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A Fresh Start For Tobacco

Jiahua Xie, Ph.D.

North Carolina’s Cash Crop Could Be A Surprising Source of Life-Saving Medicine

Tobacco is not exactly known for its health benefits. The plant contains dozens of chemicals that cause cancer, hundreds of other poisons that damage the heart and lungs, and a substance called nicotine that is one of the most addictive in the world. But despite its well-deserved bad rap, the tobacco plant might yet have a chance for redemption.

Researchers are currently restructuring tobacco's genetic code to produce a variety of life-saving medicines, from vaccines against cervical cancer to serums that treat Ebola infection. The technique, known as “biopharming,” may revolutionize drug development by creating pharmaceuticals faster, cheaper, and more effectively than traditional brick and mortar facilities.

Jiahua Xie, an associate professor of pharmaceutical sciences at NCCU’s Biomanufacturing Research Institute and Technology Enterprise (BRITE), is among those improving tobacco’s reputation. For the last nine years, Xie has been developing ways to turn tobacco plants into biological factories that manufacture human therapeutics alongside its own proteins.

“Plants have tremendous potential as a new source of drugs and therapeutic compounds,” Xie says. “The only trick is in the genetic engineering, but once you have created the transgenic plants you can grow them just like regular plants. You can scale up production very easily, simply by acquiring a bit more land, more soil, sunlight, and water.”

Before he joined the faculty at NCCU, Xie worked at Vector Tobacco, a Mebane-based company that develops and manufactures “healthier” cigarette products. There, he became intimately familiar with the genome of the tobacco plant. Xie and his colleagues cloned the gene for nicotine and effectively eliminated it in tobacco plants, an advance that led to the first nicotine-free and low nicotine cigarettes on the market.

His expertise in genetically engineering tobacco was quickly recognized within the industry. Xie was inundated with high-paying job offers to work in China, a country that produces more tobacco and has more smokers than anywhere else in the world. He turned them all down.

“I told them I couldn’t do it,” recalled Xie. “I didn’t want to continue working on a product that – even with our tweaks – was still causing health problems like cancer, emphysema, and heart disease. I would rather use tobacco to do something else. Tobacco plants are good plants, and I knew they were capable of producing good things.”

The first thing to come to mind was biopharmaceuticals – drugs that are generated by a menagerie of living organisms, including soil bacteria, tropical plants, and barnyard animals. This area of drug development has seen an explosion of activity over the last 25 years, as scientists have sought alternatives to the traditional method of synthesizing drugs from a mixture of chemicals in the laboratory.

To make biopharmaceuticals, researchers insert genetic material into their plant or animal of choice. The resulting “bioreactors” then convert their foreign cargo into proteins, just as they do with the rest of their genomes. Eventually, the therapeutic proteins can be harvested along with other products such as eggs, milk, seeds, flowers, and leaves from the genetically modified organisms. The approach has generated plant- or animal-made versions of a medications, including insulin, contraceptives, and blood-clotting agents.

Xie could see that tobacco was uniquely poised to contribute to the biopharming revolution. The plant is relatively simple to cultivate and grows from seeds to full-grown plants in a period of weeks. Its green elephantine leaves contain copious amounts of protein, many times more than crops like corn, alfalfa, and rice. Plus tobacco absorbs foreign DNA more easily than other plants, making it an ideal target for genetic modification.

All Xie had to do was figure out what drug to make first. He decided to focus his efforts on erythropoietin (EPO), a hormone that prevents anemia by helping the body make more red blood cells. This drug has become a popular blood-doping agent because it can boost the amount of oxygen the blood can carry to muscles, giving athletes more endurance. EPO also has more legitimate applications, with synthesized versions of the hormone regularly used to treat anemia developed by patients undergoing chemotherapy for cancer, as well as those suffering liver failure or who have HIV.

About 15 years ago, researchers noticed that EPO had another role besides pumping up red blood cells. The hormone can also protect tissues from the damage wrought by heart attack, stroke, diabetes, and autoimmune disease. Unfortunately, a much larger amount of EPO is required to achieve such protection than is used to treat anemia. At such high doses, the drug essentially thickens the bloodstream, triggering blood clots and injuring vital organs.

“Interestingly, these nasty side effects can be avoided by removing tiny sugars called sialic acids from the surface of the EPO protein,” Xie notes. “However, that seemingly simple step makes it even more time-consuming and expensive to pro- duce the protein in the quantities needed for it to be used in the clinic.”

Plants offer a straightforward, cost-effective solution to producing enough protein. Unlike the animal or human cells typically used to synthesize EPO, plant cells don’t add sialic acids to their proteins in the first place. As a result, EPO comes off the assembly line ready to go, no further structural modifications necessary. Plus, production costs approximately 50 times less in plant cells than in mammalian cells.

As simple as it sounds, Xie and the researchers in his laboratory still had to perform a bunch of fancy genetic maneuvers to get the system to work. First they cut and pasted together pieces of DNA to create a “transgene” that contained the instructions for making the human EPO protein. They inserted this transgene into the plant’s genomic blueprint, so EPO would become one of the building blocks of the tobacco plant. After the tobacco was fully grown, a final trick remained – isolating the one human protein out of the tens of thousands of plant proteins stored in its leafy appendages.

Once they had this new form of the EPO protein in hand, Xie’s research team tested its ability to shield cells from damage. They took a special batch of mouse cells – which other laboratories have used to study brain health and Alzheimer’s disease – and treated it with a toxic agent called staurosporine along with their plant-derived EPO protein. The researchers found that the sialic acid-free EPO saved almost half of the cells from imminent death, performing even better than regular EPO in side-by-side comparisons. They published their results in 2013 in the journal PLoS One, and are now testing the drug on cells implicated in heart disease and diabetes.

Despite his successes, Xie swears he doesn’t have a green thumb. He finds gardening a bit tedious, and gets most excited when he is working at the bench splicing together the genetic code of different species. He tells each new student that joins his laboratory that there is more to plant research than merely digging around in the soil.

“We are trying to do something that no one has ever accomplished before, and that can be difficult,” explains Xie. “It isn’t like a textbook laboratory experiment. Every day brings a challenge, because you are doing real research. Once you solve one step, you move to the next challenge, and then the next and the next. That is how science progresses.”

Xie has taught many people that lesson. So far, he has trained 13 undergraduate students and seven graduate students. He gives all of his trainees the opportunity to contribute to research discoveries in his laboratory, and most of them have published papers on their projects.

Due to their advances, North Carolina’s cash crop could become even more profitable. One hectare of regular tobacco plants can yield as much as 15,000 kilograms of fresh leaves, valued at about $10,000. If that same tract of land were used to grow transgenic tobacco instead, Xie calculates it could produce as much as 7,500 milligrams of EPO, worth up to $7.5 million dollars. He has led a patent on his technology and is applying for grants to continue to push his research forward.

But before the state’s tobacco fields can start churning out this pharmaceutical, Xie still has to prove that the drug is safe and effective by conducting studies in animals and clinical trials in humans. He has assembled a team of researchers to help with these efforts, including Ping-An Li, a neuroscientist at NCCU, and David Sane, a cardiologist at Virginia Tech Carilion School of Medicine and Research Institute.

Xie also has funding from the North Carolina Biotechnology Center to engineer tobacco plants that can produce other drugs besides EPO. Because most proteins require sialic acids, Xie has to figure out how to make plants add these sugars onto its proteins in order to expand its product line.

“My goal is to engineer tobacco plants that are capable of producing a wide range human therapeutics, easily and inexpensively,” states Xie. “Now when I drive past tobacco fields, I see plants that are full of promise. Tobacco can be made good again, and it can have a positive impact on human health.”

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