Biopharmaceuticals: Plant-based Medications for the Future
Central Washington University
While genetically modifying naturally occurring organisms for medicinal purposes is nothing new, some scientists started to mull over the idea of administering medications and life-saving vaccines around the globe in a different way. Biopharmaceuticals are on the rise, and their potential is incredible.
PLANT-BASED MEDICATIONS OF THE FUTURE 2
Though it the early stages of testing, development and regulating, delivery of vaccines and medicines orally via plants is proving to be a field worth paying attention to. The process is relatively low cost, with decently high yield, and distribution would be simple. Perhaps a utopian world where the locals can medicate themselves with the fruits from a banana is not possible just yet (Mandy, 2005), but it cannot be ruled out just yet. Biopharmaceuticals are merely in their infant stage, and will continue to improve as our science does.
History
While this field of biopharmaceuticals seems straight out of a futuristic movie plot, it is not exactly new. Biotechnology has been in place for decades, beginning with Alexander Flemming’s discovery of “mold juice”- penicillin- in 1928 (ACS, 1999). Flemming found that something as simple as this mold growth within a petri dish secreted a substance that could kill a variety of bacteria, ranging from diphtheria to streptococcus. Though it took some time before the penicillin could be properly purified and used to fight infection, the first major fungi based pharmaceutical had been manufactured (ACS, 1999), and an industry was born.
Technology has improved drastically since 1928, and by 1970 scientists were discovering the capabilities of recombinant DNA. The process involved using pieces of DNA from two different species, and joining them together to create a new, hybrid set of DNA. This hybrid would then need to be placed back into a cell, which often was that of a bacterium (NHGRI, 2013). This process of “cut and paste” DNA would eventually lead to the development of somatostatin in 1977, which is currently used to treat individuals suffering from gigantism (Uckon, 2013). This process might not have been possible without bacterium acting as a surrogate cell for these DNA cocktails.
Biopharmaceutical technology was on the upswing by the 1980s, with mass production disease fighting biopharmaceuticals (Uckon, 2013). In 1980 Cohen and Boyer were able to produce human insulin (used to regulate blood sugar levels) from genetically modified bacteria thanks to the issuance of a patent for gene cloning (ABS Australia, 2008). Human growth hormone, used to treat Creuzfeldt Jacob Disease, was produced with help from improved technology that isolated plasmids from E. coli (Ayyar, 2011).
It was becoming obvious that human and animal tissues might not have been the cheapest and safest way to synthesize molecules. Biopharmaceuticals had shown their value, and continue to be utilized and experimented with today.
The Field Today
Biotechnology has since moved on from DNA splicing and hosting in bacteria cells. These days, scientists have their eyes on placing vaccines and other drugs within plant cells, including carrots, lettuce and cereal grains, with the intention of animal and human consumption.
The glycoprotein necessary for the rabies vaccine has been successfully expressed within plants such as tomatoes, carrots and spinach, and proved to protect mice in laboratory trials (Yang et al, 2013). This was accomplished through more recombinant DNA. Scientists used pieces of the rabies glycoprotein- the signal peptide specifically, which leads the way for the chain of proteins- and implemented the “cut and paste” method to replace that peptide with another plant based protein. This process, when successful, produces plant derived rabies antigens (Yang et al, 2013), which promote the production of antibodies in the immune system to fight off this invading substance.
Yang et al (2013) considers the plant based rabies vaccine to be advantageous in terms of the early successes seen in lab trials with mice, but there are some issues with the method of storing and administering the vaccines in this way. Shelf life is a major concern, as your average tomato does not have a particularly long life span. There is also the concern that as biological materials run the course of their life, what will happen to the level at which the proteins of the vaccine are expressed? Will they drop to a level that is useless when consumed? If the plants are used for multiple generations, how will protein expression change over each? While there are many questions left to be answered, Yang et al (2013) feels that this method has excellent potential, especially if the process of growing antigen producing plants is expedited. This is a low cost, relatively safe alternative to current methods. It is possible that when these issues are addressed, domestic animals could feasibly be treated using oral, plant based vaccines (Yang et al, 2013).
As recently as October of this year (2015), scientists out of the University of Pennsylvania School of Dental Medicine announced they had successfully created plant based systems of producing shelf-stable drugs- that is, drugs that can be stored and used over longer periods of time. The drug developed promotes blood clotting, necessary for hemophilia patients, and was produced within the leaf of freeze-dried lettuce (UPSDM, 2015).
In initial trials, the researchers had used tobacco to grow the proteins that inhibit antibodies from attacking the clotting factors that hemophilia patients receive via infusion. When hemophiliac mice were used in the trials were fed the tobacco plants, their production of inhibitors virtually stopped. However, lettuce was brought in to begin to developing a similar plant-based treatment, but in a form humans could consume (UPSDM, 2015).
Though the process of producing the proteins in lettuce was different than in tobacco, due to genetic factors between the plants. Researchers used a similar technique of hitting the leaves with the desired proteins, as well as other factors that aided the protein in making it to the immune system when consumed. The plants that successfully picked up the proteins were then grown to maturity, but the question of shelf life was still unanswered. Researchers tried freeze drying the leaves, and evaluated whether the process had affected the expression of the protein through analysis to determine dosage, and eventually trials with mice. The trials were success again, as they had been with the tobacco, and the dosage was found to be flexible over “at least a 10-fold dose range” (UPSDM, 2015), which is extremely good news for human users, who metabolize and break down materials differently.
This study by the University of Pennsylvania School of Dental Medicine is hugely exciting in the field of biopharmaceuticals, since it has shown that there is truly potential for large scale commercial production of drugs through plants. The process of creating the plants is relatively inexpensive, and the number of doses that can be grown in a small area is astounding- even in a facility that doesn’t use natural light (such as a large scale pharmaceutical facility, which uses hydroponic systems), nearly 40,000 doses can be grown in an area as small as 1,000 square feet (UPSDM, 2015). Facilities like this can take advantage of vertical space, as well, since they do no rely on direct natural light, thus production could increase in that same space by tens of thousands of doses. Should other drugs, beyond clotting factors, be manufactured in plants, the production and distribution costs could be drastically reduced using these biotechnological methods.
The University of Pennsylvania School of Dental Medicine showed through their research the validity of this method in hopes of FDA approval for human use. It is possible hemophilia combatting lettuce is a possibility for humans sooner rather than later.
Impact
Biotechnology presents new and exciting, and perhaps a bit controversial options for humans as we continue to populate the Earth and struggle to distribute good and services to the poorest of nations. The process of genetically modifying organisms for human consumption (medical or nutritional) is a huge source of debate all around the globe. Biochemist Paul Berg, along with other scientists, urged for the regulation of recombinant DNA in the 1970s after producing DNA molecules. They realized the potential, but were worried that there was not enough information to confirm the method was safe, particularly when splicing DNA involved more than one species. In 1975 the Asilomar Conference was held to lay out guidelines for work with recombinant DNA, and since then the guidelines have been updated several times (NHGRI, 2013).
Even today, this form of genetic engineering is widely debated by the public, as it has cropped up most notably in the food we eat. “Round-Up Ready” seeds, which withstand the devastating effects of intense herbicides, fruit with incredible shelf life, heightened flavor and nutritional value- just to name a few (DDC, 2011). The public has been up in arms in recent years, worried over the effects of ingesting something like “roundup ready” corn, which retains chemical from the herbicide it was sprayed with (Delano, 2009). The public questions the safety of some of these products, and farmers and environmentalists alike are worried about the effects genetically modified seeds could have, and have had, on ecology and plant diversity (DDC, 2011).
Perhaps recombinant DNA has a bad reputation now, but the evolving field of biopharmaceuticals could turn public opinion around. The process of creating plant-based pharmaceuticals is relatively inexpensive, since it does not require tissues from animals (Yang et al, 2013), or fermenters, cold chain refrigeration, or purification (UPSDM, 2015). Current treatments like that of hemophilia inhibitors can cost thousands of dollars, up to even a million dollars over a lifetime, but with cost cutting done in the initial production process, patients will save a large sum of money. Biopharmaceuticals could make medications available to populations that otherwise would not have been able to afford them (UPSDM, 2015).
Mass producing the plants is also as easy as planting them just like any other crop- in soil with natural light. However, the UPSDM (2015) lettuce trials have shown us that growing plants within warehouse style hydroponic gardening systems is feasible. They found that both the plants receiving natural light, and those in the warehouse were close in terms of yields. Within the hydroponic gardens, there is room to add shelving, and capitalize on vertical space with no impact on those at lower levels (UPSDM, 2015). UPSDM (2015) was able to harvest doses from their lettuce every four to six weeks without the vertical gardens, meaning the production rate of biopharmaceuticals is extremely promising, and also cuts down on costs to the patients.
For developing nations, biopharmaceuticals could vastly improve access to healthcare. Cases of deadly infectious disease within developing nations reaches to nearly 10 million annually, even with modern vaccines, due to the expenses incurred in developing them, transporting them, and most importantly administering them in a sterile, safe way. Unsafe delivery of a vaccine (contamination, reused needles, etc.) accounts for more than 20 million infections (Kwon et al, 2012). Plant-based, ingested medications could eliminate a large portion of this risk for infection and reactions.
Pharmaceutical proteins protected within plant cells are also safe from toxins and bacteria contaminants that are associated with the use of mammal cell cultures. In addition, moving away from the use of animal tissues elements during the manufacturing process means that there are little to no risks from human pathogens (Kwon et al, 2012). This means that not only is delivery via sterile injection unnecessary, but the pharmaceutical itself has been manufactured in a safe way, with little risk to the consumer.
Modern science is moving in the direction of being able to create a plant that is familiar, will grow effectively in a particular region, and will also express within its DNA makeup, treatment for a disease or illness that region struggles with (ISAAA, 2007). Growing their own plant-based pharmaceuticals will drastically cut down costs for the nation in question, and the sheer number of doses will be much more effective than our current lab manufactured systems. The technology for hydroponic facilities, and extraction will need to be established within these countries, but after the initial set up, the benefit to the local communities will be monumental. The spread of disease in poor, developing nations could see a dramatic decrease (ISAAA, 2007).
Despite all of the great potential, there are some major concerns with the widespread production and use of biopharmaceuticals. Controlling the dosage of the expressed pharmaceutical within a plant throughout its shelf life, as well as throughout the generations has been an obstacle for the production of plant-based medications (Yang et al, 2013). Dosage levels may change when a plant is bred and seeds harvested over, and over again. If a plant is freeze dried, and able to sit in a cabinet, how will the levels change over time? This type of genetic engineering is new, thus we have little information at this time.
Another concern is cross pollination and the introduction of biopharma in to local ecology. This is particularly dangerous. It has been suggested that plants used for pharmaceuticals should never be grown outside of a greenhouse or hydroponic warehouse setting (ISAAA, 2007). By maintaining physical isolation, the crops themselves are protected from cross pollination, but more importantly fields of agricultural crops for human consumption are protected. The concern is that cross pollination could lead to the expression of pharmaceuticals within crops that will be eaten by the general public (ISAAA, 2007). This is also troublesome, since transgenic species may include DNA from more than one plant, which a consumer may not realize. If the crop has become contaminated, it is possible that a consumer could eat a soybean that has been inadvertently crossed with a soybean/Brazil nut hybrid. If the consumer is allergic to Brazil nuts, this could be harmful or even deadly (Delano, 2009).
Complete and total isolation for every transgenic crop is unrealistic though, and other solutions have been proposed to limit environmental exposure. One such idea is to have the necessary genes present within the plant, but only have them expressed to their full potential after having been treated with some kind of activator (ISAAA, 2007). This solution presents more ethical problems, as it takes a genetically engineered plant- something many consumers are already leery of- and treats it with some kind of chemical activator. It may be expensive as well, (ISAAA, 2007), in terms of manufacturing the activator, the equipment necessary for treatment, etc. Heightened costs undermine one of the very things that biopharmaceuticals are aiming to combat.
Concerns also surround the biosafety legislation, or lack thereof, of developing nations who so desperately need the cost effective, mass produced pharmaceuticals (ISAAA, 2007). While standards in the United States are often reevaluated and tweaked (NHGRI, 2013), the same cannot be said of countries with sometimes unstable government and ruling officials. Likely the nation has never had to consider regulations like this, so they may be nonexistent. Without control, seeds manufactured in the US could be bred and experimented without compliance to our biosafety standards. Ineffective crops and failed experiments actually add to the cost of the drugs themselves (due to the cost of research), and that goes for both nations following safety regulations and those outside of the regulations (ISAAA, 2007). Without control or international guidelines for biopharmaceutical production, it will be dangerous to distribute crops to other nations.
Conclusion and Future Study
With the proper biosafety regulations, both in the lab and in production, plant-based pharmaceuticals are “the way of the future,” so to speak. Though the science is in its early stages, the potential is too great to ignore. Cutting costs and increasingly availability of medications is something so desperately needed in poor communities and developing nations. To ignore an opportunity to work toward that would be irresponsible.
That being said, perhaps our approach to biopharmaceuticals needs to shift. While making medical advancements and developing more plant-based pharmaceuticals is important, just as much emphasis needs to be placed on the logistics of biopharmaceuticals in tandem with development. Regulations need to be constantly reevaluated and revised, since biosafety is of upmost concern. In order for the field to reach its full potential, all the t’s need to be crossed and i’s dotted. Perhaps their needs to be a large international committee that meets and discusses regulations for lab procedures, production and growth, and dispersal so that in the future the plants can be grown in the nations that need them most to further cut costs and increase availability.
Biopharmaceuticals have a long way to go, and more potential to be reached. The idea of a future where vaccines can be grown and delivered to rural villages to save the lives of children is an exciting one. Before we get too excited, more research needs to be done, and any and all risk-management factors need to be considered (both in consumption, and gene flow between pharmaceutical plants and standard agriculture). This is normal in the field of science and new technology. I believe as the years go by we will see an increase in successful lab trials of biopharmaceuticals, and the conversation about distribution and production will truly begin. In our lifetime, we may well see the first crop of life saving medications distributed via plants around the world.
References
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