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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. 

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