Usi and DiLA(2), legitimate or not, are more complicated. They are less simple. In order to give off the illusion of advancement, what we do next must be more complicated. The new idea must make the old idea seem simple. The narrative that the peptides be used in conjunction with Marina delivery systems remained the same. When the line between the preconceived outcome and the laboratory reality was impossible to draw, a new and more complicated reality needed to be developed.
At this point, future historians, you can see the mixing and matching of narratives. The CEO who dreamed up the library had a notion and it failed. Rather than accepting the fact that the idea failed, the failure was placed on the lab staff. Later the CEO and CSO were replaced but the idea remained. The lab work was handed over to someone else. The new execs adopted the narrative and used it to hedge their bets on the delivery problem.
"We are extremely pleased to extend our agreement with Dr. Laakkonen and the Biomedicum," said Dr. Barry Polisky, Chief Scientific Officer of Marina."There are very few people with the expertise and resources to perform this kind of science.
There goes the value in selling the library now that Marina is kaput. You have to possess magical powers to use the damn thing. In reality it's not rocket science and Dr. Laakkonens is no miracle worker. The prostrate avenue was never pursued. The truth of this project is that it was just a sciency thing to do. The Trp cage was a very interesting molecule to many scientists due to its structure. Nastech interjected the Trp cage into a phage library, a technology that presents random amino acids which will destroy the Trp cage structure. Others, in the harder sciences, have tested the Trp cage structure by removing one amino acid at a time. Imagine changing 7 of the 20 amino acids. The idea itself is bad science. The results cost a few people their jobs. No one has hailed the library as superior to others in any way.
Nonetheless, one year later:
Next we have SMARTICLES and tkRNAi. More complicated. Then we go right back to the narrative, "comprehensive set of nucleic acid delivery technologies... rapidly screen... cell specific targeting... fundamental component to developing delivery approaches..." It all sounds so professional. Surely it is true. Right? We all believed the press releases?
Was any of the science real or was it just bullshit? Trp cage, DiLA(2), Usi, SMARTICLES and so on are all very sciency ideas that evolved from the early days of Nastech. In those days most people were focused on nasal sprays. In a few short years they were 100% RNAi. Many of the technologies that went into creating the physical product, are real. Phage display is real but how do you apply it to solve the delivery problem? We can make modifications to little pieces of RNA but it requires a leap of faith the think that they will they cure a disease. Did Nastech evolve to an RNAi company destined to fail by simply offering up more and more complicated solutions. Were the solutions merely the rhetoric of bullshitters?
I offer up this little story for the future historians who want to tackle one of the biggest secrets of our current economy. Biotech didn't just lose a couple million dollars. We lose billions. So much is lost that a little company like Marina gets the press release of its demise cut and pasted onto a few "news" organizations websites and that's it. Did anyone take notice? Like an archeologist who goes over a dusty field in Egypt, is there anyone in modern times who thinks the history of this little biotech has any value in excavating?
Nonetheless, one year later:
Marina Biotech, Inc. (NASDAQ: MRNA), a leading nucleic acid-based drug discovery and development company, today announced that the U.S. Patent and Trademark Office (USPTO) has issued a Notice of Allowance for patent application with claims that cover a library of over 1×10(15) novel peptides. The patent application is part of the Company’s proprietary Trp Cage Library patent portfolio. This allowance strengthens the Company’s nucleic acid-peptide drug delivery platform, and further expands the Company’s patent protection for its comprehensive set of nucleic acid delivery technologies, which also include DiLA2™, SMARTICLES® and the tkRNAi™ system.
“A primary advantage of this patented peptide library is the ability to rapidly screen and identify novel peptides that exhibit cell specific targeting characteristics for directed delivery of nucleic acid therapeutics,” said Barry Polisky, Ph.D., Chief Scientific Officer of Marina Biotech. “Delivery remains a significant challenge in the nucleic acid therapeutic space, and peptides with high affinity and specificity are expected to be a fundamental component to developing delivery approaches to a wide spectrum of tissues and cell types. In addition, the library may also be exploited to screen for peptides that function as specific antagonists, agonists or generally exhibit drug like properties.”The library has gone from 1.28e9 novel peptides to 1.5e15 novel peptides. This is mathematically impossible. 7 random spots to be filled by one of 20 amino acids can only produce 20 to the seventh or 1.28e9 novel peptides. Once again, notice how the next thing is more complicated, less simple. How much more complicated? A billion seconds is 33 years. Ten to the fifteenth? 33 million years. And people believed it. Certainly the patent office had to believe it.
Next we have SMARTICLES and tkRNAi. More complicated. Then we go right back to the narrative, "comprehensive set of nucleic acid delivery technologies... rapidly screen... cell specific targeting... fundamental component to developing delivery approaches..." It all sounds so professional. Surely it is true. Right? We all believed the press releases?
Was any of the science real or was it just bullshit? Trp cage, DiLA(2), Usi, SMARTICLES and so on are all very sciency ideas that evolved from the early days of Nastech. In those days most people were focused on nasal sprays. In a few short years they were 100% RNAi. Many of the technologies that went into creating the physical product, are real. Phage display is real but how do you apply it to solve the delivery problem? We can make modifications to little pieces of RNA but it requires a leap of faith the think that they will they cure a disease. Did Nastech evolve to an RNAi company destined to fail by simply offering up more and more complicated solutions. Were the solutions merely the rhetoric of bullshitters?
I offer up this little story for the future historians who want to tackle one of the biggest secrets of our current economy. Biotech didn't just lose a couple million dollars. We lose billions. So much is lost that a little company like Marina gets the press release of its demise cut and pasted onto a few "news" organizations websites and that's it. Did anyone take notice? Like an archeologist who goes over a dusty field in Egypt, is there anyone in modern times who thinks the history of this little biotech has any value in excavating?
History tells us that we are bullshitters by nature. Science requires us to put the bullshit aside and learn how to uncover the truth. If you chose to ignore this history lesson you might just be the next Marina Biotech.
Friday, June 01, 2012
Marina Biotech CCS Alumni Now
Marina Biotech, led by SIRNA execs, has added another turd to the heap of RNAi companies. Earlier in the week Alnylam announced their latest RNAi failure. There seems to be a pattern here.
It's over Johnny. IT'S OVER!
Thursday, May 31, 2012
A Day in the Life Sciences
Typical day on Biospace, May 30, 2012:
- STADA Arzneimittel AG to cut 800 jobs...
- J&J Fails to win FDA OK for daily HIV pill...
- FDA warns J&J over vaginal products...
- Alnylam Pharmaceuticals lung drug fails mid-stage trial...
- Flexion Therapeutics reports positive data for osteoarthritis drug...
- Bristol Myers Squibb Company drug seen helping attack lung cancer...
Early stage - positive results: "These results represent a significant advance..." "This could be a breakthrough..." "It's a turning point..." Actual quotes from these stories
Phase IIb - mitigated failure: "The study missed the primary endpoint... We believe that these data provide important evidence..."
FDA review - failure: "The company said it is reviewing the FDA's response to its marketing application and it plans to respond as quickly as possible."
FDA Warning - "The regulator said it could not determine the adequacy of the company’s responses until J&J completed an investigation of each one and provided them to the FDA."
Notice how the people cheerleading the narrative start to fade away as a drug moves further down the line in development. The narrative starts to show signs of fallibility and the story tellers walk away. They are the positive ones. They are the ones who say things like "significant advance" and "turning point". They are not the ones who say, "missed the primary endpoint" or "failed". In the end the leaders slip behind the curtain of Oz and let the Wizard speak. We are left with that empty feeling when something happens, good or bad, and we don't know why.
Sunday, May 27, 2012
Our Method
Descartes "Rules For The Direction of The Mind" can help the Cargo Cults understand "what is missing", why there is no "wealth in their system".
Rule 5 holds that complicated problems should be reduced to their simplest parts. We then apply our “intuition” to the simplest parts and work our way back to the larger problem.
For our purposes here today, let's re-create a failed drug research project that most biotechnology companies in the past 30 years have attempted. The project is to make a drug against TNF apha.
While others had proven TNF alpha to be a target that can bring the cargo, most TNF alpha projects failed. The notion that TNF alpha projects have a high probability of success is false. What the leaders tend to do, when selecting drug targets, is disguise conjecture as a scientific method.
The larger problem is getting the molecule to validate the conjecture and assumptions of management. The simple part is good biotechnology. We know how to make the antibody. Although this knowledge fades as we go higher into the ranks of leadership, it is a very solid foundation that gives the biotech credence. Where we begin to fall apart is when we move from the known technology into the unknown outcome of drug testing.
Rule 5 holds that complicated problems should be reduced to their simplest parts. We then apply our “intuition” to the simplest parts and work our way back to the larger problem.
For our purposes here today, let's re-create a failed drug research project that most biotechnology companies in the past 30 years have attempted. The project is to make a drug against TNF apha.
Planning:
The norm is that the executive staff and the board select a drug target based on profit potential and the probability of success. This involves faith in the sound decisions of the board of directors, advised by the scientific advisory board. The target is TNF alpha.
The norm is that the executive staff and the board select a drug target based on profit potential and the probability of success. This involves faith in the sound decisions of the board of directors, advised by the scientific advisory board. The target is TNF alpha.
Descartes: Rule 3 states that we should study objects that we ourselves can clearly deduce and refrain from conjecture and reliance on the work of others.
Execution:
Have the lab staff find a molecule that interacts with the target selected in step one. For our purposes we will generate an anti-TNF antibody.
Have the lab staff find a molecule that interacts with the target selected in step one. For our purposes we will generate an anti-TNF antibody.
Descartes: Rule 5 holds that complicated problems should be reduced to their simplest parts. We then apply our “intuition” to the simplest parts and work our way back to the larger problem.
Analysis:
Descartes: Rule 2 holds that we should only study objects about which we can obtain “certain and evident cognition.” It is better not to study at all than to attempt a study when we can’t tell what’s right or wrong, true or false.
In my experience scientists at higher levels do not participate at this level. Each company has different methods, for example, on testing the binding affinity of their antibody. Some use biacore. I've been told to do the same complicated calculations from ELISA assays. The higher ranking scientists need only have a vague idea as to how a drug is being tested at the early stages. Those who required me to obtain a binding constant from an ELISA assay, had a vague idea of how things work in the lab. In order to know whether or not the test will lead to "certain and evident cognition" much more attention would be required of the higher ranking scientists. This is a critical moment in the process that is soft. If the data comes back saying, for example, that the antibody had a weak binding affinity to TNF, the laboratory staff must explain why they think that to be the case. In other words, the lab staff must convince the scientists what the truth is. The scientists have positioned themselves only to judge the methods employed by the laboratory class rather than participate in establishing that an assay will provide certain and evident cognition.
Descartes: Rule 2 holds that we should only study objects about which we can obtain “certain and evident cognition.” It is better not to study at all than to attempt a study when we can’t tell what’s right or wrong, true or false.
In my experience scientists at higher levels do not participate at this level. Each company has different methods, for example, on testing the binding affinity of their antibody. Some use biacore. I've been told to do the same complicated calculations from ELISA assays. The higher ranking scientists need only have a vague idea as to how a drug is being tested at the early stages. Those who required me to obtain a binding constant from an ELISA assay, had a vague idea of how things work in the lab. In order to know whether or not the test will lead to "certain and evident cognition" much more attention would be required of the higher ranking scientists. This is a critical moment in the process that is soft. If the data comes back saying, for example, that the antibody had a weak binding affinity to TNF, the laboratory staff must explain why they think that to be the case. In other words, the lab staff must convince the scientists what the truth is. The scientists have positioned themselves only to judge the methods employed by the laboratory class rather than participate in establishing that an assay will provide certain and evident cognition.
I've simplified the process down to its basic components. Where Descartes had rules for the direction of the mind, we have a very different set of rules. For each Descartes rule, we have a very specific unwritten rule of our own that does not match.
Rule 4 proposes that the mind requires a fixed method to discover truth. A method is defined as a set of reliable and simple rules. The goal of study through the method is to attain knowledge of all things. The human mind begins life in a pure state, and from the moment learning starts, the mind grows clouded. The method’s purpose is to return the mind to that pure state so that we can be certain of knowledge we attain.
As I've stated, there are no written methods for the larger problem. The simpler problems, (cloning, purifying, etc) have detailed written methods, SOPs. The laboratory staff must also write down specifics in a lab notebook, which often comes with a set of rules the lab staff must follow. Date each page, initial cross-outs... The scientists at the higher level have no method, no rules and no police other than themselves. Their commitment is to the illusion of success. Even if your biotech company fails, you now have experience running a biotech company. A publication is a publication, reproducible or not. Is this what Descartes outlined?
We have a random method of discovery. It's a broken system. Reproducibility, to ensure that we are dealing with the truth, is not a part of our system. What would our rules be if we were forced to write them out in an attempt to explain how we spent so many billions on failed TNF projects? Failed Amyloid beta projects? Regardless of the target, the company, the technology, we would find a pattern. There is no set of reliable and simple rules. When you look into the laboratories, you will find that the minds have grown cloudy. If you look into the offices, you will find that the minds have grown corrupt. We need a method to return our collective mind to that pure state that led us to certainty in the past.
Rule 4 proposes that the mind requires a fixed method to discover truth. A method is defined as a set of reliable and simple rules. The goal of study through the method is to attain knowledge of all things. The human mind begins life in a pure state, and from the moment learning starts, the mind grows clouded. The method’s purpose is to return the mind to that pure state so that we can be certain of knowledge we attain.
As I've stated, there are no written methods for the larger problem. The simpler problems, (cloning, purifying, etc) have detailed written methods, SOPs. The laboratory staff must also write down specifics in a lab notebook, which often comes with a set of rules the lab staff must follow. Date each page, initial cross-outs... The scientists at the higher level have no method, no rules and no police other than themselves. Their commitment is to the illusion of success. Even if your biotech company fails, you now have experience running a biotech company. A publication is a publication, reproducible or not. Is this what Descartes outlined?
We have a random method of discovery. It's a broken system. Reproducibility, to ensure that we are dealing with the truth, is not a part of our system. What would our rules be if we were forced to write them out in an attempt to explain how we spent so many billions on failed TNF projects? Failed Amyloid beta projects? Regardless of the target, the company, the technology, we would find a pattern. There is no set of reliable and simple rules. When you look into the laboratories, you will find that the minds have grown cloudy. If you look into the offices, you will find that the minds have grown corrupt. We need a method to return our collective mind to that pure state that led us to certainty in the past.
Friday, May 25, 2012
A Wealthy System
Is Science the same system it once was? Feynman said:
Wikipedia says:
Science (from Latin scientia, meaning "knowledge") is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe.[1] In an older and closely related meaning (found, for example, in Aristotle), "science" refers to the body of reliable knowledge itself, of the type that can be logically and rationally explained (see History and philosophy below).[2] Since classical antiquity science as a type of knowledge was closely linked to philosophy. In the early modern era the words "science" and "philosophy" were sometimes used interchangeably in the English language. By the 17th century, natural philosophy (which is today called "natural science") was considered a separate branch of philosophy.[3] However, "science" continued to be used in a broad sense denoting reliable knowledge about a topic, in the same way it is still used in modern terms such as library science or political science.
Even the definition of science is subject to evolution. The system changes. Currently it seems to have devolved into a religion. Is "science" the same systematic enterprise it was when Einstein was publishing papers in the early 1900s? What about when Descartes was working on his text books?
In Descartes day it was admirable to establish a body of work, not just a large quantity of publications. Not only did you set forth ideas, you used them to set up the next set of experiments. To go even deeper he wrote "Rules For The Direction Of The Mind". Rule 1 states that whatever we study should direct our minds to make “true and sound judgments” about experience. The various sciences are not independent of one another but are all facets of “human wisdom.” Possession of any kind of knowledge—if it is true—will only lead to more knowledge.
Does that resemble the system we are currently in? Once again, The Amgen Study:
We do have a system and people can learn that system and have long successful careers. It is not however, the science of antiquity. No one intends on writing a text book that will be examined by the best minds in the scientific community. Their work is not intended to be examined in the laboratory. It is sciency (pronounced - science-ee). You take the rules from Descartes, for example #3: we should study objects that we ourselves can clearly deduce and refrain from conjecture and reliance on the work of others. Now you have a method. Take the work of others, and rely upon it and get others to get the rest of the community to gravitate towards conjecture. Conjecture: a proposition that is unproven but is thought to be true and has not been disproven. Karl Popper pioneered the use of the term "conjecture" in scientific philosophy. Conjecture is contrasted by hypothesis (hence theory, axiom, principle), which is a testable statement based on accepted grounds. Our system is sciency. Work on conjecture; things that are thought to be true, such as RNAi. Don't design experiments that will jeopardize your conjecture. When an experiment does not prove your proposition, try try again.
Karl Popper was a philosopher who argued for a change in the system of science. He went deep. "Logically, no number of positive outcomes at the level of experimental testing can confirm a scientific theory, but a single counterexample is logically decisive: it shows the theory, from which the implication is derived, to be false." Where do we go from there after the Amgen study? The answer, in our current system, is to move forward ignoring the falsified studies. The 47 papers that were not reproducible shall remain anonymous because our system is not that of Karl Poppers. It is in fact, the opposite. The Amgen study matched up with the science of Dr. John Ioannidis. 90% bullshit is the current rate of scientific publications. In the labs of biotechnology the daily grind is much the same. The philosophy of yore is not a part of our system. We make money by doing what we are told. We have a very sciency life. Take this antibody or RNAi and bring me evidence that it reduces tumor size. Bring me evidence that it can be used to treat Alzheimers. I will use it in a slide presentation to extract money from investors.
That is our system. I imagine a system where the NIH opens a branch that randomly takes publicly funded research to the lab. The concept that we self-police should be abandoned. Someone needs to start policing the bullshitters. The scientist who receives public funds should be part of a system where they are randomly selected to come to Maryland and reproduce their work.
As Descartes suggests:
they follow all the apparent precepts and forms of scientific investigation, but they're missing something essential, because the planes don't land. Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Sea Islanders how they have to arrange things so that they get some wealth in their system.We know that even the most productive scientists cheated at times. In order to stay on top a person has to continue producing. That just isn't in our nature. We grow old and we get lazy. There is probably a productive time in our lives where our minds operate best in the abstract concept of science. Therefore we need a method. We need to participate in a system that keeps us honest and productive.
Wikipedia says:
Science (from Latin scientia, meaning "knowledge") is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe.[1] In an older and closely related meaning (found, for example, in Aristotle), "science" refers to the body of reliable knowledge itself, of the type that can be logically and rationally explained (see History and philosophy below).[2] Since classical antiquity science as a type of knowledge was closely linked to philosophy. In the early modern era the words "science" and "philosophy" were sometimes used interchangeably in the English language. By the 17th century, natural philosophy (which is today called "natural science") was considered a separate branch of philosophy.[3] However, "science" continued to be used in a broad sense denoting reliable knowledge about a topic, in the same way it is still used in modern terms such as library science or political science.
Even the definition of science is subject to evolution. The system changes. Currently it seems to have devolved into a religion. Is "science" the same systematic enterprise it was when Einstein was publishing papers in the early 1900s? What about when Descartes was working on his text books?
In Descartes day it was admirable to establish a body of work, not just a large quantity of publications. Not only did you set forth ideas, you used them to set up the next set of experiments. To go even deeper he wrote "Rules For The Direction Of The Mind". Rule 1 states that whatever we study should direct our minds to make “true and sound judgments” about experience. The various sciences are not independent of one another but are all facets of “human wisdom.” Possession of any kind of knowledge—if it is true—will only lead to more knowledge.
Does that resemble the system we are currently in? Once again, The Amgen Study:
Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies.If in fact we had the same system that Descartes was participating in, what kind of text book would the anonymous scientist who told "the best story" intend to write? Is this a wealthy system?
"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."
We do have a system and people can learn that system and have long successful careers. It is not however, the science of antiquity. No one intends on writing a text book that will be examined by the best minds in the scientific community. Their work is not intended to be examined in the laboratory. It is sciency (pronounced - science-ee). You take the rules from Descartes, for example #3: we should study objects that we ourselves can clearly deduce and refrain from conjecture and reliance on the work of others. Now you have a method. Take the work of others, and rely upon it and get others to get the rest of the community to gravitate towards conjecture. Conjecture: a proposition that is unproven but is thought to be true and has not been disproven. Karl Popper pioneered the use of the term "conjecture" in scientific philosophy. Conjecture is contrasted by hypothesis (hence theory, axiom, principle), which is a testable statement based on accepted grounds. Our system is sciency. Work on conjecture; things that are thought to be true, such as RNAi. Don't design experiments that will jeopardize your conjecture. When an experiment does not prove your proposition, try try again.
Karl Popper was a philosopher who argued for a change in the system of science. He went deep. "Logically, no number of positive outcomes at the level of experimental testing can confirm a scientific theory, but a single counterexample is logically decisive: it shows the theory, from which the implication is derived, to be false." Where do we go from there after the Amgen study? The answer, in our current system, is to move forward ignoring the falsified studies. The 47 papers that were not reproducible shall remain anonymous because our system is not that of Karl Poppers. It is in fact, the opposite. The Amgen study matched up with the science of Dr. John Ioannidis. 90% bullshit is the current rate of scientific publications. In the labs of biotechnology the daily grind is much the same. The philosophy of yore is not a part of our system. We make money by doing what we are told. We have a very sciency life. Take this antibody or RNAi and bring me evidence that it reduces tumor size. Bring me evidence that it can be used to treat Alzheimers. I will use it in a slide presentation to extract money from investors.
That is our system. I imagine a system where the NIH opens a branch that randomly takes publicly funded research to the lab. The concept that we self-police should be abandoned. Someone needs to start policing the bullshitters. The scientist who receives public funds should be part of a system where they are randomly selected to come to Maryland and reproduce their work.
As Descartes suggests:
The human mind begins life in a pure state, and from the moment learning starts, the mind grows clouded. The method’s purpose is to return the mind to that pure state so that we can be certain of knowledge we attain.Our system has grown cloudy. We have great minds of yore to help us out of this mess. The question is how do we get our leaders to follow the methods and philosophies that created this thing called science? It was once a very wealthy system. It is now dirt poor, ran by financially wealthy people.
Thursday, May 24, 2012
The Comment Section
Some of the most interesting things I read online are not the articles but the comments people make. A few of my favorites:
That's a comment from this article written by Derek Lowe. I came across another comment from Dereks blog, "In the Pipeline" that lead me to another blog by the commenter. He discusses why we have so many layoffs in pharma R&D:
I enjoy reading Xconomy every day. Mostly I'm looking for stories of the Cargo Cults of Seattle not getting their cargo. When I conjure the image of the natives of a cargo cult gazing to the skies during their ceremonies, looking for the big metal birds carrying cargo inside, I think of Xconomy as the sky. Sadly they don't illicit many comments. The lack of an active conversation indicates that people are not engaged.
One of the criticisms of the commenters is that they are often anonymous. Comments are little blurbs from self appointed "wise old sages" who have to get their words out. Why don't they tell us who they are? Some are picking a fight. Some are expressing their concern. Some are just trying to be witty. Not everyone accomplishes their goal but the anonymity makes the possibility of failure a risk they are willing to take. The anonymity can lead to troll behavior but it can also lead to insights we wouldn't not have had on our own with the article. Anonymity is what we see from many scientists. They are absent from the lab and the many failed experiments based on their ideas. If you were to look into the laboratory notebooks of the young people who conduct research inside the lab you will find no mention of who told them to do the work. There will be no introduction outlining the thinking of the actual thinkers. Anonymity is a tool we all use.
Some comments are interesting in their defense of Cargo Cult thinking. In a recent retraction from Gerold Schuler, one commenter came to his defense:
Machiavellian Leaders? Is this how they reach that level were "going after them" requires commenters to exercise some caution?
There is power in the comment sections that is beyond the power of prayer. In prayer you throw something out there and you hope change will come. In the new world of online conversations we speak to actual people which gives us the ability to heighten awareness. Here on the CCS we try to "go after" bullshit in the world of science. We don't like that the bullshit and the master bullshitters make a career steeped in honesty nearly impossible. Real science is "bend over backwards to prove yourself wrong" honest, as Feynman instructed. The Machiavellian competition makes life hard on those who have a heightened sense of fairness. The comment section is an outlet. It's a place to exchange ideas and challenge each other.
The real challenge for a website is to get visitors. Facebook has demonstrated the power of online traffic. Huffington Post also made a fortune by getting people talking. The comments online are different than the comments you make at a cocktail party. They are different than the comments made at a cancer conference. They are more honest. Less intelligent in general but more honest. Perhaps the science community needs to purposely "go after" the illusion of intelligence and open the doors to the "back and forth" one sees in the comment sections. We might get a little more honesty, thus wealth, into our system.
That's a comment from this article written by Derek Lowe. I came across another comment from Dereks blog, "In the Pipeline" that lead me to another blog by the commenter. He discusses why we have so many layoffs in pharma R&D:
The longer answer is that we don’t understand what’s going on inside cells and organisms well enough to even know what we want a drug to target.If you put the two comments together to try and solve the problems of drug discovery you have got something that no one wants to admit. We take the people we train to understand what's going on inside cells and organisms and we put them to work doing something their education can't help them do. The companies use the credentials of their scientific employees for purposes other than conducting science.
I enjoy reading Xconomy every day. Mostly I'm looking for stories of the Cargo Cults of Seattle not getting their cargo. When I conjure the image of the natives of a cargo cult gazing to the skies during their ceremonies, looking for the big metal birds carrying cargo inside, I think of Xconomy as the sky. Sadly they don't illicit many comments. The lack of an active conversation indicates that people are not engaged.
One of the criticisms of the commenters is that they are often anonymous. Comments are little blurbs from self appointed "wise old sages" who have to get their words out. Why don't they tell us who they are? Some are picking a fight. Some are expressing their concern. Some are just trying to be witty. Not everyone accomplishes their goal but the anonymity makes the possibility of failure a risk they are willing to take. The anonymity can lead to troll behavior but it can also lead to insights we wouldn't not have had on our own with the article. Anonymity is what we see from many scientists. They are absent from the lab and the many failed experiments based on their ideas. If you were to look into the laboratory notebooks of the young people who conduct research inside the lab you will find no mention of who told them to do the work. There will be no introduction outlining the thinking of the actual thinkers. Anonymity is a tool we all use.
Some comments are interesting in their defense of Cargo Cult thinking. In a recent retraction from Gerold Schuler, one commenter came to his defense:
Unless I am mistaken, Dieckmann is the corresponding author on this paper, so some caution should be exercised when going after Schuler.The commenter is "going after" another commenter. Going after people is common in the comment section. Going after a big time scientist is not common. They are exalted leaders. We here on the CCS recognize the amount of bullshit being put forth by our exalted leaders and we see no reason to mitigate ones speech when commenting online about their bullshit. Another commenter adds to the conversation about Gerold:
As early as 1997 the investigations started on some of the german investigators. Here is an example:Nature 387, 750 (19 June 1997) | and in 2000Abbott A: German fraud inquiry casts a wider net of suspicion…Nature 405, 871-872 (22 June 2000) | doi:10.1038/35016207Few names included in this report are currently directors of institutes…
Machiavellian Leaders? Is this how they reach that level were "going after them" requires commenters to exercise some caution?
There is power in the comment sections that is beyond the power of prayer. In prayer you throw something out there and you hope change will come. In the new world of online conversations we speak to actual people which gives us the ability to heighten awareness. Here on the CCS we try to "go after" bullshit in the world of science. We don't like that the bullshit and the master bullshitters make a career steeped in honesty nearly impossible. Real science is "bend over backwards to prove yourself wrong" honest, as Feynman instructed. The Machiavellian competition makes life hard on those who have a heightened sense of fairness. The comment section is an outlet. It's a place to exchange ideas and challenge each other.
The real challenge for a website is to get visitors. Facebook has demonstrated the power of online traffic. Huffington Post also made a fortune by getting people talking. The comments online are different than the comments you make at a cocktail party. They are different than the comments made at a cancer conference. They are more honest. Less intelligent in general but more honest. Perhaps the science community needs to purposely "go after" the illusion of intelligence and open the doors to the "back and forth" one sees in the comment sections. We might get a little more honesty, thus wealth, into our system.
Tuesday, May 22, 2012
Investments Gone Bad
Ipierian is now an Antibody company!
Ipierian, founded in July of 2009, is the combination of two companies, Pierian and iZumi Bio. Pierian was co-founded by George Daley, Doug Melton and Lee Rubin, from the Harvard Stem Cell Institute. iZumi Bio came with the leadership of Corey Goodman, chairman, and John Walker, CEO. John Walker served as a Director at Cargo Cult favorite, Geron.
iPierian’s has had four CEOs John Walker, Mike Venuti, Peter Van Vlasselaer and now Nancy Stagliano. The chief technical officer, Berta Strulovici, exited the company shortly before Venuti. The heads of finance, business development, and legal/intellectual property left shortly after Venuti. A few weeks later Corey Goodman resigned his position as chairman of the board and Doug Melton, gave up his role as a scientific advisor.
Originally the business plan was to use their stem cell technology as a tool for screening new drug candidates, and selling their services to Big Pharma. The company’s technology is used to coax ordinary adult cells into a stem-cell like state. The cells are known as induced pluripotent stem cells (iPSCs). After an iPSC line has been differentiated into the cell types of interest, a disease phenotype is investigated, revealing a disease-relevant difference between the patient-derived cells and those from healthy controls. From this disease phenotype, cell-based assays are developed to enable the discovery and validation of novel targets and molecules.
Ipierian, founded in July of 2009, is the combination of two companies, Pierian and iZumi Bio. Pierian was co-founded by George Daley, Doug Melton and Lee Rubin, from the Harvard Stem Cell Institute. iZumi Bio came with the leadership of Corey Goodman, chairman, and John Walker, CEO. John Walker served as a Director at Cargo Cult favorite, Geron.
iPierian’s has had four CEOs John Walker, Mike Venuti, Peter Van Vlasselaer and now Nancy Stagliano. The chief technical officer, Berta Strulovici, exited the company shortly before Venuti. The heads of finance, business development, and legal/intellectual property left shortly after Venuti. A few weeks later Corey Goodman resigned his position as chairman of the board and Doug Melton, gave up his role as a scientific advisor.
Originally the business plan was to use their stem cell technology as a tool for screening new drug candidates, and selling their services to Big Pharma. The company’s technology is used to coax ordinary adult cells into a stem-cell like state. The cells are known as induced pluripotent stem cells (iPSCs). After an iPSC line has been differentiated into the cell types of interest, a disease phenotype is investigated, revealing a disease-relevant difference between the patient-derived cells and those from healthy controls. From this disease phenotype, cell-based assays are developed to enable the discovery and validation of novel targets and molecules.
Enabling the discovery and validation of novel targets and molecules was the Cargo. The company was the airport. The Cargo never came. There was no wealth in the system. The airport has undergone several shake-ups in management and some remodeling of the runway. Since Big Pharma didn't buy into the airport, iPierian has no choice but to develop the drugs they were hoping big pharma would. We still have to wonder if underlying technology real or is it another fantastic narrative?
The big name scientists told a good story. The problems came when the narrative failed to fit the reality being faced in the laboratory. Without the promise coming true the executives began to fight. The company is now an antibody company with a stem cell twist. The new CEO, Nancy Stagliano is a neuroscientist by training. Her last startup (South San Francisco-based CytomX Therapeutics) is an antibody drug developer.
The only thing that matters is the ability of the technology to "enable the discovery and validation of novel targets and molecules". Management is secondary in the long term of this company.
iPierian has spent $50 million dollars to reach this point:
Look to the sky. Hope the planes come.
iPierian has spent $50 million dollars to reach this point:
iPierian used its stem cell technology in recent months which has given it new insights about targets to go after on the Tau protein and in the Complement pathway.
- Nancy StaglianoRecent months? I guess the first few years were spent firing CEOs. The latest CEO was busy on her startup CytomX Therapeutics.
Our novel platform represents a transformational drug discovery and development approach.That sounds familiar. The chairman of the board is also the chairman of Geron! Why did Nancy leave CytomX? Why did the iPierian leaders abandon their ship? Who is suppose to solve the problems created by the others? I don't have much hope that iPierian is not Cargo Cult. All of the signs are there. The founders are gone. The new leaders are doing what they did at their last job. Everyone at the top seems to have worked with each other before. That wouldn't be a bad thing if this were a more successful industry. Lots of money has been wasted and people are trying to get some of it back. Think gambling. The most difficult problems facing the company is in drug discovery. All of the PhDs from the best schools are out trying to get money from investors. The laboratory staff have been handed an exact path that they must take to success. If they fail, they lose their jobs. Money is running out so they had all better start succeeding.
Look to the sky. Hope the planes come.
Wednesday, May 16, 2012
Books
I've been reading a book written by the silent movie actor Douglas Fairbanks. It's called "Laugh and Live". It's written in a style that must have been popular back in the 20s and 30s. Very positive and nothing but self help advice from one of the most successful guys of that era. Fairbanks must have felt loved and he was giving back. I'm on a chapter now where he talks about good books.
It is the corniest book ever written but I love it. I'm probably the most negative guy that ever blogged. I know that I am a nattering nabob of negativity and that people are turned off by that energy. That is why I read Douglas Fairbanks and Dale Carnegie. I, more than most, need to be reminded that reality is what we perceive. Science is not just what we perceive but pointing out how everyone is wrong all the time is a bummer.
Still, some of my favorite books seem to point to fallacy of reasoning. A Drunkards Walk, Wrong, How We Know What Isn't So, On Bullshit and Everything Is Obvious Once You Know the Answer, are just a few of the books that have inspired me to become a more critical thinker and disregard fears of turning people off of my message. Den of Thieves, The Big Short, and 13 Bankers are some of my favorite books on people who succeed while simultaneously driving their industry into the ground. I read biographies like "I Fatty" about the rise and fall of Roscoe "Fatty" Arbuckle. Somehow his tragedy is more interesting than the mundane existence of a biotech guy destined to live an unexamined life. I'm a devout atheist but I don't care to read the latest books on the subject. It is uninteresting because I don't need any reasoning to help me clear up any thoughts on supernatural beings. I read James Randis Flim Flam and I think it's a book that should be mandatory reading at every college in the U.S. He touches on how people believe and why they fight like hell to believe in things they want to believe in, in spite of the facts. I like Malcolm Gladwell even though, as one reader informed me, is a bit of a Cargo Cult social scientist himself. Nonetheless, he has interesting notions and it makes you think. He led me to The Checklist Manifesto. Imagine the complexity of building a skyscraper or running a busy restaurant. Why is biotech so simple and such a failure? I like reading about old Hollywood. Flapper, I Fatty, Minutes of the Last Meeting, Good Night Sweet Prince, Hollywoods Hellfire Club, were all good. These people also led interesting lives and in the end they grew old and came back down to earth. They were human beings that we held up as people we want to be. In examining their lives we get an idea of who we are. Imperfect human beings who have to get up and go to work.
It's clear that I don't read much fiction. Just what I read in the science journals. Wa wa wah! Debbie Downer. What Fairbanks had to say about books is very true. They inspire us and give us thoughts that we wouldn't have on our own. That is what eats at me with modern day science. There are too many intuitive thoughts that need to be proven. Upon examination you find out that those thoughts were too simple. That is when my mind starts to search for explanations. That is also the time I'm sent back into the lab to get the data to fit the preconceived notions. The narratives of the scientists that I've worked for was fiction. Reality is so much more interesting. Without coming to an understanding of the human mind and why we believe such nonsense, why so many people get away with bullshit and rise to the top is hard to fathom. If it's hard to fathom, I'm right there, ready to take notes.
The world is full of diversions that are known to be fiction. Movies, sit coms, and books. Other things are bullshit passed off as reality such as John Edward talking to dead people. I don't mind it because I can avoid it if I don't find it amusing. What I mind is the Flim Flam that has seeped into the world where I go to get away from fiction. I want my reality to be challenging. I want to struggle to understand until one day it all hits me like a ton of bricks and I'm blown away by the amazing world that I live in. I'm not just a negative guy. I'm truly interested in this world and how it works.
Books by such men as Marden and Hubbard are great generators of the electricity of doing things. They have put into words those innermost emotions which are the instruments of success. They point out a way we may safely follow. They loan us inspiration which causes us to act for ourselves. They give us thoughts that are useful and practical which we never would have gained by virtue of our own reasoning power.
It is the corniest book ever written but I love it. I'm probably the most negative guy that ever blogged. I know that I am a nattering nabob of negativity and that people are turned off by that energy. That is why I read Douglas Fairbanks and Dale Carnegie. I, more than most, need to be reminded that reality is what we perceive. Science is not just what we perceive but pointing out how everyone is wrong all the time is a bummer.
Still, some of my favorite books seem to point to fallacy of reasoning. A Drunkards Walk, Wrong, How We Know What Isn't So, On Bullshit and Everything Is Obvious Once You Know the Answer, are just a few of the books that have inspired me to become a more critical thinker and disregard fears of turning people off of my message. Den of Thieves, The Big Short, and 13 Bankers are some of my favorite books on people who succeed while simultaneously driving their industry into the ground. I read biographies like "I Fatty" about the rise and fall of Roscoe "Fatty" Arbuckle. Somehow his tragedy is more interesting than the mundane existence of a biotech guy destined to live an unexamined life. I'm a devout atheist but I don't care to read the latest books on the subject. It is uninteresting because I don't need any reasoning to help me clear up any thoughts on supernatural beings. I read James Randis Flim Flam and I think it's a book that should be mandatory reading at every college in the U.S. He touches on how people believe and why they fight like hell to believe in things they want to believe in, in spite of the facts. I like Malcolm Gladwell even though, as one reader informed me, is a bit of a Cargo Cult social scientist himself. Nonetheless, he has interesting notions and it makes you think. He led me to The Checklist Manifesto. Imagine the complexity of building a skyscraper or running a busy restaurant. Why is biotech so simple and such a failure? I like reading about old Hollywood. Flapper, I Fatty, Minutes of the Last Meeting, Good Night Sweet Prince, Hollywoods Hellfire Club, were all good. These people also led interesting lives and in the end they grew old and came back down to earth. They were human beings that we held up as people we want to be. In examining their lives we get an idea of who we are. Imperfect human beings who have to get up and go to work.
It's clear that I don't read much fiction. Just what I read in the science journals. Wa wa wah! Debbie Downer. What Fairbanks had to say about books is very true. They inspire us and give us thoughts that we wouldn't have on our own. That is what eats at me with modern day science. There are too many intuitive thoughts that need to be proven. Upon examination you find out that those thoughts were too simple. That is when my mind starts to search for explanations. That is also the time I'm sent back into the lab to get the data to fit the preconceived notions. The narratives of the scientists that I've worked for was fiction. Reality is so much more interesting. Without coming to an understanding of the human mind and why we believe such nonsense, why so many people get away with bullshit and rise to the top is hard to fathom. If it's hard to fathom, I'm right there, ready to take notes.
The world is full of diversions that are known to be fiction. Movies, sit coms, and books. Other things are bullshit passed off as reality such as John Edward talking to dead people. I don't mind it because I can avoid it if I don't find it amusing. What I mind is the Flim Flam that has seeped into the world where I go to get away from fiction. I want my reality to be challenging. I want to struggle to understand until one day it all hits me like a ton of bricks and I'm blown away by the amazing world that I live in. I'm not just a negative guy. I'm truly interested in this world and how it works.
Tuesday, May 15, 2012
The Amgen Study
Why were 47 out of 53 landmark oncology papers studied by Amgen scientists found to be non-reproducible?
Six of the papers, 11.3% were reproducible. The assumption we should all have at this point is that around 90% of published papers are not reproducible. The Amgen study should have expected these results. The recent AACR annual meeting should have contained 90% non-reproducible information.
Each new issue of Nature, Cell and Science should have 90% non-reproducible information. The ten percent that can be used to develop a technology or advance human understanding, is science. The 90% is cargo cult, fraud, bullshit, honest mistakes, accidental or some form of fooling ourselves.
This blog is about both sides, but mostly about studying the 90%. I chose the analogy of Cargo Cults because it requires a religious type of mind to participate in the 90%. I talk about bullshit, in a serious way (ala Harry G. Franfurt, philosophy professor at Princeton), because I believe that is what the leaders are up to. The whole blog boils down to understanding the way in which we participate in non-reproducible "scientific" research and why so many defend the practice.
We begin with a narrative. Ideas get kicked around. A certain percent of those ideas get put to the test in the laboratory. The scientists (creators of the narrative) do not go into the lab and verify the research they are building upon. They do not go into the lab at any point. They send in younger weaker minds to retrieve specific results. Once the data is in it is applied to the narrative and used for writing a paper. Once published the idea must be advanced, preferably by others, to validate the mind (and career) of the person who came up with the idea.
I'd like to recount the journey of one idea and how it landed in the 90% group. It's an old story that I've told in many ways on this blog but it haunts me.
My story is about a small biotech. The company was in existence to sell an antibody against denatured type IV collagen. The mechanism of action was based on an unproven theory, the idea.
I participated in several mouse studies where it was proven to me that the antibody did not have an effect on tumor size or growth. When the mouse studies showed no effect on tumor size they simply re-measured. In their minds this was not dishonest. This is precisely the kind of research that the scientists at Amben would have been unable to reproduce. Our initial report to the scientists provided no reduction in tumor size, compared to the PBS group. A paper was later published with a 57% reduction. I'm not sure if they used the re-measured data but it was the same drug on the same mice and tumor cells.
The efficacy of this antibody was presented at AACR in 2006. Also in 2006 Micromet filed an IND. There is no information on the fate of the antibody. It was last reported on in 2007. My own work on the drug took place in the early 2000s. It was a painful experience. We lost a few good men. Eventually we handed the whole kit and kaboodle over to a group of "scientists" who knew what the narrative needed from the lab.
The people who conducted this research were intelligent people. They knew how to make their presence known in a meeting. They had impressive resumes and advanced science degrees. Their papers were well thought out and they competed well for publication. All of the authors in the 53 landmark studies evaluated by Amgen were of the same breed. Back woods hillbillies wouldn't be able to do what these men and women do. There is a skill involved. There is a culture to fit into. The knowledge of antibody structure, humanization and so on are all complicated concepts that require a certain mental capacity. My bosses had it. The papers and the posters and all of the money are of little value now however. If the goal was ever to put a drug on the market and reduce the size of tumors in cancer patients, they did not have enough intelligence. That intelligence tells you that the truth is the only way to move forward without one day shutting down because you missed something. We were always missing something and we knew it. In the Amgen study, that something was discovered in 47 out of 53 papers. We were always publishing and telling people about things we knew were not reproducible. We were smart and we knew how to avoid having to go back over our work.
What then happened to the research papers from the Amgen study?
Six of the papers, 11.3% were reproducible. The assumption we should all have at this point is that around 90% of published papers are not reproducible. The Amgen study should have expected these results. The recent AACR annual meeting should have contained 90% non-reproducible information.
Each new issue of Nature, Cell and Science should have 90% non-reproducible information. The ten percent that can be used to develop a technology or advance human understanding, is science. The 90% is cargo cult, fraud, bullshit, honest mistakes, accidental or some form of fooling ourselves.
This blog is about both sides, but mostly about studying the 90%. I chose the analogy of Cargo Cults because it requires a religious type of mind to participate in the 90%. I talk about bullshit, in a serious way (ala Harry G. Franfurt, philosophy professor at Princeton), because I believe that is what the leaders are up to. The whole blog boils down to understanding the way in which we participate in non-reproducible "scientific" research and why so many defend the practice.
We begin with a narrative. Ideas get kicked around. A certain percent of those ideas get put to the test in the laboratory. The scientists (creators of the narrative) do not go into the lab and verify the research they are building upon. They do not go into the lab at any point. They send in younger weaker minds to retrieve specific results. Once the data is in it is applied to the narrative and used for writing a paper. Once published the idea must be advanced, preferably by others, to validate the mind (and career) of the person who came up with the idea.
I'd like to recount the journey of one idea and how it landed in the 90% group. It's an old story that I've told in many ways on this blog but it haunts me.
My story is about a small biotech. The company was in existence to sell an antibody against denatured type IV collagen. The mechanism of action was based on an unproven theory, the idea.
A humanized, affinity-matured IgG1 and its parental murine IgM have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models.The, "and thereby" was the whole idea. As a tumor spreads it tears into the structural matrix of our bodies. Most of that matrix consists of collagen. Therefore, angiogenesis is working on or with the surface of that matrix and its collagen, right where the tumors are spreading. But that was just a nice narrative. They skipped past the science part of proving the theory, made an antibody and swung for a home run.
I participated in several mouse studies where it was proven to me that the antibody did not have an effect on tumor size or growth. When the mouse studies showed no effect on tumor size they simply re-measured. In their minds this was not dishonest. This is precisely the kind of research that the scientists at Amben would have been unable to reproduce. Our initial report to the scientists provided no reduction in tumor size, compared to the PBS group. A paper was later published with a 57% reduction. I'm not sure if they used the re-measured data but it was the same drug on the same mice and tumor cells.
The efficacy of this antibody was presented at AACR in 2006. Also in 2006 Micromet filed an IND. There is no information on the fate of the antibody. It was last reported on in 2007. My own work on the drug took place in the early 2000s. It was a painful experience. We lost a few good men. Eventually we handed the whole kit and kaboodle over to a group of "scientists" who knew what the narrative needed from the lab.
The people who conducted this research were intelligent people. They knew how to make their presence known in a meeting. They had impressive resumes and advanced science degrees. Their papers were well thought out and they competed well for publication. All of the authors in the 53 landmark studies evaluated by Amgen were of the same breed. Back woods hillbillies wouldn't be able to do what these men and women do. There is a skill involved. There is a culture to fit into. The knowledge of antibody structure, humanization and so on are all complicated concepts that require a certain mental capacity. My bosses had it. The papers and the posters and all of the money are of little value now however. If the goal was ever to put a drug on the market and reduce the size of tumors in cancer patients, they did not have enough intelligence. That intelligence tells you that the truth is the only way to move forward without one day shutting down because you missed something. We were always missing something and we knew it. In the Amgen study, that something was discovered in 47 out of 53 papers. We were always publishing and telling people about things we knew were not reproducible. We were smart and we knew how to avoid having to go back over our work.
What then happened to the research papers from the Amgen study?
The Amgen scientists approached the papers' original authors to discuss findings and sometimes borrowed materials to repeat the experiments. In some cases, those authors required them to sign an agreement that they would not disclose their findings about specific papers. Begley and Ellis were therefore not free to identify the irreproducible papers — a fact that the Comment should have mentioned.
Nature, like most journals, requires authors of research papers to make their data available on request. In this less formal Comment, we chose not to enforce this requirement so that Begley and Ellis could abide by the legal agreements.
The scientists at Amgen could not have implemented their study had they reserved the right to reveal the outcome for individual papers. The Comment highlights important systemic problems in preclinical cancer research, which we felt appropriate to communicate to our readers, even though the authors could not disclose the studies in question.
Monday, May 14, 2012
Bullshit Man!
I'm reading the book "On Bullshit" by Harry G. Franfurt.
In the Amgen paper regarding 53 landmark oncology papers we learned that one author published the results of one experiment that was tried 6 times. The author admitted that the reported results made for the best narrative. That was the reason he published his result. This is a lack of connection to a concern with truth.
We've hit some dark times but bullshit remains safely behind the wall of, "It's science".
Would BullshitMan help?
That is why she cannot be regarded as lying; for she does not presume that she knows the truth, and therefore she cannot be deliberately promulgating a proposition that she presumes to be false: Her statement is grounded neither in a belief that it is true nor, as a lie must be, in a belief that it is not true. It is just this lack of connection to a concern with truth - this indifference to how things really are - that I regard as of the essence of bullshit.The business of science fails when they have that lack of connection to a concern with truth. What the many people whom I have highlighted on this blog have taught us is that the truth is not a necessary part of a successful scientific career in academia or industry. Life sciences are most successfully pursued by those with the best bullshitting skills. They do not start off on a journey to find the truth. At the same time they are not deliberately being dishonest. They see the success criteria for a Cargo Cult and they know it is within their skill set to reach the higher ranks.
In the Amgen paper regarding 53 landmark oncology papers we learned that one author published the results of one experiment that was tried 6 times. The author admitted that the reported results made for the best narrative. That was the reason he published his result. This is a lack of connection to a concern with truth.
We've hit some dark times but bullshit remains safely behind the wall of, "It's science".
Would BullshitMan help?
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