The rows of sprouting green tobacco plants growing in a greenhouse aren’t in a southern U.S. state awaiting harvest and manufacture of cigarettes. This crop is being grown for an entirely different use. The expansive greenhouse in northern Israel is growing tobacco for the health care industry, a complete 180-degree turn for tobacco’s sullied reputation as a carcinogen. Welcome to CollPlant’s human collagen production lab!
Collagen, of course, is a group of naturally occurring proteins which, normally and naturally, are found exclusively in animals. In fact, we can go even further and say that collagen is found most commonly in the flesh and connective tissues of mammals. In humans it is the main component of connective tissue, and it makes up about 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament, skin, cartilage, bone, blood vessels, the gut, and intervertebral discs.
Focused on Collagen Production
CollPlant Logo/CollPlantCollPlant, established in 2004 as an incubator start-up company, has been working on a human collagen-producing tobacco since its inception. It’s not easy. “The first challenge was to establish plants that can produce collagen, which involve high-level genetic engineering work combined with classical plant genetics, agricultural and biochemistry, ” explains CEO Yehiel Tal.
“Another challenge was to extract collagen from this new source. The plant environment is very different from the animal bone, skin or tendon, therefore different extraction methods had to be developed.” Tal says that the purification process also was a step that required the company to exercise some engineering expertise and in its six years of research and development the company has automated the process, fine-tuning controls and mechanization.
Today, the company has branched out to work on the design, development and manufacture of biomaterials-based products for regenerative medicine, including scaffolds for soft and hard tissue repair for treating bone fractures, spinal fusion, and rotator cuff tears in addition to other injuries.
Benefits of a Novel Source
CollPlant has as Tal describes it, “developed a technology platform for the production of recombinant Type I human collagen in transgenic tobacco plants.”
Collagen has many applications within medicine, from being a major component in medical devices to supporting tissue regeneration. The biomaterial is used for dermal fillers, wound management and as a scaffolding in orthopedic procedures. “Collagen provides the most natural scaffold to support re-populating of damaged tissues with new cells leading to tissue repair, ” says Tal.
For instance, a study by William Rodkey, D.V.M., J. Richard Steadman, M.D., and Kenneth DeHaven, M.D., titled “Comparison of the Collagen Meniscus Implant with Partial Meniscectomy” showed that patients with chronic meniscal injury who received a collagen meniscus implant had better clinical outcomes than those treated with partial medial meniscectomy alone.
And a study from Grainne M. Cunnifee, Glenn R. Dickson, et al. titled “Development and characterisation of a collagen nano-hydroxyapatite composite scaffold for bone tissue engineering” from a 2009 issue of the Journal of Materials Science looked at the bone regeneration qualities of a novel composite collagen scaffolds that proved stronger than collagen alone.
So collagen definitely has its place in the world of orthopedics, with many applications. But why do we need a new source for it? Typically collagen has been sourced from animals (such as cows and pigs) and, from time to time, human cadavers. There are, however, several disadvantages to traditional sources of collagen. First of all there is the question of immune reaction or safety. Some patients can exhibit an immunological reaction to bovine or porcine derived collagen. Disease transmission from a cadaveric donor is nearly non-existent but some patients may still be cautious. Then there’s the issue of supply—donor derived collagen products can be supply constrained. Finally, because the CollPlant process involves the production of human collagen from the plants, using human genes, the concern that an immune reaction would occur is minimized.
But Why Tobacco?
So a plant-based expression system may be more beneficial than one derived from human, bovine or porcine sources, but why use the tobacco plant for this engineering project? According to Tal there are several good reasons for using tobacco “…as the expression system for human recombinant collagen. Tobacco was one of the early model plants used to study genetic engineering dating back to the 1980s. Since then, the scientific community has built a substantial knowledge base regarding the genetic manipulation of tobacco including developing expression vectors and optimizing transformation methods.”
Tal adds that tobacco is plain and, simply put, an easy crop to grow. “Tobacco agriculture has been practiced for hundreds of years and we benefit from the accumulated knowledge about propagation methods, nutrition schemes, and optimized environments. It yields a large biomass in short time (life cycle of plants in the greenhouse is six weeks, during which they grow over a man’s height).”
But what about tobacco’s carcinogenic qualities? Isn’t this a risky plant to use? Tal says that the carcinogenesis of tobacco products is associated with tar produced in smoking and certain alkaloids found in the plant. “The collagen extracted and purified from the leaves is free of tar or alkaloids.” Not being part of any food or feed chain means there is no risk of the engineered crop contaminating other plants.
An analysis of CollPlant’s raw collagen material has been conducted to ensure its safety and quality, which included chemical, physical, and biological studies. “Medical devices are subjected to rules and guidelines as well. The development stages, as well as the manufacturing processes, was carefully planned and continuously monitored, ” adds Tal. “Biocompatibility and bio-safety studies were conducted, and our collagen was found biocompatible and safe in all tests.”
From Tobacco to Collagen
Prof. Oded Shoseyov of the Hebrew University founded CollPlant and is today its chief scientific officer. Shoseyov is credited with developing the original process, which imitates the human body’s collagen production system.
The engineering process that allows the tobacco plant to act as the expression mechanism for collagen is a multilayered process. Tal says that due to the extremely large size of the collagen molecule, its complexity and the need to substantially modify it post-translationally for the full benefits to be realized, traditional recombinant expression techniques fail. “The challenge in collagen expression by transgenic system that made CollPlant’s technology a breakthrough, ” says Tal, “is the need for simultaneous expression of five different genes in the same cell, to make up fully functional heterotrimeric collagen.”
These five genes are at the heart of CollPlant’s engineering and production process. Tal says this is the first time five different human genes have been introduced into one plant—genes that work together to produce the human recombinant Type I collagen. To begin this process, Shoseyov first identified the genes that contribute to collagen production. He then placed two of these genes into one tobacco plant and the rest into another. Good old fashioned crossbreeding then created a stable strain of tobacco plants capable of imitating the manufacturing of human collagen.
Pharma’s Growing Interest
About two weeks ago, a story appeared in the Israeli magazine Globes which reported that CollPlant had entered into product development talks with Pfizer Inc. and Edwards Pharmaceuticals Inc. So far CollPlant has not issued a press release regarding these discussions but since the article appeared, the company’s stock rose 40% on the Israeli stock exchange.
According to the Globes article, CollPlant’s negotiations with Pfizer are the more advanced and revolve around a wound treatment that CollPlant is currently developing on its own. Pfizer recently bought Wyeth, which had significant operations in that area.
Publically, CollPlant is not saying very much and CEO Tal told OTW that the company is in discussions with several companies on several fronts but no definitive names were mentioned and no press releases have been issued.
Product Pipeline/CollPlantWe suspect that the rising levels of interest in CollPlant may be due to a recent communication from the FDA. In August the FDA told the company its Vergenix wound dressing, which uses the tobacco-derived collagen, would be classified as a medical device, not a drug or biologic product, which will likely mean a quicker, simplified review process. Vergenix is the first product in part of CollPlant’s business plan which turns away from raw material production to the more profitable product market in reconstructive orthopedics. Vergenix, indicated for chronic wounds and skin ulcers (pressure sores and diabetic wounds), is collagen-based sponge which has been submitted to the FDA for clearance.
It appears like the leaves of the tobacco plant, CollPlant is branching out to offer a complete line of products, all centered around the collagen production capabilities.
