Geroscience, the science of aging, is a relatively young field. Despite steady increases in life expectancy across much of the globe, we have yet to see any drastic leaps or breakthroughs in human lifespan extension. Neither have we seen radical augmentations of the human healthspan — the length of time during which a person enjoys good health, before the onset of chronic age-related diseases. The main underlying factor behind this lack of progress is technological — the tools at our disposal have only recently reached a crucial tipping point of sophistication, ushering radical lifespan and healthspan extension out of the realm of science fiction and into the realm of real possibility. This has drawn the attention of the scientific community and added weight and urgency to the question: How do we go about developing an effective treatment for aging?
Biotech firms, research laboratories, and other entities with interests vested in this problem have taken varying approaches to its solution: while some have applied massive computing power to big datasets in an attempt to suss out the mechanisms behind aging, others have attempted developing pharmaceutical treatments or focused their resources on senotherapeutics. Hundreds of millions of dollars and decades of time have been invested in single-drug compounds and gene therapies targeted at a single gene or small number of genes. To find an effective, viable solution to aging, we must come to the realization that more advanced and complex technologies will be needed. Aging, unfortunately, cannot be solved with a single magic pill that grants immortality.
On the other hand, by leveraging our ability to engineer the human genome and developing techniques to make cells and organs that hold up robustly to time and damage, we can actually solve the problem of longevity.
It is with this aim that Centaura has begun developing the Human Artificial Chromosome (HAC) — the most promising gene-delivery technology currently known to geroscience.
The Aging Profile: A Guide to Identifying Targets
As is the case with any gene therapy, HAC treatments cannot be carried out without a specific understanding of which genes must be targeted, and in which order. This varies significantly from individual to individual, which has born the necessity for Aging Profiles — personalized overview detailing the idiosyncratic ways in which different individuals age — as an invaluable tool for developing effective therapies. In the case of some rare diseases caused by a single mutation, a solution may entail a relatively limited therapy that simply delivers a normal version of a single gene or a gene-base editor to correct the mutation. Meanwhile, other conditions will require much more complex approaches.
Once a gene target is identified, the next step is the actual delivery of the therapy. How this delivery is implemented relies on many factors: the organ being targeted, the efficiency that can be expected from the therapy (some individuals respond up to 10x more positively to a given gene therapy than others), and potential adverse effects of the therapy, among others.
We anticipate that the genetic targets for aging therapies will be far from simple. There is no single gene or protein that is known to prolong lifespan across the human population. Due to varied, individual responses to therapies, there can be no universal panacea for aging. That’s where Aging Profiles come in, along with well-developed gene therapies that effectively target multiple genes and pathways.
The Human Artificial Chromosome: A New Era of Human Genome Engineering
Human artificial chromosomes (HACs) have been under development since the 1990s. For context, artificial chromosomes for bacteria and yeast — which served as early model organisms for humans — were already being widely implemented as early as the 1980s.
Fast forward 30 years to today, and we are already capable of re-writing whole paragraphs of genetic code for these simpler organisms. For instance, using artificial chromosomes to implement targeted edits to the genome, scientists can make yeasts that produce opioids and anti-malarial drugs. However, for humans, with their comparatively vast complexity, we can still barely fix a single mutation or edit out a lone-standing typo.
By overcoming this technological barrier and successfully engineering HACs, we will be able to write entire new paragraphs into the story of our individual genomes, going far beyond edits that address individual misspelling and typos.
Once developed, HACs promise to herald in a new era of genome engineering for human cells.
Building the HAC
There are two general approaches to constructing HACs. The first approach is “top-down,” starting with a naturally existing chromosome which is then truncated as much as possible and filled in with the desired genes. The second approach works from the “bottom up,” building the HAC de novo using selected genes.
In the top-down approach, a full chromosome is selected and cut down to, ideally, just its telomeres and centromere (the central segment of the chromosome required for proper segregation of the chromosome during cell division). HACs constructed using this method have been successfully transplanted into mice, which were able to pass the genetic information from the HAC on to their offspring.
In the bottom-up approach, HACs are typically constructed by copying sequences from natural human chromosomes. Centaura considers this method to be the most viable, as de novo synthesis of chromosomes is far simpler and more reliable than the selection and subsequent reduction of natural chromosomes down to their desired elements. Using this bottom-up method, it is also possible to synthesize circular DNA, eliminating the need for the construction of complex telomere end-caps.
One of the greatest hurdles facing HAC synthesis is the problem of the centromere, which is essential in the process of cell replications and division. The difficulty boils down to the fact that centromeres still remain poorly defined. Size requirements and genetic sequence requirements for the construction of an artificial centromere still remain ambiguous, and the number of known proteins that can be used to establish de novo centromeres are limited.
HACs and CRISPR
HACs, though in and of themselves fully-fledged tools for genetic engineering, also promise to complement other gene-therapy methods, such as CRISPR/Cas-9 technologies. While CRISPR is good for implementing targeted, small changes in an existing genome — such as deletions, insertions, and mutations — the technique is unable to deliver the large quantities of genetic material necessary to treat certain conditions. This limitation eliminates CRISPR/Cas-9 as a viable independent solution for treating aging.
Meanwhile, as explained by Dr. Alina Chan of the Broad Institute of MIT and Harvard, “HACs are for large, megabase-scale genome recoding. They have the power to house and test multiple pathways that would otherwise take an incredible amount of labor and time to engineer with CRISPR/Cas.” Dr. Chan is currently working with Centaura as a consultant on the development of HACs.
Why HACs Weren’t Developed Years (or Decades) Ago
Up until recently, the human genome had never been fully sequenced. Although the Human Genome Project was completed in 2003, the more complex segments of the genetic code still remained unsequenced at that time. The first full Nanopore sequencing of the human genome was completed only in 2018, and nascent epigenetic tools that could be used to develop HACs only began appearing in 2014. Until today, almost all HACs that have been developed have relied on the blind copying of sequences from the human genome. These have proven to be unwieldy and unpredictable tools, which only a handful of labs around the world are equipped for and able to use — and even so, only at very low efficiency.
However, armed with recent advances in chromosome biology, as well as in gene sequencing and synthesis, we are now on the brink of a new generation of HACs. The journey forward will not be easy — gene therapies and even antibiotics take years to develop, let alone complex anti-aging therapies. Yet that gives us all the more reason to begin this research now, so that we can see the wide-reaching beneficial impacts of HACs on studies and clinical treatments as soon as possible.