Pharming: Past, Present, and Future
By Owen Yingling
Pharm Livin’ is The Life for Me
By Patricia Patnode
Green Acres is, perhaps, the most perfect show ever to grace American television screens. The main character Oliver Wendell Douglas (played by Eddie Albert) is a wealthy New York City attorney who abandoned his law practice and moved to a run-down farm. Throughout the series he explains, and re-explains, his emotional motivations for changing career directions.
"This has been the dream of my life to buy a farm. Move away from the city, plow my own fields, plant my own soil, to get my hands dirty! Sweat and strain to make things grow. To join hands with you, the farmers. The backbone of our economy,” says Farmer Douglas.
With his beautiful Hungarian wife (played by Eva Gabor) in tow and a dozen zany side characters added, the American public was blessed with six seasons of agricultural joy.
But, it wasn’t easy. Oliver persistently struggled with growing healthy plants, and keeping happy cows, like many farmers do in real life.
Oliver and Lisa moved to, by all accounts, what we would consider a hobby farm. A relatively small parcel of land that could not independently compete revenue-wise (at least today) unless they specialized in a particular crop or animal that had a motivated consumer audience (e.g. organic greens, friendly named-cows with Instagram pages, free-range eggs laid by chickens with personalized coops, etc.).
The American farm is not what it once was.
There are more than 2 million farms in the U.S., but they vary greatly in size. For example, annual gross revenue for a “farm” can range from as little as $1,000 to more than $5 million. Zoning laws permitting, it could be possible to run, what the USDA would consider, a “farm” out of a large urban condo, especially with today’s indoor growth technology.
Still, even with that broad definition and today’s technological leaps in agriculture, not many lawyers are escaping to green fields in Nebraska. This is partly because farmland is expensive and partly because there’s a steep learning curve. Underlying these two realities are large farm growth and land accumulation.
“After peaking at 6.8 million farms in 1935, the number of U.S. farms fell sharply until the early 1970s. Rapidly falling farm numbers during the earlier period reflected growing productivity in agriculture and increased nonfarm employment opportunities. Since 1982, the number of U.S. farms has continued to decline..” (Source: USDA)
Farm life is a beautiful, difficult, worthy endeavor— Green Acres got that right. Looking to the future, with our food science innovations and increasing demand for specialized food products, it will be possible for diverse, small farms to be profitable.
Pharmaceutical-farming (pharming), vertical farming, genetic engineering and growing organic and free range interests could revive the small family farm model and revive a fading way of life for a new generation of Americans.
Key Recommendations:
Eliminate land use regulations that stand in the way of serious innovations in agriculture.
See: Zoning Policies Intended to Support Agricultural Abundance Are Failing By Emily Hamilton.
FDA and USDA should create a clearly defined, common sense regulatory framework for pharming so that companies can operate instead of stagnate.
FDA has been publicly developing their regulatory capacity for lab-grown meat since at least 2018. However, it took the FDA a little under two years to approve cultivated chicken for sale after companies initially applied for approval. Being the first in an industry, there were likely collaboration quirks that needed to be worked out between FDA and USDA. Going forward, FDA should streamline the inspection of production facilities to meet consumer demand and allow for market growth.
See: Lab Grown Meat: To Eat Or Not To Eat? A Response To The Cultivated Meat Panic By Patricia Patnode and Owen Yingling
Highlights from the essay:
“The story of pharming is tragic because it shows how uncoupled scientific progress and concrete real world success can be”
“Our smartest scientists often face an uphill battle after they discover or invent things of enormous importance because of irrational regulatory barriers or public misconceptions about their work.”
Pharming: Past, Present, and Future
By Owen Yingling
Pharming: The process of genetically modifying plants and animals so that they produce substances which may be used as pharmaceuticals.
In February 2002, a small biotech company called ProdiGene Inc. was ecstatic: they had been using a novel production method to produce recombinant proteins — proteins expressed by foreign genes inserted in host cells which are crucial for the production of many pharmaceuticals — and were beginning to scale up their operations. In less than a year their business had fallen apart; headlines declared that, “PRODIGENE OFFICIALS MAY FACE JAIL” and they were forced to burn millions of dollars worth of their crops on top of a $3 million dollar fine from the FDA. Worse, ProdiGene’s fall took down what was once one of biotech’s most promising sectors with it. The near collapse of an innovative and promising branch of biotechnology over a virtually harmless bad PR incident and its, at least in the eyes of the broader market, stagnation in the years since is an important reminder of how disconnected the world of products, regulations, and profits and the world of the lab can be. Our smartest scientists often face an uphill battle after they discover or invent things of enormous importance because of irrational regulatory barriers or public misconceptions about their work. We need to ensure that the world changing power of human research is not hidden in the world of the lab, only kept alive by occasional journal articles lamenting the “potential” of new technologies if they could only escape crushing regulatory burdens and a fear-mongering media.
How did they do it?
Traditionally recombinant proteins, whether enzymes, antibodies, or tissue cells, are manufactured in mammalian or yeast cells cultured in bioreactors, cylindrical tanks containing a liquid medium engineered to spur the growth of the desired cells. While effective, production using bioreactors is often expensive, requires a large capital investment, and is not easily scalable to meet demand — downsides that have become very apparent recently given the new need for bio-pharmaceutical agents in growing sectors like the cultivated meat industry. But beginning in the 1980s, scientists experimented with another way to produce proteins: genetically engineering plants to express desired proteins and then planting and harvesting them like regular crops. The technique became known as “pharming.”
Pharming promised easily scalable protein production at a much lower cost than traditional methods — in a practical sense the ability to easily meet the growing demand for proteins, particularly antibodies, which could have had an enormous impact on global health efforts. But that wasn’t pharming’s only benefit: researchers looked for ways to derive disease cures directly from the transgenic plants and even toyed with the idea of not just using pharming to create recombinant proteins to be harvested but also leaving pathogen antigens inside food crops, in essence creating edible vaccines that could be easily transported and administered. While this might seem a bit worrying: “the government will put stuff in my food…give me drugs against my will…etc,” it’s worth noting that a majority of medicines are already delivered orally via tablets or dissolvable powders, so a truly “edible” delivery system is just one more step in a chain of drug delivery innovations away from uncomfortable shots and nasal sprays.
More than 1.5 million people die a year of vaccine preventable diseases, almost always due to lack of access to the necessary vaccines. One of the primary reasons for this are the strict temperature requirements for the storage of many vaccines. If the expressed antigens are left in the plant they are easier to transport than traditional vaccines, since the seeds and fruits don’t need to be kept at a certain temperature. This could make transport easier, greatly simplify logistics, and potentially increase the reach of vaccination programs in the developing world. Pharming could also save lives by reducing the price of vaccines — for instance, it’s estimated that enough anthrax vaccine to inoculate the entire US could be grown on one acre of tobacco at a price far cheaper than the hundreds of millions that the US spent on anthrax vaccines in the early 2000s. Additionally, the risk of pandemics and other disease outbreaks are always present, and pharming could offer another path for vaccine development which could speed up the global health reaction to new threats.
By 2003, over 100 different recombinant proteins had been produced using transgenic plants as the expression vector and scientists estimated that proteins could be produced at “0.1% of the cost of mammalian cell cultures.” At the time, the industry was growing rapidly and was made up of a number of small companies focused on a few products each. Initially the sector was generally aligned with regulators who, while recognizing the potential risk of crop contamination, were generally supportive of pharming efforts: in 2002 the FDA hosted a conference on pharming along with a number of representatives from different interest groups and created a report that, while cautious, offered a balanced perspective that is striking given the anti-GMO sentiment at the time. And between 1995 and 2002 the USDA approved the planting of pharming crops at over 300 different test sites.
Yet socially and regulatorily pharming companies were still in a precarious situation: the anti-GMO movement was growing in strength and had seized on incidents like the Starlink corn recall in 2000 to argue that any growing of genetically modified crops risked endangering the food supply, even if the crops were not being produced for consumption. The pharming industry generally assumed that the dramatic benefits provided by their technology would be enough to win over regulators and skeptics.
They were wrong.
In 2001, ProdiGene planted and harvested a test crop of corn plants modified to produce the protein aprotinin but some of the corn was left and later harvested with a conventional soybean crop planted in the same field and intended for human consumption. This sparked national outrage and numerous calls from US food companies to ban the usage of food crops to produce pharmaceuticals. The National Food Processors Association even declared that pharming posed an “unacceptable risk to the integrity of the food supply.”
There was additional hysteria over early reports that the genetically modified crop was producing an experimental AIDS vaccine or a blood thickening agent. But ProdiGene destroyed the remaining crops that the FDA believed had been contaminated and no cases of harm were ever linked to the incident. The ProdiGene “incident” and subsequent waves of anti-GMO lobbying delivered the pharming industry a crippling blow.
Pharmaceutical companies were reluctant to continue sourcing drugs from genetically modified plants — many smaller companies, although not ProdiGene because it was quickly purchased by Stine Seed Company, folded and several larger biotech companies including Monsanto, who had once been a pioneer in genetic engineering innovation, completely dropped their research into plant-made pharmaceuticals.
The FDA used the situation as an opportunity to wield the regulatory hammer against the nascent pharming industry — they tightened rules for field trials in 2003 and released a draft guidance regarding “Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals,” which, while legally only a recommendation, controlled pharming regulatory policy until its withdrawal in 2015.
Under the new FDA regulatory framework, unlike other genetically modified plants, plants designed for farming were not eligible for a deregulated status and require a full permit for any “import, interstate movement, or field release.” Deregulated genetically modified plants, of which there are over sixty, only required a report for any of these actions — a significant reduction in red tape compared to the process for pharming plants. Additionally the USDA changed their approval process for planting transgenic plants used to produce pharmaceuticals from only needing notification of planting from the company to forcing them to go through a permit process for every crop before authorization. The USDA also increased the stringency of their containment policies to further mollify fears of contamination raised after the ProdiGene incident.
The regulatory impact on experimentation and innovation was immediate: from July 1, 2001 to June 30, 2002 the USDA issued 25 permits for pharming crops, in the year after the ProdiGene incident they only issued four. And to this day, there are only a handful of plant derived drug products that have been approved by regulatory agencies and entered the market.
The story of pharming is tragic because it shows how uncoupled scientific progress and concrete real world success can be.
Pharming is an incredibly well studied field and there seems to be a consensus that if scaled up, it could significantly reduce costs in the recombinant protein industry. But the gap between its theoretical advantages and real world application has been significantly widened by challenges unrelated to the feasibility of the technology itself, namely its intensive regulation by the FDA and USDA and the resulting unwillingness of many larger pharmaceutical companies to go beyond just investing in research and development to actually try and help small pharming companies scale and get regulatory approval. And, of course, the original withdrawal of biopharmaceutical industry support after the ProdiGene incident sent pharming back to square one and resulted in the ascendancy of more expensive but less risky fermentation methods of recombinant protein production.
But, there still may be hope in the future for pharming: a transgenic plant derived antibody treatment called ZMAPP was used during the 2014 Ebola Crisis, Canada approved a plant based Covid-19 vaccine that was shown to be 78.8% effective against severe infections, and pharming company ORF Genetics has commercialized both human epidermal growth factors and human growth hormones in recent years. Additionally investment seems to be returning: in the past decade several commercial scale facilities for pharming products have been built with three receiving funding from the Defense Department.
Currently, innovators still face a multitiered regulatory system. They must get permits from the USDA to transport and field test their products and then go through the entire FDA drug approval process before pharming products can enter the market. If these agencies did anything to streamline the process, particularly the cumbersome USDA field test and transportation permits, it would tremendously benefit the industry and eventually perhaps the entire global healthcare system.
Pharming’s recent achievements are impressive and the increase in investment is a welcoming sign. Yet, pharming will only be able to succeed if the FDA and USDA, who have left pharming stagnating for the past two decades, can create a clearly defined common sense regulatory framework that can spur growth and let pharming finally deliver on the benefits that it has promised for so long.
Owen Yingling is a Mercatus intern and student at The University of Chicago (Class of 2027)
Further Reading:
Discourse | Zoning Out American Families by Emily Hamilton
Mercatus Policy Brief | Housing Reform in the States: A Menu of Options for 2023By Salim Furth & Emily Hamilton
Farming Abundance | Phony Demand and Underpopulation: Problems Plaguing American Farmers By Matthew Yglesias
Farming Abundance | Lab Grown Meat: To Eat Or Not To Eat? A Response To The Cultivated Meat Panic By Patricia Patnode and Owen Yingling