SCIENCE science.org 24 DECEMBER 2021 • VOL 374 ISSUE 6575 1565scale capacity, intentionally providing fund-
ing for maintaining necessary staffing, cre-
ation of a network to improve accessibility,
and greater incorporation of these facilities
into training programs.
Current academic training is primarily fo-
cused on biocatalyst development with mini-
mal bioprocess optimization, owing in part
to the lack of access to pilot-scale facilities.
Along with restricting bioprocess develop-
ment, training of students is similarly ham-
pered. Without training in bioprocess and
technological development, and the equip-
ment needed to do so, biocatalytic advances
that culminate in high-performing enzymes
or microbes will continue to be very difficult
to deploy commercially because the lack of
suitable bioprocess infrastructure will pre-
vent realization of laboratory-demonstrated
TRY (titer, rate, and yield) at scale and there-
fore economies of scale.
A parallel need, although at the oppo-
site end of the spectrum, exists for reliable
scale-down methodologies and equipment.
Modern genetic methods can generate a
wealth of microbial variants in the quest
for overproducing strains. The potential of
these strain candidates must be assessed
under conditions that resemble as closely as
possible the actual bioprocess environment.
This task requires small-scale equipment to
evaluate multiple strains in parallel and thus
increase throughput and reduce cost. Several
miniaturized systems have been developed
recently ( 10 ), but further validation is needed
to ensure that they accurately recreate scale-
up conditions. To accomplish this, access to
scale-up facilities is required, and accurate
strain characterization may require “omics”
systems biology measurements in addition to
macroscopic process measurements. These
measurements will allow faithful recreation
of the commercial-scale environment with
the small-scale systems. One may never be
able to create an accurate scale-down system
if the large-scale system is undercharacter-
ized. In particular, there is an acute need for
greater emphasis on scaled-down systems re-
capitulating cell stresses (and thus resulting
phenotypes) of large-scale cultivation, such
as shear effects, gradients of pH, tempera-
ture, dissolved gasses, substrates and nutri-
ents, and other limitations of mass transfer.
Once achieved, accurate scale-down systems
are invaluable for more rapid strain engineer-
ing because they will allow the generation of
datasets for testing numerous strain (genetic)
variants under different conditions. This ap-
proach is in contrast to most current datasets
that screen many parameters or conditions,
but for only a few strains. If successful, these
scale-down systems could represent a major
advance in addressing the “test” step of the
strain optimization cycle.
E D U CAT I O N
There has been a decline in teaching bio-
chemical engineering fundamentals among
many universities. Courses on cell growth and
product formation, bioenergetics, enzymol-
ogy of single enzymes and bioreaction net-
works, bioreactor design, and bioseparations
have been exchanged for emerging fields
such as nanotechnology, molecular biotech-
nology, biomaterials, and drug delivery. This
is part of a general shift toward the molecular
scale and pure sciences at the expense of en-
gineering emphasis ( 11 ). Yet, biochemical en-
gineering topics are central to understanding
cell function and to the design and success-
ful operation of bioprocess equipment of any
scale. The primary drivers of this educational
shift are research funding, scientific journal
recognition, and the overall reward system
that emphasizes molecular over bioprocess
research and development, often placing a
priority on novelty over problem solving and
real-world impact. This is a serious issue that
impairs the overall enterprise of industrial
biotechnology because graduates lack experi-
ence and training to fill key positions, such as
those involved in fermentation and scale up
of downstream processes ( 12 ).
This issue needs to be addressed at mul-
tiple levels. At academic institutions, one
possibility is through increased or renewed
investment in master’s-level courses and
training that will cover the basics of industrial
biotechnology, particularly training students
versed in engineering fundamentals (kinet-
ics, thermodynamics, and transport phenom-
ena), bioprocess (vessel design, operation,
and sterility), and bioseparations. In these
programs, an emphasis should be placed
on solving open-ended design problems in
multidisciplinary teams, acknowledging that
complex solutions require diverse expertise
(for example, bioreactor design and automa-
tion requires biochemical, mechanical, and
electrical engineering skills). For example,
the Masters of Bioprocess Engineering in the
Department of Chemistry at the University
of California, Berkeley provides hands-on ex-
perience through industrial internship and
their partnership with the Advanced Biofuels
Processing Demonstration Unit.
Training in these areas must be differenti-
ated from that of pharmaceuticals because,
for example, it is a different challenge to
concentrate (remove water from) a protein
solution than it is to concentrate chemical
products. There also needs to be greater part-
nership in the formulation of these courses,
across academia and industry. Very few en-
gineering departments carry the full breadth
of expertise to teach all necessary courses,
but in the era of virtual classrooms, academic
consortia could be formed to bring the nec-
essary skills and provide broad coverage ofthe curriculum. With respect to industrial
involvement, there would be benefit from in-
creased opportunity for site visits, with co-op
opportunities for hands-on experience, and
the possible creation of modified or redacted
case studies provided by industry for aca-
demic settings. And there would be benefit
from investment at the community college
level, helping train students for roles such as
equipment operator.
With respect to professional recognition,
translational research ought to be given a
higher profile. For example, advancing titers
of milligram to multigram per liter values at
pilot plant scales or works that provide inno-
vative downstream processing techniques for
separation of challenging products involve
ingenuity and novelty that often go unrec-
ognized by academic reward systems. The
reward system should be reevaluated to rec-
ognize the importance of problem-solving , as
opposed to the present focus on novelty and
curiosity, and this should be reflected in jour-
nal publications as well as research funding
decisions. Novelty is important, but so are
solutions to real problems that impair inno-
vation and industrial productivity. Just like
the National Science Foundation investment
in the Massachussetts Institute of Technology
Biotechnology Process Engineering Center
undergirded the rise of the cell-culture indus-
try, a similar program focused on industrial
biotechnology could revitalize this critical
industry today.
Ultimately, to reap the potential benefits of
industrial biotechnology, appreciation must
be given to, and investments made in, the
innovation and ingenuity required for trans-
lating to practice emerging scientific break-
throughs. jREFERENCES AND NOTES- C. J. Paddon et al., Nature 496 , 528 (2013).
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ACKNOWLEDGMENTS
This manuscript is the product of discussions at a work-
shop convened in Augusta, Georgia, USA, by Manus Bio in
November 2019. For a resource-related workshop, the follow-
ing website has been prepared: http://www.rcm-biomanufacturing.
org. We gratefully acknowledge T. Papoutsakis, J. Liao, and
C. Cooney for their careful reading of and feedback on this
manuscript. K.E.J.T., C.N.S.S., P.K.A., and G.S. have financial
interest in Manus Bio.10.1126/science.abj5040