Even with his celebrated skill for making meticulous observations of nature, Charles Darwin never could have seen anything like the E. coli glowing fluorescent green in a laboratory at the University of Minnesota.
The natural forces of evolution Darwin described so famously 150 years ago did not craft these bacteria.
Laboratory workers did. They took the basic parts list for life — DNA’s four defining chemicals — and created a suite of genes that aren’t naturally present in E. coli. The synthetic genes transformed the bacteria into living microprocessors, capable of the logic exercises you find on a silicon chip.
Such are the products of an exciting and controversial scientific thrust called synthetic biology.
Biologists are poised to take over evolution, diverting species from their natural Darwinian courses and turning them in directions scientists want them to take.
Darwin observed evolution. Synthetic biologists are learning to control it — breaking down and reassembling life’s basic parts as if they were so many Lego bricks on the floor on Christmas morning.
In the process, they are amplifying debate over one of the most profound questions humans face: Is the world ours to make and transform as we wish?
Ordering life by email
Instead of waiting for Darwinian evolution to produce useful mutations as it has for some 4 billion years, synthetic biologists can sit down at a computer, type out a combination of the letters signifying DNA’s basic chemicals — A, T, C and G — and order the ingredients for a new life form.
That’s what professor Yiannis Kaznessis did to create those E. coli microprocessors at the U of M.
Kaznessis and his team wanted bacteria that function like simple computers with logic gates that open under certain conditions and release a signal. The signal would be a green glow. Scientists discovered the fluorescence gene years ago, and they often use it as a marker when they are manipulating genes for other traits. In this case, the “other traits” come from genes that trigger reactions to certain chemicals.
Such an invention could have many applications. It could be deployed, for example, to help detect cancer. If these E. coli found malignancy in a tumor, they could signal the discovery by turning neon green.
“Very simply, the engineered E. coli in our lab process inputs that we give them, perform a computation and then give an output that we can see,” Kaznessis said.
Some of the genes Kaznessis needed to concoct these chemical sleuths were naturally available from other living creatures. Some were entirely new strings of DNA you wouldn’t find in nature.
So Kaznessis sent emails to a university genomics center across Washington Avenue from his office, literally spelling out his order in the four letters of DNA’s alphabet.
“They can synthesize DNA from scratch,” he said. “They have the four bottles of the chemicals, A, C, G, and T. They use micro plumbing … connect them in the sequence we ordered and send it to us in two or three days.”
Of course, getting it to actually work all of the way to practical application is not at all simple. It’s a painstaking process that can take years. Kaznessis’ team reported in Biochemical Engineering Journal this year that the signaling system is set up in E. coli. But they’re not yet ready to deploy it for practical tasks.
“This is mind-boggling stuff,” I blurted out during our interview.
Kaznessis paused for a moment and then said quietly, “It is staggering. Yes.”
It is a giant step beyond the biotechnology of the ’80s and ’90s, when genetic engineers stirred controversy by inserting single genes into corn and other plants.
Even then, critics accused scientists of tinkering with life, playing God.
“In the biosphere right now the DNA sequences that are available are the ones that have been successful in an evolutionary context,” Kaznesses said. “With synthetic biology, we become tinkerers ourselves, and there is a conscious process to change the DNA sequences, to enrich the biosphere with additional sequences that wouldn’t have been there. … So we make nature behave in our intended way.”
Kaznessis didn’t dodge questions about the safety and morality of his work. He welcomed them.
“It’s incumbent upon us to explain how and why we do this,” he said.
Indeed, this technology could be turned for dangerous purposes — intentionally or otherwise. It could be used to make new viruses, relatively simple chemical constructs. It could be used to mass produce explosives and biological weapons. It could pose environmental hazards we don’t fully understand at this point.
Kaznessis said his work is done in secure labs, and he only experiments with organisms that have no chance of surviving outside the lab: “They rely heavily on us to feed them with nutrients, and in the absence of sources of nutrients they simply die out.”
As for moral questions, Kaznessis said, “I justify doing this because of the potential good that can come out of it.”
The three areas where the technology has great potential are in diagnosing and treating diseases, environmental cleanup and creating cheaper, safer energy.
In one sense, Kaznessis said, this new application of human intelligence is a continuation of Darwinian evolution: “We are products of evolution. Our thought processes and our consciousness are part of evolution and (we are) using these.”
This is not the first application of human intelligence to change the course of evolution, he noted. Farmers have done it for 10,000 years by selecting crops for traits that benefit people more than they benefit the plants.
Kaznessis is not alone by any means on this biological frontier.
Tiny living factories
At the U of M’s St. Paul campus, Prof. Claudia Schmidt-Dannert and her research team have transformed E. coli and yeast molecules into tiny factories capable of making ingredients for healing drugs, nutritional supplements and cheap biofuels.
The work begins with exhaustive analysis of genes that perform certain tasks in nature. For example, the may apple or mandrake plant makes toxins that are commonly used in chemotherapy for fighting cancer. Schmidt-Dannert’s team is fishing for the genes involved.
Once found, the DNA could be synthesized and engineered into E. coli. Then the cancer-fighters could be mass produced with the bacteria working as biofactories.
“We put new genes in there that encode the enzyme machinery,” Schmidt-Dannert said. “We either recombine them from different organisms, and put them together and test them. Or, maybe we even modify the genes so we get better function.”
That’s the simple description. The actual process takes many rounds of modeling and testing.
“You have to first engineer all of these systems and test drive them,” she said.
But the pace is picking up. Automated DNA sequencing, ever more sophisticated computer power and the ability to mass produce DNA molecules are propelling biology much the way digital technology raced ahead during the 20th century.
“This is, of course, a gigantic leap forward, and it’s getting faster and faster,” she said.
“Certain things I simply don’t do”
Schmidt-Dannert has patented some of her creations — for bacterial production of food supplements, for example — and licensed them to companies.
But she turned down a request from the Office of Naval Research to design a bacterial pathway for making explosive compounds.
“We can do this, but the question is, ‘Should we?’ ” she said. “It’s everybody’s responsibility to think about that question: ‘Do you really want to do everything that you could do?’ There are certain things I simply don’t do.”
In November, Schmidt-Dannert joined other synthetic biologists at a symposium organized by the National Academies to discuss the ethics of their work, among other topics. Related podcasts are here.
The Hastings Center, a nonpartisan research group devoted to bioethics and the public interest, is one of many other organizations grappling with the ethics.
“This rapidly advancing technology raises ethical questions about benefits and harms that have not been thoroughly addressed,” said the Hastings Center’s overview.
“Some of these are concrete physical worries, akin to the safety and security concerns first identified with the invention of recombinant DNA technology,” Hastings researchers said. “Other concerns tap into … our inner instincts about what is natural, and what is our relationship to the natural world, as well as scientific freedom, justice and access to the benefits of technology, and intellectual property rights.”
A critical set of questions confronts the prospects for creating whole synthetic organisms — not just hijacking the scaffolding of an E. coli molecule, but building free-standing organisms that never have existed before.
J. Craig Venter, who plowed new ground in the sequencing of the human genome a few years ago, now leads research that has produced an entire genome from scratch, using nothing but chemicals in a laboratory. The scientific press dubbed the creation “Synthia.” Now Venter’s team is taking the crucial next step, working to transplant synthetic genomes into independent cells where they could function as new species.
An affront to God?
“This feat will surely be achieved in the next few years,” the journal Nature editorialized.
“Many a technology has at some time or another been deemed an affront to God, but perhaps none invites the accusation as directly as synthetic biology,” Nature’s editors wrote. “The idea that such creation is a momentous step has deep roots running from the medieval homunculus portrayed by Paracelsus and the golem of Jewish legend to the modern faustian myth of Frankenstein.”
If anything, though, modern-day biologists are forcing us to reconsider the profound question of what constitutes life. Nature’s editors suggested that is not a question to be answered by scientists alone: “It would be a service to more than synthetic biology if we might now be permitted to dismiss the idea that life is a precise scientific concept.”
Life is not Synthia — not a solitary genome or even one complex collection of cells. It is a rich array of colonies and ecosystems.
And, after all, the synthetic biologists are not creating whole new parts for life. They are using nature’s pre-existing parts to spell out new forms: DNA’s natural alphabet of A, C, T and G.
Even that bold step does not explain how life began in the first place. Darwin didn’t do that either. The landmark theory he published 150 years ago explained in profound fashion the origin of the species — not the origin of life.
When it comes right down to basics, “we don’t know how to define life very well,” said U of M professor Mark Borrello, a science historian.
“It’s a very complicated idea,” he said. “And similar to Darwin in some ways, we still don’t know what the pre-biotic soup looked like. … This is something that Aristotle grappled with, something that theologians grapple with and something that scientists grapple with.”
Many scientists thought they were close, including James Watson and Francis Crick who changed biology forever in 1953 with a discovery they made in a laboratory at the same university where Darwin worked, Cambridge University in England.
“They figure out the structure of DNA, and they go wheeling into the Eagle Pub in Cambridge saying, ‘We found the secret of life!’ ” Borrello said.
“Most people would say, ‘No, not really … you have a big pile of DNA on your table. If you were to dump it into the garbage I don’t think anyone would say you’ve thrown life into the garbage. You’ve thrown a molecule in the garbage.”
Full grandeur of life
In the same vein, a lineup of synthetic genes is not the same thing as life itself in all of its grandeur and complexity.
Still, it is not surprising that synthetic biology spurs intense opposition on religious grounds. Schmidt-Dannert said she has received angry hand-written letters objecting to her work.
More surprising is that theologians representing many religions are prepared to take this development in stride.
“We still don’t have a decent scientific theory of where life came from although they are getting closer,” said Alan Padgett, who teaches systematic theology at Luther Seminary in St. Paul.
Does that pose theological challenges?
“No,” he said calmly. “I know there are some people trying to argue that life has been designed. I think that’s right, but I think the whole thing has been designed — not each little thing. God didn’t make each beetle or each tree. God made the whole thing. … God makes the world, and the world brings forth living things.”
Across town at St. Catherine University, Thomas West teaches systematic theology from a Roman Catholic perspective.
“No one is going to create anything out of nothing — no scientist is going to figure that out,” he said. “Christians believe that God has that power. … So the very idea that there is something and not nothing, and that we have conscious life capable of freely entering into relationships of love with other people — to us those two things will never be scientifically explicable without some reference to the sacred.”
At Temple Israel in Minneapolis, Rabbi Marcia Zimmerman was equally calm.
“Religion and science have different ends,” she said. “They are asking different questions, and that is important because the whole picture demands different questions. Science is asking how. Religion is asking why. Both need to be asked, so why do they need to be in contradiction? They can inform each other.”
As for Darwin, he thought expansively about the potential for evolutionary developments he could not have foreseen 150 years ago. In the last sentence of “On the Origin of the Species,” he said: “There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that, whilst this planet has gone circling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved.”
Sharon Schmickle covers science, international affairs, Greater Minnesota and other topics for MinnPost.