Thoughts from Professor Adam Arkin, UC Berkeley, leading scholar in systems and synthetic biology.
The world situation
There are a number of large global problems facing humanity today. Possibly the largest is food. By 2050 or 2060 we expect to have 9 billion people on the planet, and by some estimates to feed those people we need to increase our food production by about 40%.
At the same time, the amount of land we can use for cropping is going down, the quality of land and water are being degraded, and scarcity is an increasing problem. As we become more populous infectious disease becomes incredibly important.
If we’re going to solve those problems, which become very significant on the order of our lifetimes, and certainly in the lifetimes of our children, we have to get moving.
There are a number regulatory, civil and mechanical things that can and should be done to ameliorate these problems, but biology is always in the loop here. Good sources of food, for example, rely on healthy and plentiful plants or animals, and these are reliant on—and themselves deeply impact—their surrounding ecology.
Biology represents a store of chemical, mechanical and physical activities unparalleled by our human-made technology. Microbes, for example, encode enzymes with otherwise inaccessible chemical activities that open up new vistas for synthesis and production of novel and renewable chemicals, pharmaceuticals, materials, and even edible products.
This storehouse is vast. There are about 10^35 bacteria on earth, existing just about anywhere, from the bottom of thermal heat vents in the ocean, to the center of the earth, to inside us. They are “small programs” that have solved the problem of living nearly anywhere with limited resources and variable, harsh conditions. They’ve evolved to interface with their environment and transform it in ways that are conducive to life, and use the available resources effectively.
A side effect is that, with efficient use of a large variety of resources, they can make stuff that can be of benefit to mankind. Further, they have evolved to live directly with us, our animals, and our plants. While in some cases they are parasites or other diseases, the vast majority of interfacing microbes benefit our extraction of nutrition, enhance our immunology, and can actual protect against infection and increase our resilience to environmental change.
What systems and synthetic biology is about is about trying to harness the genetic potential of the earth to solve some of these problems in soil quality, water quality, plant productivity, nutrition, and human-impacted health. To do that we have to evolve a series of technologies.
Where we are now
In the last 15 years people have recognized that we are at a technical inflection point—our ability to read DNA is incredibly cheaper and faster than it was before, and key technologies such as mass spectrometry and imaging have made incredible strides in accuracy, speed and resolution—so our insight into the genetic and biochemical basis of all these processes has increased enormously.
Genetic engineering, which has been around since the 70s, has also hit an inflection point. Our ability to synthesize DNA and implant it effectively into cells has changed to such an extent that we’re able to synthesize whole chromosomes and genomes from scratch, recode them for safety, and “boot” them into host cells.
This, along with innovation and discovery that give us the ability to edit genomes rapidly, in particular the CRISPR system, changes the way we think about the genetic engineering that we can do with cells.
Emerging out of these is the first formation of seriously operating biological foundries that allow manufacturing of cells with modified DNA at astounding rates. At these few facilities, one of which is here, you can sit down at a computer, specify in a formal programming language a circuit you want to build in a cell, and it will compile the DNA you need and transplant it to the cell automatically.
While currently these foundries and their software are fairly limited in application and domains of function, we’ve reached that first stage of a true engineering discipline that allows us to specify desired function at a high level and, with relatively high confidence, manufacture the desired biological object.
Now, what do we want?
That’s harder, because we still don’t know entirely what we need to solve the problems.
For a large number of desired chemical and material products, for example, it is unclear what enzymatic pathways or even what bacterial hosts are necessary to produce the targets. While there are celebrated examples of success, such as Jay Keasling’s engineering of the pathway to make the world’s supply of artemisinin for malaria, the functional space for new antibiotics or advanced polymeric materials is vast and the enzymatic world still less characterized than we need.
If we wish to protect people from infections or immune issues such as Crohn’s disease, how do we design/enhance gut microbial communities to be most effective, persistent, and safe? If we wish improve plant productivity with less fertilizer in non-ideal soils, how do we modify the plant and its root and leaf communities to be stress tolerant, a more effective user of in situ resources, and even more nutritive?
The core challenges come in at least three varieties. First, there is still an amazing amount to learn about the core mechanistic biology of the diversity of life on the planet. For even the best-studied microbes we still don’t really know much about what 30% of the genes are doing.
Second, we have still have very little understanding of how these organisms function in natural ecological settings. While this is improving, understanding the mechanistic principles of ecological and environmental function is a key challenge.
Third, the ability to rapidly and predictably engineer organisms with desired functions, while improving, is still nascent, and an effective design-build-test-learn cycle needs to be built out and industrialized for a number of different application types and in the uncertain environments that exist beyond the bioreactors used for chemical production.
Some things are coming that are extremely exciting.
Number one: people, including my lab, are working on how to build organisms that are themselves designed from the ground up to be able to accept circuitry and components quickly, and that are so well characterized that we can predict how they operate within those cells and under different conditions.
Number two: We have built technologies using high-throughput genetics and genomics that allow us to rapidly harness and manipulate new organisms, and very quickly query every single gene for its functional operation in situ, under lots of environments.
For example, my group has been collaborating to examine the function of every gene in several organisms under, in some cases, hundreds of conditions. These hundreds of thousands of queries of genetic function have allowed us to annotate and correct annotations for thousands of genes in just a few years in a great diversity of otherwise uncharacterized organisms. That’s more that have been annotated I think in the previous decade. Other people are beginning to deploy mass spectrometry technologies on that same scale. My team leads the development of computational platforms that integrate all this information and allow scientists to openly and collaboratively build actionable models of microbial and plant function that we are beginning to use in design of new biological function.
On top of this, our group has been developing methods to quantitatively control expression of these genes and transplant complex circuits containing them in different hosts. Putting this all together, we are working with others to transfer these technologies to the emerging biological foundries that enable the scientific community and industry to accelerate production of biological solutions.
Now we are in a position to have an extreme effect on the manufacturing pipelines of the world, making them greener and more renewable in just the next 5-10 years. There are a few things that have happened that make this much more possible.
First, we’ve become much, much better at doing modest modifications of the diverse organisms that operate already in these environments, therefore reducing the risk that we’re going to cause something untoward to happen or cause that system to fail because we don’t understand it well enough.
Second, our ability to characterize and modify the ecological dynamics and activity of organisms, even complex communities of organisms, in situ has greatly improved and we know a lot more about what makes a healthy ecology, what is safe, and what is necessary for fitness than ever before.
Third, our ability to monitor and contain engineered organisms has become better.
The next transformative step is moving beyond the bioreactor.
Given the pressing global problems mentioned above, we need to engineer plants and microbes that can survive in and clean filthy water, and that can better utilize nitrogen and phosphate, so we don’t have to overuse fertilizer and end up with these in our water supply or cause eutrophication of our lakes.
We’re also beginning to be able to understand how the microbiome affects health and behavior, and the rules for cultivating and feeding those microbiomes so that they become healthier, and for engineering them to do tasks that they wouldn’t do otherwise that are to our benefit.
We’re seeing an increasing ability to respond to disease. For example, right now it is possible to go from field measurement of an emerging influenza strain in China, to synthesizing a vaccine strain in San Diego, in 4-8 days. It’s an amazing leap in ability to deal with infectious disease.
Because of our huge amount of knowledge about microbes and their ecology, we’re beginning to see whole new classes of natural products, including the potential for the first new effective antibiotics in over 20 years. We’re gaining the ability to mine the genes responsible for mediating the natural ecologies amongst plants and microbes and locate the genes that allow them to fight infection or fend off predators. They were invisible to use before and now we can find them.
So we’re going to see, I think, an increase in the chemical diversity of the pharmaceuticals we have to treat diseases, and infectious diseases.
Upcoming growth areas
Because of the onslaught of the ability to measure everything, the amount of data we are producing is extraordinary. We are finally reaching the level where we can really and seriously call this big data.
In biology we have challenges that most big data problems don’t have, in that it’s not a uniform type. We have truly multi-instrument, massively structured data sets, which are very much informed by the context in which they are taken.
The data science to operate on that information is emerging as critical in every area of biology. Personalized medicine is founded on our ability to analyze datasets about huge human populations to come up with an individualized treatment for you. Advances in agriculture are based on the ability to measure everything from large climate models dynamics all the way down to how microbes operate at the pore level of soil. Precision ecology is the next frontier from the microbiome on your skin to that which mediates carbon-uptake in the ocean.
Data management, data science, data analysis and visualization, are going to be absolutely key to almost every field going forward and is a huge area for growth.
Also, we need to go ubiquitous and continuous. I want to be wearing things that are measuring my health state, I want things in the soil that are measuring the health of the soil, I want things in the water—just everywhere. Remote low-power or no-power microelectronics is going to be enormous.
The idea that we can pack large amounts of sensors in small cheap packages, and interface them to biological sensors, is incredibly important, and we’re seeing innovation in making things out of non-traditional materials like paper, so we can create on-demand without having a large foundry.
This could change the way we deliver health and information in underserved communities. We could, for example, build a diagnostic for the Zika virus very quickly with rapid, cheap, scalable manufacturing of the chip and microfluidics, and with the molecular engineering necessary to build the biosensors themselves.
And finally I think that because this engineering is so intimately attached to the ecology of the earth, getting a fine understanding of how things operate in situ is a big deal, and getting much finer understanding of the ecology is critical.
A unique opportunity for perspective and focus
Many of the students from our program have ended up thinking about law, policy, economy, and sociology. They are really thinking about the impact this technology has on us as humans, and how laws should be made so this isn’t abused, so that we can co-design our solutions with better regulations and better distribution.
It’s important to ask how we can ensure that the communities we’re serving will accept the technologies we’re developing for them. A lesson stands in Golden Rice, a strain engineered with three genes for beta-carotene production designed for communities with endemic Vitamin A deficiency, which leads to forms of blindness, susceptibility to measles, and other infections. In addition to the standard objections to GMO foods, the community initially viewed the rice as foreign or substandard.
We have to understand what our community needs and how to best communicate with, learn from, and teach those communities what we can do for them. Of course, we must remember that not all solutions need to be biotechnological.
We need people who understand how to meld technology and economy, because we have to really understand what the barriers are in making a product impactful and profitable. In metabolic engineering, for example, barriers can exist at the enzymatic level, the microbial growth level, the product extraction level, the formulation for delivery and shelf-life, the transportation costs, etc.
A trained bioengineer who is willing to learn how to do the economic modeling can have a profound effect in focusing our efforts on the right topics as opposed to things we just find interesting.
Berkeley is a great place to be doing this work because of our amazing intellectual community, with deep benches in molecular and environmental biology, biotechnology, public health, public policy, and big data. Also critical are our close ties with UCSF and with Lawrence Berkeley Lab scientists and infrastructure like the Joint Genome Institute, the Molecular Foundry and the National Energy Research Scientific Computing Center, and elsewhere. We have a wonderful ecology of people here.
Because Berkeley is a public university and has public service at its heart, it is a place where we can bring together those resources for these large scale problems. We’ve also really supported a culture of academics who are engaged in the community and will ensure that we are serving that community well.
We’re able to take on problems of scale here that are interdisciplinary, that are far more than the sum of their parts. This is the perfect place to do this work if we can organize ourselves to do that.