OP-markers: disco light for surgeons

3. February 2012
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When one Nobel Prize winner and one particular surgeon sit together at a table, tumors light up like stars in the desert sky and nerves willingly reveal their exact pathway. Intraoperative labelling of tissues with fluorescent markers could open new dimensions of accuracy for surgery. As long as man holds true to what is promised by mouse.

Sometimes circumstances simply fit too well. While surgeon Quyen Nguyen eight years ago was a young doctor in the Department of Head and Neck Surgery at the University of California at San Diego, she met a person who knew his way around quite well on the topic of fluorescent proteins. The man’s name was Roger Y. Tsien and he was to receive, a couple of years later in 2008, for his contribution to the discovery and development of green fluorescent protein (GFP), the Nobel Prize for Chemistry. At the time of our story though this still had nothing to do with reality.

This is the first stage …

In the year 2004, Tsien was occupied with, among other things, the fluorescent labelling of cancer cells. As a surgeon who carried with her some amount of knowledge on tumor-specific cell markers, Nguyen found this exciting and got on board. One result of this cooperative enterprise, on which she recently reported at the TED 2011 event in San Diego, was a fusion molecule consisting of a fluorescent marker and a non-specific tissue marker. The molecule also made use of a type of switch that turns off the fluorescence. This switch is connected to the fluorescent end of the molecule via a molecular bridge, which can only be snipped by certain proteases which are highly specific to cancer tissue. If this construct comes into contact with cancer cells, the molecular bridge is cut, the switch that blocked the fluorescence is gone, and the tissue involved then begins to fluoresce. Everywhere else in the body, nothing happens: The construct does get attached to tissue in other places, but as long as the “switch” stays intact it doesn’t luminesce.
Fluorescent cancer tissues could be very helpful in standard surgical practice, Nguyen believes. “If we operate, we often do not know whether we have actually removed all the tumor tissue”. In order to resolve any such doubts, there exists – in principle – frozen section diagnosis. “This however demands time. And often we then learn a few days later, that in the final pathology tumor tissue was in fact found. Then we have to either operate on the patient again or conduct some other subsequent treatment”. If tumor tissue could be reliably highlighted during surgery, the frozen section diagnosis would perhaps be superfluous, and the results could even be better than in classical tumor surgery.

The “Proof of Principle” has already been started by Nguyen and Tsien: A year ago, they reported in the journal PNAS (2010; 107:4317-4322) on a series of operations on mice in which, after an operation, they tracked down remaining tumor cells using highly sensitive PCR methods. The result: when the tumor was made to fluoresce by means of intravenously-administered marker construct during an operation, there remained significantly fewer cancer cells than in the classical approach. Nguyen sees potential practical applications of tumor fluorescence for example in the resection of sentinel lymph nodes, especially in situations where the lymph anatomy happens to be complex. Using fluorescence it would immediately be clear which lymph nodes are infected and thus be resected as a sentinel.

And the second follows immediately

All this thus far has been fully impressive. But it keeps going. In Nature Biotechnology (2011; 29:352-356) Nguyen and Tsien have now reported on similar experiments in which they have, on this occasion, brought light not to tumors, but rather to peripheral nerves. This picture also has a surgical background: For many surgical procedures it is necessary to protect nerves as much as possible, so as to avoid postoperative complications. In the field of head and neck surgery this is a big issue, as it also is in prostate surgery. Electrical stimulation, a common tool employed in so-called nerve-sparing surgical techniques, unfortunately does not work equally well for all operations. Nerves are often simply too small or too variable in their anatomy. This is especially true for the prostate. “Actually, we are still learning, that nerves can be located anywhere on the prostate”, says Nguyen. The consequences, despite nerve-saving surgery, are sometimes high complication rates.

In order to get the nerves to light up, the California researchers injected an intravenous application of a fluorescent peptide into the mice, the peptides binding preferentially to peripheral nerves. Within two hours, all peripheral nerves were recognisable and visible to the naked eye. Within a time window of eight hours, the contrast with the surrounding tissue was so strong that the state was categorised as being clinically useful.

The question remains whether and when these fluorescence methods could be used in humans. The peptide, which brings a glow to the nerves of mice, also appears to bind to nerve cells in human cell cultures. With this finding, one basic prerequisite already seems to have been met. Equally important is toxicity data, which thus far only exists in rudimentary form. But that of course can change.

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Gerardus HOOGLAND
Gerardus HOOGLAND

Very interesting article, do you know which companies are pursuing commercial applications of this technology ?

thanks and regards, Gert Hoogland

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