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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

Trustus Data

How did they get our data from the angiogensis CAM assay?

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:

  1. Our industry consists of simple, complicated, complex and chaotic areas.  The science is more complicated than the business, not the other way around. 
  2. Biotechnology in general does not train it's people. We assume that people are trained for biotechnology careers at the Universities they attend.
  3. 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.
  4. 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.
  5. 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:
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.
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:
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!