Reflections on 30 Years Traversing the Ag Biotech Landscape: Insights on Big Data, Digital Ag, and the Rise of Biologicals

Reflections on 30 Years Traversing
the Ag Biotech Landscape
Steven L Evans, Ph.D.
Re-Knowvate LLC
steve.evans@re-knowvate.com
Feb 11, 2020 NCSU GES 1
Re•orienting yesterday’s know•ledge to catalyze how we inno•vate today

Two Views Of The Ag Biotech Landscape
• Using contemporaneous story lines
1) How did rDNA for Ag turn into a Big Data / Software / Robotics ?
2) What happened to recombinant microbes in Ag - are they back as
“biologicals”?
• Some recurring themes
• Current discussions often have clear predicates
• Genetic technologies alone usually are insufficient to make a go of a business
this field

Initial Observations From My Trajectory
• Ag biotech landscapes can have vastly different representations
• Over any given decade a landscape view changes because companies
draw in allied technologies not historically ‘tied’ to biotech or
agriculture
• Because actual vs imagined product development timelines are
decades-long, things may cycle back in ways not obvious to current
practitioners

My Path Through One Landscape
KenMayberry,LinkedIn
https://www.linkedin.com/feed/update/urn:li:activity:6628003307828899841/?comm
entUrn=urn:li:comment:(ugcPost:6620344930638315521,6628003257191063552)

Last Week - A Focus On Seed Companies
Today how did “Digital Ag” emerge from Seed Companies?

Traditional Map Of Ag Biotech –
Seed Company Focused
https://philhowardnet.files.wordpress.com/2018/12/Seed2009.png
• To get from the lab to the
field one needed scale
(the large chemical or
pharma companies in
orange)
• Seed companies (blue)
were the key to getting
into the value chain
• The few yellow entities
were some of the
remaining biotech
companies
Flavr savr tomato 1994
GM tomato paste UK 1996
Golden Rice 2000
Bt cotton / RR soy 1996

First Seeds, 15 Years Later Big Data

Dupont Pioneer Into Farm Management
Software
https://agfundernews.com/dupont-acquires-farm-management-
software-granular-300m.html

Equipment Maker Seeks Machine Learning

Did Anybody See Big Data For Ag?
Blast from the Past - OTA 1992
The OTA operated from 1972 – 1995. Its mission enabled it to “became a key
resource for Congressional members and staff confronting technological
issues in crafting public policy.”
https://www.princeton.edu/~ota/ns20/cong_f.html

Vision Articulated Clearly – 1992
Ag needed vastly more information and decision support tools for ICM
In particular, expert systems should be considered for
integrated crop management decisions that would encompass
irrigation, nutrition, fertilization, weed control-cultivation,
herbicide application, insect control, and insecticide and/or
nematicide application (64).
Artificial intelligence can help automate one type of knowledge
acquisition (21, 66), that of rule formation. Machine learning, for
example, is an artificial intelligence technique for automatically
generating rules from a set of examples. This is sometimes called
“learning from examples. ” It can be used to assist experts to develop
rules or fill in where experts do not exist. For instance, rules for a crop
disease diagnostic expert system can be generated using a machine
learning system with a database of plant descriptions and associated
diseases.

More From Chapter 4, 1992
Another method of rapidly delivering information is through a wide-area computer
network. Much of the west- ern world currently is criss-crossed with multiple
computer networks. Two of the original computer networks are BITNET (figure 4-7)
and ARPANET. BITNET was initiated at the City [University of New York and was used
to connect major educational institutions. ARPANET was initiated by the
Department of Defense. Today there are national computer networks for the
government. commercial companies, and educational institutions.
Agricultural robotics research is proceeding in two directions. One involves sensor
technology (see following section) and machine vision. This is because, unlike pro-
duction line robots, agricultural robots will operate in environments where
interferences will be encountered.
Another major use of robots will be to micromanage crops. For example, a robot
with an image sensor to detect weeds could be used to spot-spray herbicides.
• Identified a key role for what would become the Internet in Ag technologies
• Clear articulation of Ag robotics in sensor tech and machine vision
• Described a future image-guided, spot-spraying robots for in-field weed control

One Of Several Detailed Lists -
Specific & Actionable

https://www.ecorobotix.com/en/
Besides Blue River (Deere)
Example, a Swiss company
founded 2011

The Wired Farm, 2000 & USDA 2019
https://ucanr.edu/repository/fileAccessPublic.cfm?calag=issuecoverpdf/ca540
4p1.pdf&url_attachment=N

A View Of The Start-Up Ag Landscape
Not focused on Seed Companies

Reflections On The First Story Line
• Genetic technologies are critical enablers but:
• products require more than just a gene(s) and
• business models require more than just an interesting
trait
• There existed specific and actionable information
about likely directions of the future, but info may
reside in information silos disconnected from
practitioners
• Ag technology today has a lot of stuff in it that is
neither obviously Ag nor obviously biotech
https://odditymall.com/giant-swiss-army-knife

A Dive Into The Genetically Modified Part
Some general themes
• Optimism about technology outpaces full implementation
• The cycle times of Idea to Industrial Implementation (I to I2) are long
• “Small” decisions in development cycles (by researchers, businesses,
regulators, stakeholders) are often disproportionally consequential
for ultimate acceptance or success

Story 2: The Plant Biotech Landscape ~2017
Start Now And Move Backward to the 1980’s
https://biofortified.org/biotech-companies/
2 areas of
PLANT biotech
dominated by
what are often
microbes aka
‘biologicals’

Microbes Historically Enable Ag Biotechnology
• Organisms themselves
• Inoculants, biopesticides, plant nutrition (metals, phytohormones)
• Antibiotics
• Frost protection / disease suppression
• Agrobacterium transformation
• Proteins
• Restriction endonucleases
• Fok nucleases
• TAL effectors
• Oh yeah, CRISPR-CAS
• Genes
• HT genes
• BT genes
• Drought Tolerance
• Transformation selection genes /visual markers
• Fermentation / Food Science / Colorants / Flavorings / Ag waste remediation
Essentially all of rDNA technology and gene /
genome editing is founded on enzymes from
microbes

Patents On Microbes In Ag Are Not New

Patents And Living GM Organisms
1980 - SCOTUS

Rise Of ”Biologicals” Discussed By NRC In 2000
https://www.nap.edu/catalog/1005/agricultural-
biotechnology-strategies-for-national-competitiveness

Money And Time Are Differentiators
https://www.nap.edu/catalog/1005/agricultural-
biotechnology-strategies-for-national-competitiveness
https://croplife.org/plant-biotechnology/regulatory-
2/cost-of-bringing-a-biotech-crop-to-market/

More Granular – A Trend-ish
https://croplife.org/wp-content/uploads/2018/11/Phillips-McDougall-Evolution-of-
the-Crop-Protection-Industry-since-1960-FINAL.pdf

Biopesticide Data Within Crop Protection
https://croplife.org/wp-content/uploads/2018/11/Phillips-McDougall-Evolution-of-
the-Crop-Protection-Industry-since-1960-FINAL.pdf
Growth of biopesticides is projected to
outpace that of chemical pesticides, with
compounded annual growth rates of
more than 15% [7]. It is expected that
biopesticides will equalize with
synthetics, in terms of market size,
between the late 2040s and the early
2050s, but major uncertainties in the
rates of uptake, especially in areas like
Africa and Southeast Asia, account for a
major portion of the flexibility in those
projections [8].
https://www.mdpi.com/2077-0472/8/1/13
In about 20 yrs it increased ~10x to 5.6% and in another 20+ years
may increase ~10X to 50%

A Look At Optimism:
1987 A Pervasive Technology
The power of biotechnology is no longer fantasy.
Biotechnology offers tremendous potential for
improving
• crop production
• animal agriculture
• bioprocessing
(yield, nutrition, disease resistance, stress resistance,
reduced fertilization, reduced chemical inputs)
(animal therapeutics and vaccines for disease
control)
(manufacture new products and foods, treat and use
wastes, and use renewable resources for fuel)
(forestry, fiber crops, and chemical feed stocks)
https://www.nap.edu/catalog/1005/agricultural-biotechnology-
strategies-for-national-competitiveness

It Was Crossing The Lab Threshold –
Dozens of GM Organisms Contemplated For Release

Table 1.1 .—Some Representative Pending and Potential Environmental
Applications of Genetically Engineered Organisms (1988)
Microbes
• Bacteria as pesticides. “ice-minus” bacteria to reduce frost damage to agricultural crops.
• Bacteria carrying Bacillus thuringiensis toxin to reduce loss of corn crops to black cutworm.
• Mycorrhizal fungi to increase plant growth rates by improving efficiency of root uptake of nutrients.
• Plant symbionts. Nitrogen-fixing bacteria to increase nitrogen available to plants, and decrease need for fertilizers
• Toxic waste disposal. Bacteria engineered to enhance their existing abilities to degrade compounds found in sludge in waste treatment plants.
• Bacteria engineered to enhance their abilities to degrade compounds in landfills, dumps, runoff deposits, and contaminated soils.
• Heavy metal recovery. Engineered enhancements possible to several species of bacteria now used to recover metals from low-grade ores (e.g.,
copper and cobalt).
• Pollution control. Possible increased utility of bacteria in purifying water supplies of phosphorus, ammonia, and other compounds.
• Viruses as pesticides. insect viruses with narrowed host specificity or increased virulence against specific agricultural insect pests, including cabbage
looper, pine beauty moth, cutworms, and other pests.
• Myxoma virus modified so as to restore its virulence against rabbits (which became resistant during early biocontrol efforts in Australia).
• Viruses as vaccines. Vaccines against human diseases
• Vaccines against animal diseases

My Work At Mycogen – Right In The Thick Of It
https://www.epa.gov/sites/production/files/2015-09/documents/ch4-wozniak-
etal-fifra-ffdca-tsca-112012_0.pdf
Because of the issues to be discussed
next, Mycogen developed and
commercialized dead recombinant
biopesticides.

BETTING THE FARM ON BIOTECH
By Keith Schneider June 10, 1990 New York Times
This is the agricultural landscape of the 21st century as envisioned by Howard A.
Schneiderman, senior vice president of research and development and chief
scientist at the Monsanto Company.
The sun beats down on green fields of corn that have never seen chemical
insecticides or weed killers. Over the ridge, docile Holsteins are producing more
milk on less feed than has ever before been possible, and piglets are growing into
lean adults at uncommon speed. The air is free of dust from eroding topsoil and a
stream drains the gentle slopes, its waters as sweet and pure as a mountain spring.
Supermarkets are jammed with the bounty of a skillful, careful farming that is as
safe as it is productive.
https://www.nytimes.com/1990/06/10/magazine/betting-the-farm-on-
biotech.html

''Monsanto is developing a way to use Mother Nature to modify organisms to serve us better,'' says Schneiderman, whose
favorite word for the technology is ''fantastic.’’
''The kind of biotechnology that Monsanto has embarked upon is silver-bullet technology that will prolong the system of
agriculture we have now,'' says Jack Doyle, director of the agriculture and biotechnology project at Friends of the Earth, an
environmental group in Washington.
''Two years from now every crop in the world will be easily manipulated,'' says Fraley. ''Ten years from now, in some plant
we'll know every gene, every protein, every function. There are no longer any technical restraints.''
Fervor and portent give this place the kind of electricity that must have charged the atmosphere at Columbia University in
the years just before World War II, when Enrico Fermi and Leo Szilard were testing theories for sustaining a nuclear chain
reaction. Indeed, genetic engineering could be as pervasively influential - and as enduringly controversial - in the 21st century
as atomic energy has been in the 20th.

Rifkin and Monsanto have clashed on other biotechnology fronts. In 1986 the company
announced it was ready to field-test genetically engineered bacteria designed to live
among the roots of corn plants and kill destructive worms
Monsanto shelved the field test after an investment of roughly $2 million…
but the episode - like the more recent BST flap - helped convince Monsanto of the need to
sell biotechnology to the American public.
''I think the ability to communicate in plain language to nonscientists hasn't been a fine
art,'' says Schneiderman, ''and a lot of people in the industry haven't thought it was very
important. There has been a certain arrogance about science, sort of like the church in the
Middle Ages.''

• From the previous slide 1986 was significant regarding field testing recombinant bacteria
• There was a predicate, BST & PST, that was shaping decision-making at Monsanto $300 mm
• The non-obvious (today) predicate for much of what became crop biotech was experience with
rBST
• The critical role of science communication was already acknowledged
Monsanto has spent $300 million developing the genetically engineered growth hormone for cows
three other companies have also been racing to bring to market (note: American Cyanamid, Eli Lilly and
Upjohn)

According to the Congressional Office of Technology Assessment, more than 400 American companies may be
spending as much as $2 billion a year on biotechnology research and development, not only for farming but for
medical and industrial uses as well. The major players in agricultural biotechnology include American Cyanamid, Dow
Chemical, Du Pont, Eli Lilly, Upjohn and W. R. Grace.
It is a business requiring huge investments that offer no immediate, or certain, return. Many small biotechnology
startups, especially those concentrating on agriculture, have been forced to merge with or sell out to bigger
companies - or have failed altogether. The pressure to show results is even falling on corporations the size of
Monsanto, the nation's fourth-largest chemical company, with sales last year of $8.68 billion.
• Even in 1990 the trajectory on consolidation was evident
• Technology companies had a tough time lasting 10 years
• Big companies will have a tough time lasting 30 years

A Field Release Of A GMO – Ice Minus
https://www.epa.gov/sites/production/files/2015-09/documents/ch4-wozniak-
etal-fifra-ffdca-tsca-112012_0.pdf
A single-gene clean genetic deletion of
part of the ice nucleation gene
No added genetic elements, no ‘vector
parts’, markers, no transgenes, etc.
Without the gene the organism no
longer produced an outer membrane
protein that promoted ice nucleation
(and therefore frost damage) on crops
Regulatory approvals but lawsuits
ensued

A Field Release Of A GMO ~1985-1987
Same Story. Three Lenses.
https://ucanr.edu/sites/calagjournal/archive/?image=img6602p48h.jpg https://science.sciencemag.org/content/237/482
1/1413.pdf-extract.jpeg
https://www.nytimes.com/1987/06/10/business/altered-
bacteria-fight-frost.html
Cal Berkeley and Advanced Genetic
Systems (AGS) with field releases
UC Ag Archives Science New York Times

Per EPA Some Biologicals Are Pesticides
Nothing To Do With GE, FIFRA Controls These

“The Jumpsuit” Became An Enduring Symbol
DESCRIPTION (BRIEF)
This jumpsuit was worn by a scientist from Advanced
Genetic Systems during the first release of genetically
modified microorganisms into the environment approved by
the federal government.
“Although the protective garb she wears implies that the altered
bacteria are hazardous to humans, they are safe. U. S. law requires
that protective gear be worn until the bacteria are approved for
use as a pesticide.” (caption in Science article)
This is why Mycogen began developing dead
recombinant products, the ability to release a live
recombinant product practically evaporated in 1987

What Happened To AGS?
Merged Then Re-directed Back To “Natural” Microbes
AGS- Frostban™ GM
DNAP- Frostban® Native
Plant Health Tech - Blightban® Native
*York International- Snowmax® Native (AGS > Eastman Kodak)
Food processing – Pseudomonas to Xanthomonas

“Fast” Forward 30 Years To Current Time
A GE Nitrogen Fixing Microbe
https://www.pivotbio.com/product

From Pivot’s Patent Application –
What is intergeneric??
• [M]any industry players in the microbial arena are focused on creating
intergeneric microbes.
• However, there is a heavy regulatory burden placed on engineered microbes that
are characterized/classified as intergeneric.
• These intergeneric microbes face not only a higher regulatory burden, which
makes widespread adoption and implementation difficult, but they also face a
great deal of public perception scrutiny.
• Currently, there are no engineered microbes on the market that are non-
intergeneric …
• This dearth of such a microbe is a missing element in helping to usher in a truly
environmentally friendly and more sustainable 21st century agricultural system.
• These microbes are not characterized/classified as intergeneric microbes and
thus will not face the steep regulatory burdens of such.

What Is Non-Intergeneric?
• [An] “intergeneric microorganism” is a
microorganism formed by the deliberate
combination of genetic material originally
isolated from organisms of different taxonomic
genera.
• Further explanation can be found, inter alia, in
40 C.F.R. § 725.3.
• In aspects, microbes taught herein are “non-
intergeneric,” which means that the microbes
are not intergeneric.
https://www.govinfo.gov/content/pkg/FR-1997-04-11/pdf/97-
8669.pdf
Rule issued 1997
TSCA not FIFRA

A GM Bacterium In Open Release?
Not Intergeneric & Not A Pesticide
• Pivot Bio’s microbes fall into
EPA’s soil amendments
category and are therefore
regulated by individual states
…. we are registered in 23
states and counting!
• https://blog.pivotbio.com/bio
logical-products-for-cleaner-
water
https://www.epa.gov/pesticides/epa-releases-public-comment-draft-guidance-
plant-regulators-including-plant-biostimulants

Draft Guidance – NOT Pesticides

Something To Contemplate –
Frostban-Like “Engineered” Organism in 2020
• Remember…
• It used rDNA to create a deletion with no added
transgenes
• TODAY
• Could be accomplished today via multiple
techniques including CRISPR
• In fact, EMS mutants were field tested
contemporaneously with the GM version
• Likely would not fall under MCAN, not
intergeneric
• However
• Likely still under FIFRA as a pesticide
• Can one contemplate a mechanism of action
that does not involve pesticidal action against
the ice plus organisms
https://www3.epa.gov/pesticides/chem_search/pp
ls/064004-00002-20001215.pdf
Even the non-GE microbes are regulated under FIFRA

A Few Quick Hits
• Examples with long historical predicates but no time to elaborate….

Predicate For Food Labeling - In The UK
PlantBiotechnologyJournal(2016)14,pp.835–838doi:10.1111/pbi.12463
U. Nottingham and Zeneca
Silenced polygalacturonase
Improved viscosity, better flavor
(not heat treated)
First GM food in US and UK
Competitively priced and clearly
labelled
~1.8 mm cans 1996-1999
https://theecologist.org/2015/feb/05/20-years-ago-today-what-have-we-
learned-gmo-flavr-savr-tomato

GM Salmon: Took A Long Time To Grow Fast
https://biofortified.org/wp-
content/uploads/2019/03/AquAdvantageSalmonV1.png

Biotech In The Press: Golden Rice
https://source.wustl.edu/2020/02/no-clear-path-for-golden-rice-to-reach-consumers/
https://www.nytimes.com/2000/05/16/business/astrazeneca-to-sell-a-
genetically-engineered-strain-of-rice.html
AstraZeneca to Sell a Genetically
Engineered Strain of Rice
By David Barboza
May 16, 2000
AstraZeneca P.L.C., a giant pharmaceutical
company, said today that it would sell a
genetically altered strain of ''golden rice'' in the
developed world and also help make the
technology freely available to the world's
poorest countries.
The London-based company, which announced
the agreement here in a news conference with
one of the scientists who invented the rice,
said it would be made available in three years.

Phage Recurrence
https://cns.utexas.edu/news/explaining-the-science-a-look-at-the-potential-
of-bacteriophages-in-a-post-antibiotics-world
2. Phage treatments aren't as new as the news
would you have think.
Phage therapy was discovered about 100 years
ago and was one of the only options to treat
bacterial infections for decades. The therapy
could be hit-or-miss, largely because scientists at
the time understood very little about how phages
worked. For example, a phage preparation meant
to treat cholera in India was preserved using a
mercury derivative for the long trip to a hot
climate. It turns out, preservative inactivates
phages.
When penicillin became commercially available,
phage therapy fell out of use quickly and research
funding to study phages largely dried up in the
1970s, Molineux explained. (italics added)

Environmental GM Biosensors – TNT Detection
1997 (Lockheed) … 2017 (Israel)
https://www.osti.gov/servlets/purl/463656

In Closing > 2017 IGEM Team From France
Re-thinking GM Frost/Heat Protection
http://2017.igem.org/wiki/images/4/4b/Ionisparis-
Applied_design_-_Frostban-report.pdf

In Conclusion…For Now
• Technology changes faster than do products
• Tech enthusiasm seems to hit a reality wall in ~ 5 years
• Product cycles can still be decades-long even if the front end is faster
• Technology companies cannot usually hold out that long
• Pioneering researchers are ‘aging out’ >80 if at Asilomar
• <33 not even born for Ice-minus
• There is a lot of information about the future out there, but it may be hard
to find (hint, look at DARPA & IARPA today)
• Do not know that we have fully implement effective communication with
society
• If you think what you’re working on is BRAND new, have coffee with
someone who has been around in the area at least 20 years

Thank You!
• Questions

The “Ideas to Industrial Implementation”
Funding Challenge
This publication is a Technical
report by the Joint Research Centre
(JRC), the European Commission’s
science and knowledge service. It
aims to provide evidence-based
scientific support to the European
policymaking process.
https://s3platform.jrc.ec.europa.eu/documents/20182
/201464/Drawing+funding+and+financing+scenarios+f
or+effective+implementation+of+Smart+Specialisation
+Strategies/4296838f-13ea-433e-88c2-689456f01b95

Hype Cycles
The concept of
Gartner Hype Cycles
might be useful more
broadly in biotech

June 2019 An Example With Crispr
https://mycrispr.blog/2019/06/26/crispr-slipping-into-
disillusionment/

What Was Hot In Plant Biotech 25 Years Ago
http://dels.nas.edu/Report/Future-Role-Pesticides/9598

House Testimony AGS 1986
Ice-minus, A Case Study of EPA's
Review of Genetically Engineered
Microbial Pesticides : Hearing
Before the Subcommittee on
Investigations and Oversight of the
Committee on Science and
Technology, House of
Representatives, Ninety-ninth
Congress, Second Session, March 4,
1986 – United States. Congress.
House. Committee on Science and
Technology. Subcommittee on
Investigations and Oversight
https://play.google.com/store/book
s/details?id=1BYMrlYFQwwC&rdid=
book-1BYMrlYFQwwC&rdot=1

2017 IGEM Team from France
Re-thinking frost/heat protection
It was very informative to compare Softer
Shock with Frostban because it gave insight
into how GMOs and synthetic biology have
evolved technologically during the last 30
years. An example of this are the killswitch
mechanisms that have recently emerged, as
well as synthetic auxotrophy. Scientists around
the world, with lessons from projects like
Frostban, can now work on making better
GMO and synthetic biology products with
better containment and engineering. Perhaps
in the coming years more containment
mechanisms will be created and society might
accept synthetic biology, if it is correctly done
and if the people are correctly informed.
http://2017.igem.org/wiki/images/4/4b/Ionisparis-
Applied_design_-_Frostban-report.pdf

An Early Kill Switch Work –
Not Created By Synthetic Biology

Figure Shows The Low Amount Of Work on
Auxotrophy And Kill Switches Post 1987
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC355495
8/pdf/fmicb-04-00005.pdf

“First & Last” Again? Thirty One Years Apart

An Additional Value Of Germplasm Once
Genomics Became Cost Effective
https://doi.org/10.1016/j.xplc.2019.100005

Animal Genome Editing
https://www.nature.com/magazine-assets/d41586-019-
00600-4/d41586-019-00600-4.pdf

About Steve
• 30 years in small/large ag and environmental biotech
• Technical leader for bioanalytical chemistry Mycogen biopesticides
• Fellow at Dow AgroSciences/Corteva in biochemistry, advanced
analytical technologies, Zinc Finger technology… and synthetic biology
• Extensive work in public-private partnerships
• Work with experts here on societal impacts
• Formed Re-Knowvate LLC in Q2 2019
Vision for re•Knōw• vate: Orienting your organization’s innovation so you can solve today’s most pressing problems

Reflections on 30 Years Traversing the Ag Biotech Landscape: Insights on Big Data, Digital Ag, and the Rise of Biologicals

Recommended

Recommended

More Related Content

Similar to Reflections on 30 Years Traversing the Ag Biotech Landscape: Insights on Big Data, Digital Ag, and the Rise of Biologicals

Similar to Reflections on 30 Years Traversing the Ag Biotech Landscape: Insights on Big Data, Digital Ag, and the Rise of Biologicals (20)

More from Genetic Engineering & Society Center

More from Genetic Engineering & Society Center (17)

Recently uploaded

Recently uploaded (20)

Reflections on 30 Years Traversing the Ag Biotech Landscape: Insights on Big Data, Digital Ag, and the Rise of Biologicals