Programming Cures with Synthetic Biology

Tim Lu uses his extensive background in computer programming, electrical engineering and micrcobiology to engineer cells to act as living therapeutics. At TEDMED 2018, Tim Lu shared how his work in bioengineered medicine is enabling dynamic responses to disease in previously unseen ways. Watch his Talk, “Biological engineering—the nexus between computer programming and medicine” and read his post below to learn more about his pioneering work.

Ever since the human genome was decoded, we’ve gained considerable insights into the origins of disease. The biological programs encoded by the DNA inside our cells are highly interconnected, allowing them to orchestrate the complex activities of life. When these fine-tuned interconnections within cells and between cells go awry, disease results.

With an increasing understanding of these dysfunctional biological programs and their role in human illness, scientists are trying to develop new ways to cure disease, not simply keep it at bay. However, our current armamentarium of medicines is dominated by small-molecule drugs and biologics, such as antibodies and enzymes. Although these medicines have resulted in tremendous advancements in human health, they are fundamentally limited in their activity and are nowhere as sophisticated as the disease networks they are trying to address.

For example, these drugs distribute systemically throughout the body and are not easily activated (if more activity is needed) or suppressed (if side effects are encountered). In addition, these medicines often only target a single mechanism of action, which may be insufficient to cure diseases. The basic problem is that we are using static, simple, non-living medicines to treat indications that are inherently dynamic, multi-factorial and living.

Fortunately, while we’ve been decoding our DNA and the biological programs we’re born with, we’ve also been learning how to design DNA to create new programs in living cells. The engineering discipline of synthetic biology has the potential to create powerful new medicines that can match the complexity of disease with even more sophisticated therapeutic programs. These medicines are called (1) cell therapies, where living cells are reprogrammed with artificial DNA programs and delivered into patients, and (2) gene therapies, where the artificial DNA programs are administered directly into patients, typically using a virus or a chemical carrier.

We’re already seeing these living cell and gene therapies have an impact on certain diseases, such as acute lymphoblastic leukemia (ALL). For example, a new class of medicines called CAR-T cells are made by extracting T cells from ALL patients, engineering them to kill any cells expressing a protein called CD19, and then reinfusing the living drug into the body, wherein the CAR-T cells eliminate CD19-positive leukemia cells, as well as normal B cells. These CD19-targeting CAR-T cells have achieved tremendous success in the clinic, with more than 80 percent complete response rates in some studies.

However, we’re only scratching the surface of what is possible with current cell and gene therapies. For example, CAR-T cells don’t work particularly well against solid tumors, such as ovarian, lung and liver cancers, or difficult-to-treat liquid tumors, such as acute myeloid leukemia (AML). Solid tumors have evolved multiple ways to block T cells from being active within the tumors, so that CAR-T cells can’t exert maximal killing activity against cancer cells.

More sophisticated genetic programming through synthetic biology can help overcome this challenge. For example, CAR-T cells can be engineered not only to kill cancer cells, but also to secrete multiple additional drugs that counteract solid tumor defenses in a multi-factorial fashion. Combination therapy encoded within a living cell therapy can address the complexity of cancer disease networks and significantly improve treatment effectiveness.

Moreover, diseases, such as AML, are highly heterogeneous, so that it’s difficult to find a single antigen target that can discriminate between cancer and healthy cells. Antibodies and CAR-T cells that only go after a single target can generate significant side effects by also killing healthy cells. This isn’t a major problem with CD19-targeting therapies in ALL, because people can survive ablation of all their healthy B cells (which make antibodies) by being supplemented with antibody infusions. However, when the healthy tissues that are inadvertently killed are irreplaceable — such as stem cells, cardiac tissue or lung cells — these side effects can cause substantial toxicity.

Fortunately, we no longer have to be satisfied with drugs that only rely on a single protein to distinguish between diseased and healthy cells. Leveraging synthetic biology, we can design cell therapies to sense multiple disease biomarkers and to respond only when a specific combination of biomarkers is encountered. For example, CAR-T cells can be outfitted with a “NOT gate” program to kill tumors when they express biomarker A but NOT biomarker B, and to prevent killing of healthy tissues that express both biomarker A and B. By doing so, we can significantly increase the safety margin of these drugs and enable enhanced potency against cancer cells.

These biological programs are just a few examples of how programming sophisticated living drugs can improve therapeutic outcomes. The emerging synthetic biology toolbox also enables living medicines that can be turned on or off by administering orally dosed FDA-approved small molecule drugs. Such medicines can be narrowly targeted against specific cell types or tissues, and that can even adapt their activity to dynamic and evolving diseases. A new era of programmable drugs is coming, and has the promise to deliver cures that match the complexity of human diseases.

Advancing Synthetic Biology: Q&A with Floyd Romesberg

Floyd Romesberg, synthetic biology expert
Floyd Romesberg

In his TEDMED 2015 talk, Scripps Chemistry Professor Floyd Romesberg shares his enthusiasm for developing artificial DNA and its implications for novel protein therapeutics. We caught up with Floyd to learn more about the exciting work of his lab.

TEDMED: What has your lab been up to since you spoke at TEDMED?

FLOYD: Since I spoke at TEDMED, my lab has continued to nurture and optimize our semi-synthetic organism. The nascent organism I described in my talk was the first to replicate DNA containing a third base pair, but only a single pair, and the poorly growing organism rapidly lost the unnatural base pair under all but the most controlled conditions. It was an incredible proof of principle, but lacked the fortitude of real life. The newly improved organism still relies on the same protein to take up the unnatural nucleotide precursors of our unnatural base pair, but we have engineered the protein to be less toxic and are now utilizing a newer, chemically optimized unnatural base pair. In addition, we have optimized the host cell. The result is a semi-synthetic bacterial organism that can be grown like any other laboratory strain and that retains multiple unnatural base pairs in virtually any sequence context – the first semi-synthetic form of life that stores genetic information using a six-letter, three base pair alphabet.

TEDMED: What’s next for you?

FLOYD: We’re continuing to push forward with the semi-synthetic organism. Since we reached the milestone of unrestricted storage of increased genetic information, the next step has been to focus on information retrieval in the form of messenger and transfer RNA transcribed from the six-letter DNA. The unnatural base pair will be one third of a new amino acid codon, and we’re also working on engineering the components to decode the new codon into a novel amino acid during protein synthesis. There are a lot of moving parts to coordinate, and we have to get each part to work but we also have to make sure the parts all work together. It might sound like an insurmountable problem, but that’s what people thought about our efforts to expand the genetic alphabet. It may take some time, but getting bacteria to produce unnatural proteins should be possible. When we accomplish this, we will have created the first form of synthetic life that stores and retrieves increased information and which can access forms and functions not otherwise possible in the fully natural world.

TEDMED: What does the future of medicine look like with protein therapeutics?

FLOYD: Protein therapeutics have revolutionized medicine, but their potential activities and uses are limited by their being composed of only the natural twenty amino acids and in the challenges of their specific modification. The future of protein therapeutics lies in methodologies to include any chemical functionality into their composition, thereby imparting novel or optimized activities and properties. With development of our semi-synthetic organism, we will be able to produce the unnatural proteins directly during their synthesis within the cell. In this manner we should be able to extend the potential application of protein therapeutics to diseases that have been difficult to target, such as infectious diseases and cancer. The possibilities are essentially endless.

TEDMED: What kind of impact do you want your research to have?

FLOYD: I would like our research to impact our conceptual understanding of life– what it can be and how it might have evolved– and also influence our practical uses of it, by producing modified proteins to treat disease.