#77 Dr. George Church: Rewriting Genomes to Eradicate Disease and Aging

Posted on August 23rd 2022 (over 2 years)

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George Church, Ph.D. is a professor of genetics at Harvard Medical School and of health sciences and technology at both Harvard and the Massachusetts Institute of Technology. Dr. Church played an instrumental role in the Human Genome Project and is widely recognized as one of the premier scientists in the fields of gene editing technology and synthetic biology.

In this episode, Dr. Church and I discuss:

  • Genome Project-Write and the increasingly credible goal of being able to write large or entire genomes from scratch, starting with the human Y chromosome.
  • The ability to change cells or even entire organisms at the level of the DNA so profoundly that viruses cannot infect and utilize the cells' ribosomal translation machinery – a process called genetic recoding.
  • How projects like the Vertebrate Genomes Project – a massive endeavor to sequence all known vertebrates – may help save keystone species, protect or reintegrate past genetic diversity, and participate in preventing or reversing the process of extinction.
  • How gene editing could be used to eliminate zoonotic diseases that spill over from livestock.
  • How a technique called base editing, the next step beyond CRISPR/Cas9, may be the key to unlocking the full potential of gene editing to make thousands or even millions of genome edits, making biology more amenable to principles of engineering than ever before.
  • How Dr. Church is working on a combination gene therapy to reverse age-related biomarkers, focusing on genes with cell non-autonomous effects, producing soluble factors that can rejuvenate the whole body – similar to how factors in young blood revitalized old organs in animal studies.
  • Why he thinks initially developing a veterinary product for dog aging and his xenotransplantation project may be the ideal pipelines toward creating therapeutics that can unlock human potential.
  • Making animal organs suitable for human transplant by engineering them to be universal donors and possessing qualities like tolerance to cryopreservation, resistance to DNA damage, and other enhancements above and beyond those of ordinary human tissues.
  • His perspectives on controversies surrounding whether there can be responsible use of germline editing, and complex issues like equality of access to biotechnology.
  • How a type of genetic engineering called Gene Drive, a technique so powerful that it bends the laws of Mendelian inheritance, may make insects or animals unable to carry diseases that affect humans, such as malaria or Lyme disease.

The history of genome sequencing, an exponential undertaking

"I think we didn't realize that we were on an exponential when we started sequencing." - George Church, Ph.D. Click To Tweet

On February 28, 1953, scientists James Watson and Francis Crick made a remarkable announcement. Building on nearly a century of groundwork laid by a handful of other scientists, Watson and Crick proposed that DNA, the fundamental genetic material of nearly all living organisms, was arranged in a double-helix, a ladder-like structure that twisted on itself into its now well-known corkscrew shape. Research on DNA grew by leaps and bounds in the years that followed, but an understanding of the role the twisted molecule played in health and disease was hindered by an incomplete picture of its sequence.

Efforts to unravel that sequence came to fruition some 50 years later, when scientists made an even more remarkable announcement: They had sequenced the human genome – the entire set of genetic instructions found in a cell. This monumental task was made possible by the Human Genome Project, a multinational effort involving government agencies, research institutes, corporations, and countless scientists. Their draft covered 99 percent of the euchromatic genome (the part enriched with genes) and was estimated to be 99.99 percent accurate.

The Project was no small undertaking, lasting 13 years and costing nearly $3 billion. Since then, advances in sequencing technology have made genome sequencing exponentially faster and widely available – at a fraction of the cost. With the genome sequenced, scientists are now embarking on even more ambitious projects, focused on understanding and preventing many chronic diseases and ushering in a new era in which synthetic biology – redesigning organisms and engineering them to have new capabilities – offers the promise of a healthier future for not only humans, but other species, too, with applications in the worlds of ecology, conservation, agriculture, and likely others.

The knowledge gained from the Project has given rise to many new therapies, including the now-famous CRISPR-Cas9, "CRISPR" for short, a powerful gene-editing technology that allows scientists to tweak a single disease-causing gene, essentially nipping the disease in the bud. But CRISPR, which Dr. Church sometimes refers to as a "hatchet" or "genome vandalism," has its flaws. It is notably imprecise and limited in its scope. He and others in the gene-editing world are now employing multiplexed gene-editing technologies, targeting not just one, but multiple, specific DNA regions in a genome with high precision.

Writing large genomes from scratch, the new exponential

Having achieved the initial sequencing aim of the Human Genome Project, sometimes retroactively designated Genome Project-Read, a new project has come to the fore: Genome Project-Write, which aims to reduce the costs of writing and testing large genomes and synthesizing entire genomes, starting with the Y chromosome, which contains the fewest genes – from scratch.

Sometimes termed CRISPR2.0, a recent and exciting advance in gene editing technology called base editing has enhanced the precision – without introducing double-strand breaks. In one iteration, one of Cas9's cutting enzymes, a nuclease, is deactivated, and another enzyme, a deaminase, is introduced. This new CRISPR complex, known as a "base editor," can modify a single DNA nucleotide without introducing toxic double-strand breaks. This technology has greatly expanded the multiplicity of edits that can be introduced into a given cell, a type of genomic editing known as multiplexed editing. Their efficiency, specificity, and low genome damage make base editors ideal tools for multiplexed genome editing. While this is a remarkable advance, Dr. Church proclaims that many other powerful tools are on the horizon.

An example of base editing has now reached human clinical trials involving the PCSK9 gene and familial hypercholesterolemia.

The number of per cell edits continues to increase: from 62 edits in its first iteration to deactivate porcine retroviruses, which prevent pig organs from being transplantable to recently, 26,000 edits. This was accomplished through the use of new base editors that don't impose the cytotoxic double-strand DNA breaks made when genomic engineers instead use the original CRISPR, which relies on the native Cas9 enzyme.

As each new milestone in editing is surpassed, entirely new paradigms of what may be possible with genome engineering emerge. One example of mind-boggling applications that Dr. Church and his colleagues hope to develop: producing human cells with perfect viral resistance.

What if we could eliminate viral disease?

Viruses have played extraordinary roles in human evolution, shaping and influencing our modern bodies. But viruses and the diseases they cause have exacted an immense toll along the way, leaving in their wake a swath of misery, suffering, and death. Smallpox, the deadly disease caused by the variola virus, ravaged humans for thousands of years, claiming the lives of as many as 500 million people in the last century alone. The disease was eradicated, however, in 1980, after a global effort of vaccination, testing, and containment. Many deadly viruses remain, including Ebola virus and human immunodeficiency virus, and new viruses will likely emerge in the future.

But what if we could eradicate all viral diseases by making cells resistant to the viruses that cause them? While this seems a radical and vast undertaking, Dr. Church thinks it may be possible within the next decade, starting with industrial microorganisms, such as those used in large-scale manufacturing processes, and genetically engineered cells, such as those used for immunotherapies. His laboratory has already made progress on this feat with the bacterium Escherichia coli, the first of what might be a host of genomically recoded organisms and perhaps setting the stage for preventing many other diseases, including cancer.

Exploiting codon degeneracy to build a viral firewall

Making cells resistant to viruses exploits a fundamental aspect of how the instructions in DNA are converted into a functional product. Each strand of DNA is composed of four nucleotide bases, identified by their initials, A, C, G, and T, and strung together by chemical bonds. Translating the strand into a protein is famously made possible by a process that involves specific combinations of three adjacent nucleotides called codons. Codons are interpreted by the ribosomal and translational machinery of cells as the genetic instructions for making specific amino acids, which form the basis of proteins.

Translation of these triplet codons to the corresponding amino acids is universal across the tree of life, from single-celled organisms to mammals, and comes packed with redundancy. Sixty-four possible codons code for only 20 amino acids and a single stop signal. Consequently, some amino acids can be made from multiple codons. For example, serine and leucine correspond to six different codons each, making them particularly interesting for genetic manipulation.

Codon degeneracy, the term for when several codons translate to the same amino acid, arises because there are more codons than encodable amino acids. Exploiting this phenomenon allows scientists to build a firewall against viral gene transfer – an essential aspect of viral replication.

An opportunity for "refactoring the code," with surprising results

Borrowing from a concept of computer programming, reorganizing code without changing its underlying function is sometimes termed "refactoring." Herein, we might find an elegant analogy!

What if DNA itself could be refactored? If such a thing were possible, one result might be what is now known as a genomically recoded organism, something that could only exist in an era of multiplexed editing.

Dr. Church's lab has explored many concepts not too far removed from such scenarios:

  • In 2013, using multiplexed genome editing, they genomically recoded E. coli by replacing all instances of a particular triplet codon across the bacteria's entire genome. The recoded bacteria had enhanced resistance to bacteriophage T7 – a virus that infects bacteria.
  • In 2016, they made significant progress toward reducing the number of codons in E. coli from 64 to 57, tailoring a genome to a scale not seen before.
  • In 2022, they showed that recoding the genome was not enough to fully impart viral resistance. (Parts of the translational machinery could be brought in by viruses themselves or via mobile genetic elements.) But, making a few more genetic tweaks, including reassigning two of the six serine codons to leucine during translation, was enough to generate multi-virus resistance by mistranslating viral proteomes. Dr. Church asserts that this process should work in any host. In fact, his lab has even taken the first step toward the complex task of recoding the human genome by switching two stop codons in 33 essential genes using base editing.

A disruption to the expectations of eons of viral evolution

"All viruses, as far as we know, depend on the host genetic code, the translation ribosomal machinery. If you can change that code enough without hurting the host, the virus can't mutate." - George Church, Ph.D. Click To Tweet

Theoretically, if a host's genome could be precisely recoded with fewer or, better still, swapped codons, it might happily continue chugging along making the same proteins. Viruses, on the other hand, will encounter an immense challenge: far from parsimonious, they have grown accustomed to utilizing the entire universal codon alphabet, including the redundant codons, to replicate themselves within cells. A virus in this setting will find itself in an unfavorable translational environment – and rendered impotent. Presumably, the host will be functionally intact because of the code's redundancy: it can still make all the proteins it needs, but it now has viral resistance. The magic of refactoring – improving the design of a legacy system while maintaining function and, in this case, imparting a generalized "firewall" – prevents viral infection.

A gap too large to easily be surmounted by viral mutation

With enough changes to the translation machinery and codons of a host cell, a virus likely cannot evolve to compensate. The gap between the expectations of its program, shaped by eons of evolution, may be simply too great to easily adapt to the new translational environment of the engineered cells, an opinion held by Dr. Church and other synthetic biologists.

As Dr. Church explains, this technique has immense implications due to its generalizability. While it requires vast and precise multiplexed editing capability or even rewriting the genome from scratch, it may work across the entire tree of life. That's because the technique changes not just the translational apparatus, but also all variations of the codons.

Applying the computer programming concept of refactoring to a biological system paved the way for the paradigm-shifting innovation of recoding. Cells could be programmed to behave and function as they ordinarily would but with profound differences in their underlying code and translation apparatus, making them immune to all viruses and even horizontal gene transfer – a boon to preventing the unintentional spread of lab-produced genetics to wild-type organisms.

Aging as an evolved program

Of course, viral diseases aren't the only afflictions from which humans suffer. Aging, and the diseases that accompany it, likely represents an evolved species-specific developmental program. It is one of the key drivers of disease and death and is characterized by a host of observable biological patterns, or hallmarks, of dysfunction.

Addressing these hallmarks, which include genomic instability, epigenetic alterations, and loss of proteostasis, among others, is essential to forestalling aging and restoring youthfulness. Dr. Church and his colleagues are addressing some of these hallmarks via delivery of genetic instructions for making growth factors in dogs. Our canine friends make excellent models for studying the effects of the growth factors because they share so many of the same environmental exposures as humans – and because we care so much about them.

The Human Genome Project and its legacy projects have opened the door to myriad possibilities in eradicating disease and promoting healthspan and longevity. In this episode, Dr. George Church and I discuss many of these possibilities, as well as the scientific and ethical challenges researchers face in pursuing these goals.

Selected publications

Learn more about Dr. George Church

Biotech companies

  • eGenesis - co-founded by George Church to produce human-compatible organs in the bodies of gene-edited pigs
  • Colossal - a biotech startup funded by Thomas Tull introducing some of the genetic diversity of ancient wooly mammoths, as well as traits like virus resistance, into Asian elephants with the goal of rewilding the Arctic tundra.
  • Manifold Bio - a biotech firm that specializes in protein "barcoding," a form of protein labeling, to facilitate protein therapeutics development.1
  • Rejuvenate Bio - a biotech company that is developing gene therapies designed to increase the health and lifespan. Currently exploring a (solubilized) TGF-beta / FGF21 / alphaKlotho therapeutic.

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