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Wednesday, November 28, 2012

Pills for Fat People

It's been a while since the leaders have offered up an anti-obesity pill. The FDA caught a little flack for the Fen Phen fiasco. The latest prescription diet pill, Vivus' Qsymia, came out recently but has seen slow sales. Maybe the diet and exercise secret has been let out. The real reason for this post however is something I came across while looking into the Vivus pill. I thought maybe Qsymia was PYY. Who would be so foolish as to try and make PYY into a diet pill and would the FDA approve such a thing. It turns out that leaders at the Novo Nordisk Cargo Cult put together a PYY program in 2011.

We first brought up the PYY story in 2006 when the now defunct Nastech crashed and burned in their attempt to make a drug out of the hormone PYY. In this post I pointed out the absurdity of this biotech company attempting to hammer this square peg through a round hole. Merck entered into a collaboration with Nastech but found no reason to continue pumping money into the project.

Novo Nordisk is of course an important and useful company, not a simple Cargo Cult. They have the experience and expertise to provide useful insulin products. They have plenty to teach us here in the Cargo Cults. At some point however, all companies run into a Cargo Cult area. They have to do research and someone will make the decision that will set newly employed scientific team on a path of no return. These new scientists will have only one choice, make PYY a drug or find a new job.

The question for the Cargo Cult Scientist is whether or not PYY is involved in satiety. Many scientist don't believe the research. As I pointed out long ago, not only does PYY fail to impress in the nasal spray form, it might just be another N-Ray in the life sciences.
Science 9 July 2004:Vol. 305. no. 5681, pp. 158 - 159DOI: 10.1126/science.305.5681.158

OBESITY RESEARCH:Labs Fail to Reproduce Protein's Appetite-Suppressing Effects

by Trisha Gura

"In an unusual joint letter in Nature this week, more than 40 scientists announced that they cannot reproduce the central findings of a 2002 Nature paper that showed that a molecule called peptide YY3-36, when injected into rodents, dampens appetite for 12 hours or more."
Once again we have a candidate for the Reproducibility Initiave! What would they do differently than Nastech, Merck, Novo, Dr. Bloom or any of the 40 scientists in the Nature letter lised above? Who could help resolve this issue? Let Novo take a stab at this molecule. But what about basic research? Is PYY what we think it is? Can anyone help us place bets on Novos chances?

Saturday, November 17, 2012

Alnylam and Tekmira RNAi Cargo Delivery

Tekmira and Alnylam made the news this week after settling their legal dispute over the use of Tekmiras RNAi delivery technology. According to Xconomy they have:
agreed to resolve all their ongoing litigation, and that the companies have restructured and clarified their relationship, so that Alnylam still has a license to Tekmira’s lipid-nanoparticle delivery technology.
For $65 million dollars Alnylam gets out of the manufacturing contract and they have restructured the licensing agreement for the use of the Tekmira delivery technology.  In 2007 the two companies formed their alliance and further added to it in 2009 with a manufacturing agreement. Then came the accusations from Tekmira that Alnylam was abusing the relationship by using Tekmiras intellectual property to create their own delivery system and sharing information with a third party. One has to wonder why Alnylam would feel the need to improve such an expensive technology that they had researched and selected over the many other options. 

The way forward for these companies? Alnylam is going to take over the manufacturing and Tekmira is going to develop drugs. Xconomy, ever the biotech cheerleaders with a special fondness for Alnylam describes the latest fiasco:

But now each company is on its own, and can’t count on the other side for help. Instead of relying on Tekmira as a contract manufacturer, Alnylam plans to focus on doing in-house manufacturing of the lipid-nanoparticles that it needs to deliver RNAi drugs into cells. The company has been building up that capability for a year, he says, and it has enough capacity to make batches of its lead drug candidate ALN-TTR02 for clinical trials, and into “early commercialization” of the product, Maraganore says. Alnylam also has been focusing on building up internal R&D strength for RNAi delivery. Alnylam’s in-house delivery group developed some new technology that is enabling it to start the first clinical trials later this year with an RNAi drug can be given through a subcutaneous injection—which goes just beneath the skin and is generally more convenient than intravenous delivery.
They have built up manufacturing AND delivery R&D? After laying off a third of their work force in 2010 they turned around and laid off a third of the remaining tribe in 2012. According to Julie M. Donnely at the Boston Business Journal: 
The layoffs include high-level positions including senior director of biotherapeutics, a senior director of business development, a senior director of pharma operations and a senior director of information technology. Nine senior scientists and 14 research associates positions will also be eliminated.
When did Alnylam make this commitment to improving their manufacturing capabilities? What did they do? How much did they invest? Who did they snag from what CMO? What about the delivery system they have developed? What was wrong with Tekmiras? They aren't getting rid of the technology. They've only restructured the agreement. Now they have yet another delivery technology? What is going on with the delivery of RNAi at Alnylam?

Of course we don't really know anything about actual data at Alnylam or Tekmira. Tekmiras claim to become a drug development company is equally as bizarre as the continued existence of Alnylam. They deserved each other. With no clear path, each company will continue to zig zag their way to oblivion. RNAi continues to be our number one Cargo Cult.

Tuesday, November 13, 2012

Tamiflu You

We know that Cargo Cults do not actually succeed at obtaining cargo from airplanes that they summon to land upon the runways. Likewise the leaders of pharma cargo cults know that they won't make it rich curing or even effectively treating disease. Not that they wouldn't want to have effective drugs. It is actaully very difficult to put together a group of humans and ask them to participate in a group think experiment in which the outcome would be to cure some disease. Endpoints become the goal. Convincing the FDA to approve a drug by paving your own path then taking the FDA on a walk down the path is a skill. A little insider help can't hurt.

The real issue we have always had with Tamiflu is the basic concept that such a vaccine would be worth so much. Annual flu vaccines are merely random guesses that make people lots of money. All you need is a group of leaders to give their stamp of approval on the vaccine. Why Tamiflu?

The latest in this saga is an example of how the leaders operate and to whom they must answer. No one!
Last year, Tamiflu was included in a list of 'essential medicines' by the World Health Organization, a list that often prompts governments or donor agencies to buy the drug.
Our leaders have the clout to get governments to buy drugs but they lack to ability to get evidence that they work. In a democracy such as ours we don't get to vote on things like this.

Some might think this is switching gears too fast but stay with me. RNAi has long been my own personal Tamiflu. It doesn't work. It's useless. The latest bit of evidence here demonstrates that large profits can be made by useless things. And it all takes place on the Cargo Cults of biotech/pharma.

Our Cargo Cult leaders create huge promises and ask for huge profits. When they lose they go easy on us and only ask for less millions. They stop selling us the crap and keep the profits they already made. The cargo never comes.

Sunday, November 11, 2012

Harry Makopolis

We need a guy like this:

We each have a story to tell. It leads to one of the biggest sins against science of our time. It's not just Silvia Bulfone-Paus or David Baltimore and their bullying leadership. Cumulatively we have a story that leads to a scam that has cost society hundreds of times more than Madoff. What we report in the journals is too good to be true. We aren't all that scientific. We aren't making investors money. We aren't having healthy careers. Something is a amiss. But our leaders are doing quite well. Where could we go to tell our stories and confess our sins against science? Would anyone listen?

Sinatra Was A Tough Guy

When you live a life like Frank Sinatra you leave behind plenty of film footage. There is one piece that I've seen on two separate documentaries. In the first documentary you see Sinatra surrounded by a bunch of burly men. They are rehearsing a scene for a movie while Frank is recording music at Capital Records. The thesis of this scene in the documentary is that Frank is a workaholic. In the next documentary you have the same film footage. It starts just when the rehearsing begins. The scene Frank and friends are going over is one where Frank is playing a tough guy. He calls one of the other men out while the rest stand back in deference to the boss. In this documentary they leave out the fact that the men are only acting. The thesis is that Frank really is the tough guy he is playing. 

The point here of course, is that context matters. Bullshitting, as I've mentioned, does not care about the truth. Bullshitting can take something that really happened, such as this Sinatra scene, and tell a number of stories. In everyday life we fall prey to such deceptions but they don't really harm people who take an active interest. In time, any Sinatra fan will come across the actual scene that took place in the first documentary. They will learn the truth. Frank is still a tough guy but he's not that big of a bully. 

What about stories that come from the lab of a published group of scientists? The stories that come out in the journals allegedly depict something that took place in a laboratory. The scientists who dictate the thesis behind the published work are not the guys who work in the lab. They are more like the producers of the latter Sinatra documentary. They begin with a thesis, they look for data/information that supports the thesis, and they present what they find. Some editing is required. The data/information that is left out often times will tell a different story. One in opposition to the original thesis. What then are the safeguards employed by journal editors and peer reviewers to avoid believing the wrong story?

I have written up a few of my experiences. Here is a cancer study using an antibody against denatured collagen. Here is a phage library that contains the holy grail peptide of RNAi drug delivery. Here is a computer program that pulls out drug targets from published information. Here is the origen of Prusiners prion theory. In each case I sat watching as a laboratory worker highly interested in the big picture science. What role does collagen play in tumor growth? How do we follow a drug molecule after it enters the body? Can we use published data, do we have enough information in the books, to begin to mine for molecules in a disease pathway. On each occasion I watched from my laboratory seat. I saw the whole scene, then read the version of the story that was published. Like Sinatra surrounded by his cronies, we had a scene. We had only to manipulate that scene, edit out the stuff that would hurt the narrative, and offer it up to the journals. Eventually some journal would accept the bullshit, and we could put the publication down on our resumes. After the publications, and maybe a patent or two, we would flounder with what we had put forth. We had to employ the political skill of saving face and distancing ourselves from what we said. If we couldn't use our science to advance our project goals, what were the chances of others succeeding? That was none of our business.

The cases I've listed are all MIA, missing in action. I can't track down the outcome of the work in which I took part. Long ago I had a role but I was removed through company buy-outs, lay-offs, temporary suspensions of projects and me just up and leaving. There is only one project that remains. It is the biggest scam of all. It is the 50,000 liter manufacturing claim from a company that expresses antibodies in yeast. The claim is bullshit. The bullshit claim was accepted by one of the major pharmaceutical companies. They shelled out over $100 million so far because the antibody may have a chance in demonstrating efficacy in comparison to the already approved drug. The question then becomes, can we make the drug in a cost effective manner to steal away sales from the competition? Like Sinatra and the tough guy scene, does the bullshit deception damn the project? Will that claim lead to another MIA biotech product? Would a full disclosure of the problems with manufacturing have prevented the potential loss of capital towards yet another biotech product? 

The potential loss in faith is something that is affecting everyone in biotech/pharma. Job losses have been massive. The promise of the science has not been realized by the scientists. We have to take some of the blame ourselves for not standing up and pointing out that truth. If we were in the room when Sinatra was rehearsing and someone is telling the story as if it were Sinatra being himself, someone should state the truth. Who will listen? Like the MIA projects from my own past, one has to wonder if anyone cares? Hundreds of millions of dollars of other peoples money is also MIA. I know where a lot of that money went. Cars, houses, and plenty of nice things by the people who were in the proverbial room when Sinatra was rehearsing. We all knew it was acting and we helped our leaders tell the world it was real. We get in our new cars and drive to our nice homes and hope we never get caught. 

Wednesday, November 07, 2012

Cutting Edge World Class Science Leader Wanted

I was watching the election coverage last night. Billions of dollars per candidate were spent and we are pretty much back to the same old people running the show. One of the talking heads lamented, "What could we have done by putting that money into medical research?" As if money equals progress.

Here is a prime example of how it does not. Intellectual ventures is a patent troll company that has made plenty of money from nonsensical science patents. They've decided to get into the biotech biz. Step one: Find someone who knows what this biotech BS is all about. They may have had to hire a consultant to write up this job description since the world leading research team needs to be set up by the guy they hire. I've added a few notes in red:

Job Description

Intellectual Ventures Laboratory (IVL) discovers, invents & develops advanced technology solutions in a wide variety of fields. With broadly interdisciplinary teams of physicists, engineers, chemists, biologists, and physicians, we attack pressing technical problems in energy, medicine, communications, and global health.

Purpose of the Position:

The purpose of this position is to set up and lead a cutting edge and world class biotechnology laboratory to support new technology development projects in fields as diverse as medicine, food science, energy, and renewable chemicals.

They have figured out how to become cutting edge and world class. HIRE SOMEONE ELSE TO GET THE JOB DONE!!!  I hope the guy they hires doesn't realize that his genius could be spent on his own cutting edge world class laboratory.


•Position is for a project leader who will be expected to develop clearly defined projects, lead small groups of scientists and engineers to complete the projects, and clearly communicate expectations and results to project stakeholders.

This scientist must cleary define the projects that Intellectual Venture Labs envisions as being fan-fucking-tastic. Beyond that IVL does not really know what their new genius has in mind. They do know that it will involve small groups of scientists and engineers. 

•Must demonstrate a broad knowledge base in the field of applied molecular biology and experience using project management tools to complete important projects in the field

They need a molecular biologist to lead engineers?
•Position is primarily a project leader role which requires frequent and clear communication with multiple internal and external customers and stakeholders.

•Limited travel required

•Must be able to lead biotechnology projects that broadly require manipulation of DNA, proteins, microorganism, and possibly plant and animal cells to solve diverse science and technology problems.

I'm getting the idea that they want someone to lead projects. Is the science getting a little broad here? The scientist must be an expert in molecular biology. This kind of scientist will manipulate DNA, proteins, microogranisms, and maybe... just maybe, plant and animal cells. These are the tools that will solve science and technology problems.  The "how?" is up to the new hire.

•Must help specify, purchase, set up, operate, and maintain molecular biology equipment and instrumentation as needed.

Ever seen a PI set up, operate and maintain lab equipment? What they have not specified yet is that they want a principal investigator with job functions at the RA level. 

•Must have experience leading teams which routinely perform several of the following kinds of tasks in the laboratory to solve problems:

•DNA manipulations including primer and gene design, routine PCR, vector construction, high throughput library construction. Pretty advanced buzz words in the mol bio biz! 

•Optimization of heterologous expression of wild type and modified proteins in various types of host organisms

•Engineering host cells via gene integration and gene knock-outs.

•Use of fermenters to grow and use wild type and engineered microorganisms

•Use of analytical instruments such HPLC and UV-vis to characterize proteins and engineered cells. We need a PI who knows UV-vis! 

•Must work with other technical teams (chemistry, physics, engineering) and customers to identify biotechnology needs and design projects to efficiently solve problems. It sounds like they've already started designing a project. 

•Must develop, plan, staff, and complete independent research projects in applied molecular biology

•Must safely work with biological agents, chemicals and compressed gases and coach others to do the same

•Must keep detailed documentation for all work and communicate results in clearly composed reports and presentations. A PI with a lab book.

•Must assist with the organization of data and other literature for reports and other communications and in files on the company’s server.


Qualifications and Skills:

•Master’s or Ph.D. in a Biological or Chemical/Chemical Engineering science. Excellent attention to detail skills. Chemical/Chemical Engineer indeed! 
What does a chemical engineer know about molecular biology?

•Degree and research experience in field which required extensive use of molecular biology techniques.
Didn't they just specifiy what your degree had to be? 

•Education and work experience that demonstrates fundamental knowledge of biochemical and molecular biology concepts and use of diverse array of equipment and instrumentation to do lab work in these areas.
So... molecular biology is required?

•At least 5 years of industrial project management experience in an active applied molecular biology laboratory and demonstrated success at defining and then completing those projects on time and on budget.

•Excellent verbal, written, and interactive communication skills are required.

•Being comfortable with freedom to explore is required

I am sure I come across snarky. I can't help it. If the leaders judge us, why not judge them? This is their best effort in searching for the man or woman who will lead their cutting edge world class laboratory. The first thing the new scientist must do is make their small team cutting edge and world class. IVL has already started advertising their greatness. They designed their cargo cult airport. They just need a manager. It's up to the new guy to bring the cargo.  

Sunday, November 04, 2012

The Brain Drain

Long ago, the Allied forces built and ran the airports that the cargo cults still to this day try to emulate. The aeronautics, logistics, geography and so on were put together in a system that escaped the observations of the natives. They recreated only what their eyes saw from behind the palm trees.

Likewise, the scientists of long ago created bodies of knowledge in a manner that is not practiced by the Cargo Cults of modern science. The first thing they held dear was reproducibility. Usefullness beyond ones career. As Newton pointed out in Principia Mathematica:
Rule I. We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances.
Rule II. Therefore to the same natural effects we must, as far as possible, assign the same causes.
First, these scientists of yore had to apply the scientific method to conduct their research, form explanations and causes. After years of honing explanations and causes they organized and wrote down their thoughts in the form of a text. They all felt that their understanding of mathematics or the natural world was worthy of passing on to future generations. Newton was so impressed with himself that he wrote Principia Mathematica in latin to discourage the wrong people from bastardizing his work. The great scientists of yore knew they were right and they had great confidence that what they had to say was reproducible and extremely useful. Lacking computers, the large collections of paper with hand written information were organized and kept until they day they brought them to the publisher. Therefore the information was in a very precarious position. What if a fire broke out? The information had to sit inside their heads until it was put down on that highly flammable paper. Lucky for us it has survived.
What then can we say about the body of knowledge that has been formed through biotechnology? Thanks to computers, it can be kept safe, if only someone were to take the time to write about our science. Occasionally we get ancillary texts. Lars Hagel, has written the seminal work on downstream process development. It's not a philosophical piece on how biotechnology research works. It's about one technology that is required in the business. He has published two editions of "Handbook of Process Chromatography". This is an example of good science. Anyone who has a job in downstream process development needs to read this book. Lars Hagel put it all down for the industry and future generations. He is just one example of a modern scientist who has something to say, people willing to let him say it, and an audience willing to listen and learn.

What about an individual company? I've worked for five. All but one no longer exist. The one that does is among the worst offenders when it comes to creating a Cargo Cult culture. If they were to write a text book for the benefit of others what would it say? What is the path from nothing to a drug on the market? What is that drug, what does it do, and how did we figure that out? It is not a simple nor is it complex. It is complicated. Thus, we could write a text book that is understandable to most people with an interest in science. We're not talking about Principia Mathematica here. The reason this text will not be written however is because the "scientists", all of whom have PhDs from very good schools, are now businessmen. They do not have the same interests that scientists of yore had. Rather than a text book laying out a lifetime of science, they have a string of biotech companies and executive positions. They have money in the bank. Yet the world will not benefit from their lives.

Who will even bother to make an attempt to put down in writing the science of biotechnology 1980 to 2012? We have ancillary texts like Lars Hagels book but it's not biotechnology. It's chemistry. It's physics. It's math. Drug development biotechnology is science, business, FDA regulations, clinical trial enrollment, patents, human resources, milestone payments, contract organizations, alliance management, and on and on. Many of these things will not be relevant to future  generations. The FDA will change (it must). The laws will change. The investors and doctors will all have a different set of rules. So what can we write a text book about? How to clone a piece of DNA? There are ancillary text books on this subject as well. The complicated task of writing a text book for future generations on how to create a successful science/technology company should begin with a similar set of rules as Newton. By now we should know that there are limitations to what we can do. We should also know that reproducible work is essential.
The leaders of the actual Cargo Cults in the Pacific Islands could write a book on aeronautics. It would be fun to read. If each tribesman could write out a description of their daily duties we could begin to study the leaders. Therein is the beginning of our study of the Cargo Cults of biotechnology. The leaders have many things in common. Likewise the tribesmen have things in common, that distinguish them from the leaders. There are patterns to identify and write down. There are philosophies to follow such as the preference for sexy narratives over boring reproducible science. The study of  biotech Cargo Cults however is losing very important information. With every round of layoffs from Pfizer, Astra Zeneca and so on, we lose a handful of long term tribesmen (and some leaders) to their inability to carry on. They take with them a knowledge of a daily life that we can learn from. Some of us learn a great deal from our mistakes. Each tribesman can speak of the mistakes they've been involved in. They can speak about the culture of their tribe. They can give us job descriptions and their titles. Did each watchman wear the same coconut headset and what did they do with it?

Once the information is gathered we would have to sit down and sort it all out. What were the trends? Was there a common thread among the success stories that the failures were missing? In the real cargo cults we could point to the study of aeronautics being absent among the cults but present in the Allied forces. If we were martians looking at this world we would come to the conclusion that aeronautics was essential. Likewise, to take a case from my own experience, Lars Hagels knowledge in process chromatography is essential. The company I worked for did not believe so and they had to suffer great expense. It is still possible this aspect of the company will be their downfall. If so, we could have an essential element to write down in our text. It comes with a philosophy as well. Process chromatography is an area in which a drug development company must employ highly skilled people, just as an airplane manufacturer must hire aeronautical engineers.

Our story is ready to be written. If you've worked in the business and you think you have something to say, organize our thoughts. Offer them to PLOS ONE and the Reproducibility Initiative. Someday the cargo culture will begin to shift. Someday perhaps, when Susan Koman wants to invest their research dollars will skip the Cargo Cult minefield and invest in someone else. Imagine a multi-million dollar project that involves reproducing work and finding the most promising paths to walk down. Imagine having the first edition of a text that will help lead the way. We've spent the money. We have thousands of minds to tap into.

It's not fire that threatens our text. It is our own apathy.

Thursday, November 01, 2012

Who Wants It

I believe that future generations will look back on us as Feynman looked back to the middle ages:
During the Middle Ages there were all kinds of crazy ideas, such as that a piece of rhinoceros horn would increase potency. Then a method was discovered for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course, into science.
The idea of reproducing someone elses experiments is nothing new. What is new is the idea that such a project would create so much dissent. A piece of rhino horn used for erectile disfunction could be put to the test in a Viagra style study these days. It would be put to the test if some proponent of its use had the clout to get the research put in motion. Therein is the pickle we find ourselves in with reproducibility. The people with the clout are the ones whose work needs to be subjected to reproducibility studies.
Now when I talk about the actual Reproducibility Initiative I am using it as an example of one such effort to get the conversation started about what actaully takes place in the lives and careers of any modern day participant in the scientific world. I think any reproducible science, even boring science that doesn't rise to the sexy standards narrative science, is better than the cargo cult science. You can get rich, you can get published, but that is not the primary concern with this conversation. What I am thinking about is a Utopian world where the members of the cargo cult begin to be skeptics. They lose their jobs in the watch towers because, as their leaders informed them, they were not wearing the coconut antennas properly. They begin to question the antennas. They build confidence in their own ability to distinguish bullshit from the pile of clever sciencey narratives that their leaders pile on them. They discover a method for separating the ideas--to try one and see if it worked, and if it didn't work, to eliminate it.

Having started with this concept, that science began not so long ago with the idea of testing popular ideas, I'll address the comment from my last post. (Thanks for the comment btw)

As long as the incentives are not directed towards reproducibility, it won't be happen. The Amgen study was great but we didn't hear about until years after the original work and the authors had left the company and felt free to publish.
And of course we still don't know which studies or which labs were involved due to confidentiality agreements.
I'm not sure what is meant here. The incentives in reproducible science is that it leads to bigger and better things. We see so far because we stand on the shoulders of giants.

For academics funding is limiting and precious. If you tell an academic "here is $10,000 and you can spend it on reproducing your own work or you can spend it on a new project which will bring you more money and more publications", which will they choose?
Who would be so foolish as to give someone this choice? I've never worked with anyone who would volunteer for an outside reproducibility study of their own work. As I said at the end of my last post however, we have to be creative. Step out of the mindset of an academic scientist. Think in terms of a beaurocrat who decides on the NIH budget or an investor who wants to give biotech one more chance. You have a choice: Fund the same old guys who burned you back in the 90s and 2000s, or tap into a new paradigm. Only fund people who agree to have their work double checked. We're all only human. That is what the same old guys don't want you to know. Don't believe them. If they don't want the money, find someone else.
If you ask academics, all of them will insist to you that their work is reproducible so why would any of them consider trying to reproduce it?
Again, the academics are not the consumers (yet). They are the ones in whom we've lost faith. A Reproducibility Initiative must first do business with the consumers of good and bad science. The consumers can continue to lose money like they have in the past or they can try and see what certifiably reproducible work can do for them.

tldr: You don't get into Science and Nature by reproducing published research.
Again, no one is trying to get into Science and Nature here. They are trying to get Science and Nature to get into reproducible science.
Thanks to whomever this commenter was. You are absolutely correct with everything you said. The issues you bring up are the exact issues to attack. The question is how. Can we find a stunt like the Carnegie elephant crossing a steel bridge stunt? We have to be creative. The academic scientist is not the guy who wants a reproducibility group hanging over their research. In time however, the people with the money will come to find investments in reproducible science to be far more lucrative than the investments they made without this safety net. Soon scientists will have no choice, if they want funding, but to conduct the kind of work that will be subjected to reproducibility.

I know I'm only dreaming. But this is all just a thought experiment.