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    Image: PlantForm Corporation

    These Bioengineered Tobacco Plants are Growing Pharmaceuticals of the Future

    Written by Mark Mann

    Are cigarettes the new cure for cancer? No, definitely not. But thanks to developments in genetic engineering, tobacco farming has become an unlikely way to produce cancer-treating drugs.

    Plant-derived medicines have been around forever, but until the development of a process called biopharming, they've been restricted to whatever naturally-occurring medicines the plants themselves could produce. Now scientists are converting plants like Nicotiana benthamiana and Nicotiana tobaccum into manufacturing platforms for a wide range of targeted protein-based therapies to treat Ebola, cancer and HIV/AIDS.

    PlantForm, a Guelph, Ontario-based company, is one of a few dozen biotech firms around the world developing these plant-made pharmaceuticals (PMPs). Only one such drug has so far made it to market—Elelyso, which is made by an an Israeli company called Protalix and used to treat a rare disease called Gaucher disease. But many more are on the way, including PlantForm's version of the breast cancer drug Herceptin, scheduled to become available in 2018. The first phase of human clinical trials are planned for next year.

    PlantForm senior technician John Teat, left, and research scientist Dr. Haifeng Wang, inspect tobacco plants that are producing antibodies. Image: PlantForm Corporation

    Even though the existing crop of plant-produced drugs is small, the potential is apparently enormous. "We can make virtually any biological drug," said Don Stewart, the company's president and CEO—and they can do it much more cheaply and quickly than traditional methods, he claims.

    Techniques for bio-engineering pharmaceuticals have existed for decades, many of them based on fermenting animal-cell cultures in large bioreactors. (A common source of these cultures are ovaries from Chinese hamsters.) But producing biological drugs that way is complex and expensive. According to Stewart, the manufacturing cost for one dose of Herceptin is $1000, but using its proprietary tobacco-based vivoXPRESS system, PlantForm can produce that same drug for around $100 per dose.

    Despite the traditional challenges of producing biologics efficiently, the appetite for these drugs is already huge. In 2013, the global market for biologics was valued at $200 billion. The market for Herceptin in particular is $6.8 billion, and PlantForm estimates that the market for biosimilar drugs—basically, copies of the original that do the same thing—is $4 or $5 billion. The reason is simple: biologics work extremely well, because they are capable of targeting specific diseases—including diabetes, Alzheimer's disease, cystic fibrosis, and many others—very accurately and effectively.

    PlantForm research associate Zach LeBlanc propagates a tobacco plant that has been engineered to produce a biologic drug product. Image: PlantForm Corporation

    The potential for plant-made versions of biological drugs first broke into the mainstream consciousness last year, when the experimental drug ZMapp was used successfully to treat two Americans, a doctor and a missionary, for Ebola, which they'd contracted while working on the outbreak in Liberia. Apart from the fact that until then it had only been tested in monkeys, another fact stood out: ZMapp is grown in tobacco leaves.

    Biological drugs use protein-based compounds that can be engineered from the elemental building blocks of life. The most common proteins in biological drugs are antibodies, which the body generates on its own to fight disease. Antibodies bind to matching antigens on the virus or bacteria, and then signal to the immune system to get rid of them. Biopharming mimics that process with artificial antibodies, which the body treats as if they were natural.

    For example, the drug that PlantForm works on, Herceptin, is an antibody, and the antigen it corresponds to is called HER2, which is found in high levels in some kinds of breast cancer. When the Herceptin antibody finds its HER2 antigen counterpart, it triggers the body's immune system to prevent any more from being produced and to start attacking the cancer.

    The plants are immersed in the Agrobacterium suspension and then placed in a vacuum chamber, which is sealed and pressure applied to draw the Agrobacterium into every leaf. Image: PlantForm Corporation

    Once a biopharming company has designed the antibody or other protein cell that it needs to fight a specific disease, all it needs to do is make more. Growing cells is no mystery to science, and fermentation does the trick handily. But with a little light and water, plants can also multiply cells very efficiently. Other crops used in biopharming also include maize, alfalfa, safflower, and rice, but tobacco is particularly useful because it grows quickly and at a high volume, allowing companies to express more cells faster and at a lower cost than if they used bioreactors.

    In order to get the plant to produce the desired cells, bioengineers introduce genetic control mechanisms into the plant that will cause it to express the particular antibody they want. This is done by infecting the plant with a specific kind of bacteria called agrobacterium that conveys the genetic material.

    At PlantForm, this whole process takes about eight weeks. For the first six, the plants grow on their own in a greenhouse. Then they are infected with the bacterium and given one more week to express the drug in a controlled growth spurt. Finally, technicians cut the plants to the ground and throw them all together in a big blender. The drug is extracted from the resulting green slurry.

    PlantForm technician Erin McMichael prepares an Agrobacterium suspension that will be used to inoculate the tobacco plants with the genetic material necessary to produce a biologic drug. Image: PlantForm Corporation

    Unlike most techniques used today, the first wave of biopharming companies in the early 2000s attempted to grow the plants outdoors. There are two big problems with that approach: one is the the plants can be contaminated by other elements in the environment, and, more importantly, the genetically modified plants can cross over into other crops. When the inevitable happened and a strain of corn that had been altered for pharmaceutical purposes was found in a crop meant for consumption in 2002, it was a major setback for the whole industry.

    To avoid this outcome, PlantForm and similar companies like Quebec’s Medicago grow their plants in controlled environments. PlantForm has teamed up with a team of researchers from the University of Guelph in Ontario that designs greenhouses for space stations. ("It's not as difficult as difficult to grow plants to produce drugs as it is to grow lettuce in a space station,” said Stewart.) The two teams have worked together to modify variables like air pressure, humidity, and light to elicit the best possible growth for these antibody-producing tobacco plants.

    The other big difference between current techniques and previous failed attempts at biopharming is that companies like PlantForm don’t permanently modify the plants. The traits that are introduced through the agrobacterium don’t pass from one generation to the next, so there’s less risk of contamination with other plants.

    PlantForm technician Rebecca Pastora readies tobacco plants for the drug production process. Image: PlantForm Corporation

    Because PlantForm can foreseeably produce these complex protein drugs so quickly and in such large quantities, the company has drawn investors like the Bill and Melinda Gates Foundation to develop a treatment for HIV/AIDS that can be grown in sub-Saharan Africa, as well as the US Defence Advanced Research Projects Agency (DARPA) and Defence Canada to stockpile vaccines for sarin gas poisoning and other forms of bioterrorism.

    Genti Kostandini, an agricultural economist at the University of Georgia, predicts that biopharming in plants will continue to expand and possibly achieve large-scale production in the next ten years. "The potential for huge savings is very high, especially in markets that are served with only one or two drugs," he said. The pharmaceutical industry is beset by monopolies, in which biological drugs for specific diseases are produced by only one company. If they can get their patents approved, biopharming companies with plant-made biosimilar drugs entering these markets can expect big profits. That's great news for companies such as PlantForm—but it's even better news for patients, who may no longer have to trade life-saving treatment for crippling debt.

    Correction 05/05: A previous version of this article stated that PlantForm's version of the breast cancer drug Herceptin was schedule to become available in 2016. This is incorrect. Rather, the first phase of human clinical trials are planned for 2016, and the drug is scheduled to become available in 2018.