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Scenario: Disasters Waiting To Happen

Meet Gillian Niher, M.D., Ph.D. She has developed a stellar reputation as an up-and- coming neuronal researcher. Her focus has been on therapies for neural injuries, primarily peripheral nerves. >From a brief teaching position at Smallville Medical School, she found a tenure-track position at NIH, in a lab with facilities in the NIH Clinical Center. Unfortunately, she was stuck for ideas for her next blockbuster study; though generally interested in a variety of cutting-edge technologies, she had not yet settled on one. Then, her very close college friend, Alan Prophet, Ph.D., came to Bethesda on a business trip, and stopped by. Over lunch, Alan told Gillian about his gene-therapy research at Tate State University (a private institution in Maryland that does not rely on grants from NIH to support its bioscience research, but several projects are funded by industry).

Alan mentioned that Tate State sponsored "spin-off" companies for professors who invent new bioscience products. He also mentioned that he was named as a co-inventor on a recently issued patent on the genetic sequence of a recently discovered neuronal growth factor. With support from Tate State, Alan and his colleagues created a small company called Neurion to develop this gene. They had found some support from a group of venture capitalists, who received a large share of corporate control in exchange for financing. The company had already succeeded using the gene in several in vitro models. They also had recently done some toxicity and efficacy tests in injured rats and rabbits, but the results were not yet public. Alan invited Gillian to visit Neurion’s facilities, and Gillian excitedly agreed.

Two weeks later, she went to Neurion’s small facilities near the Tate State campus. When she arrived, Alan told her that before he could give her a tour, she would have to sign a form the lawyers drafted to make sure trade secrets stayed secret, and Gillian agreed to comply. Then, Alan showed her preliminary data that demonstrated the growth factor was surprisingly effective in stimulating neuron regrowth, either when the growth factor protein was delivered directly to the site of neuronal injury, or when a plasmid incorporating the gene was applied to the extracellular matrix.

Impressed with these results, Gillian saw an opportunity to establish a collaboration: Neurion’s growth factor entering clinical trials at NIH. She consulted her Scientific Director about the project, and was pleased that he was very interested. Alan -- and his partners in Neurion -- were equally excited when she made that suggestion to them. Alan and Gillian quickly drafted a protocol for human trials, which was favorably received by Gillian’s Laboratory Chief and Scientific Director, as well as by the venture-capital group. Once Gillian signed some of Neurion’s forms, Neurion sent large amounts of GMP-grade materials for Gillian to use at NIH. The process of establishing the study appeared on the fast track to success.

Shortly after, while reviewing the final animal-study data Alan had provided, Gillian noticed two things Neurion had missed. First, the rabbits in the "control" group (those given only blank plasmid) had no noticeable neuronal growth -- that is, the number of nerve endings was unchanged with the injection of the plasmid -- but they seemed improved in terms of muscle movement and strength. Upon closer examination of the rabbits, she found that the original injured nerve endings had in fact regrown. In contrast, those rabbits that received the gene all had completely new nerves growing in addition to the original ones, and those rabbits that received nothing all had no neuronal stimulation at all. Something in the plasmid itself appeared to have activity. Second, she noticed that those rabbits receiving the gene had exuberant growth of neurons -- even in regions where all the original neurons were dead.

Alan was naturally excited to hear about these observations, but told Gillian to keep them quiet just long enough so that Neurion could file a patent application. Reluctantly, Gillian agreed. However, she quietly sent samples of the plasmid, with and without the gene, to John Rogers, M.D., a colleague of hers still at Smallville, for careful analysis of the plasmid’s sequence. The clinical trials began, and over the following weeks, the pair began collecting data.

Then the big problems began. Alan and Gillian continued to prepare the manuscript for the paper disclosing Gillian’s discoveries, but Neurion insisted Alan delay his efforts, telling Gillian that the delay was needed because the patent application was not yet ready. This created a problem for Gillian, who was obligated to publish her results as soon as possible. Then, while on a visit to Alan’s offices at Neurion, Gillian saw some documents indicating that a patent application had already been filed by Neurion describing her discoveries -- but she was not named as an inventor. Furious, Gillian quickly polished the rough draft, and submitted the manuscript immediately. Upon learning of this act, Neurion demanded that Gillian retract the publication, return all remaining stores of the gene, and terminate the study, but Gillian refused.

To make matters worse, ten subjects in the clinical trial were experiencing something very strange. The regions of tissue receiving the gene were experiencing hypersensitivity, to the point of severe pain. Histological analysis of the tissue revealed that the neurons were growing far more exuberantly in humans than in either rats or rabbits. The stimulating factor was out of control. As if matters were not bad enough, John used Gillian’s sample plasmids to generate a large quantity, of gene-bearing plasmid, which he had injected into ten undergraduate volunteers at Smallville College -- without securing IRB approval, acquiring informed consent, or even controlling the quality of the materials he had injected. Six of these students have experienced the neuronal hyperplasia.

Gillian is now being sued by Neurion for breaches of their contracts, misappropriation of trade secrets, and patent infringement. Although the injured patients and students are suing Neurion for making the dangerous materials, Neurion has asked the court to order Gillian to pay Neurion’s legal bills and any judgment associated with that product-liability suit -- on the grounds that Gillian had agreed to do so in her various contracts. The media, having heard of the Smallville incident, has placed the whole story on national news. Congress has issued subpoenas to her entire lab, asking why the NIH is sponsoring secret clinical trials of unproven, dangerous genes in our nation’s children. The Scientific Director personally has asked her to resign. Finally, Gillian’s attorney has told her the Assistant U.S. Attorney is investigating whether to charge her with criminal sanctions.

What went wrong, and how could the tools of technology development helped avoid these problems? By unraveling the complicated mess, and reviewing each piece, we will illuminate the traps and show the tools that would help avoid them.

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