Turning back time with cellular reprogramming: Shift raises $16 million in seed funding

Can we reverse the aging process? That is what Shift Bioscience is aiming for through gene discovery, artificial intelligence (AI)-driven simulations, and cellular reprogramming. The Cambridge-based company raised $16 million in seed funding just last week. The funding round, led by BGF with participation from Kindred Capital, and Jonathan Milner, will accelerate the development of Shift’s AI platform, which predicts gene-based interventions capable of safely rejuvenating human cells.

The company’s approach leverages generative AI and biological aging clocks to simulate the results of potential interventions, allowing them to identify promising gene candidates more efficiently. This technology aims to tackle age-related diseases by reprogramming cells without inducing risky pluripotent states, positioning Shift Bioscience at the forefront of the cellular reprogramming field.

Shift Bioscience’s chief executive officer (CEO) Daniel Ives noted that the additional funding will not only advance their research into multiple human cell types and animal models but will also bring them closer to clinical trials for age-related disease therapeutics​. 

So, let’s see how Shift Bioscience could help us get younger – or at least get old later.

Rewinding the epigenetic clock: The science behind Shift Bioscience’s approach

At the heart of Shift Bioscience’s mission is the concept of the epigenetic clock, a biomarker that correlates closely with chronological age across human tissues. Developed by Steve Horvath, this clock measures age-related DNA methylation changes, providing a precise indicator of biological aging. 

As Ives explains, “The epigenetic aging clock is the measure that gives us the most confidence that we are either successfully or unsuccessfully intervening in the physiological aging process.”​ By using this tool, the company aims to turn back the biological clock and slow, or even reverse, the aging process at a cellular level.

What sets Shift Bioscience apart is its use of a single-cell aging clock, a gene signature that correlates with the epigenetic clock and can be measured in individual cells. This allows them to perform more experiments in a shorter time frame, a process that would be impossible using traditional methods requiring larger quantities of cells. 

“The epigenetic clock measurements require a much larger number of cells. Creating this gene signature required a huge investment of time and capital in the construction of a bespoke dataset, and perhaps because of this, no other group has yet reported an equivalent technology,” said Ives.

Another key component in their approach is the integration of cell simulations, leveraging generative AI. By simulating real-world experiments in virtual cells, Shift Bioscience can rapidly test interventions and predict outcomes. “Experimental campaigns that would have taken centuries in the real world can be performed in less than a year inside cell simulations,” noted Ives. These simulations allow Shift to explore combinatorial gene-based interventions more quickly than it would be feasible through traditional laboratory work.

As part of this accelerated discovery process, Shift Bioscience has already identified six gene-based interventions that reverse the epigenetic clock without inducing risky pluripotent states, which is a major limitation of current cellular reprogramming methods using Yamanaka factors.

Yamanaka factors are a set of four specific genes (Oct4, Sox2, Klf4, and c-Myc) that were discovered by Dr. Shinya Yamanaka in 2006. These genes can reprogram adult cells back into a pluripotent state, meaning they can essentially reset the cells to behave like embryonic stem cells. However, while Yamanaka factors can effectively rejuvenate cells, they also carry risks, such as the potential to form tumors, due to their reprogramming of cells into a pluripotent state.

This is where Shift Bioscience has an edge over other cellular reprogramming methods, avoiding that potentially dangerous pluripotent state. While Shift Bioscience is still in the early stages, it certainly has a lot to look forward to in this emerging field.

“We fit into the high-risk but high-reward part of the field known as ‘cellular reprogramming’, which is currently attracting more than 50% of total investment in the aging space. To steal a quote from science communicator Andrew Steele, cellular reprogramming ‘feels like a piece of technology that’s fallen through a wormhole from the future,’” reflected Ives.

The broader context of cellular reprogramming into anti-aging research

Cellular reprogramming has become one of the most exciting areas in aging research. At the core of this technology is the concept of reverting mature cells to a pluripotent state to reset their biological age. The process was pioneered by Dr. Shinya Yamanaka, whose discovery of the Yamanaka factors earned him a Nobel Prize. 

However, as Ives pointed out Yamanaka’s method comes with significant challenges as reprogrammed cells can form tumors due to uncontrolled growth. Additionally, the practical use of induced pluripotent stem cells (iPSCs) in humans is still in the early stages.

Several other companies and researchers are tackling these challenges in different ways. For example, Altos Labs, with Yamanaka himself as scientific advisor, is exploring how reprogramming technologies could rejuvenate tissues and organs without inducing pluripotency by fine-tuning the reprogramming process. This means resetting cells to a more youthful, healthy state while maintaining their specialized functions. Rather than fully reprogramming cells into iPSCs, Altos Labs’ approach focuses on partial reprogramming – a controlled process that resets the biological clock without destabilizing the cell. 

Another company focused on partial reprogramming is Life Bioscience. The company uses a partial epigenetic reprogramming therapy that targets the retinal ganglion cells. This approach is showing promise in restoring visual function by reducing the damage caused to retinal cells in optic neuropathies such as glaucoma. The company recently presented data at the 2024 American Association of Ophthalmology (AAO) annual meeting and human trials for ER-100 are expected to begin in 2025.

While cellular reprogramming offers a promising route to rejuvenate aging cells, other approaches target aging in different ways. Senolytic drugs and CRISPR-based gene editing are two such strategies that aim to either eliminate damaged or aged cells or repair underlying genetic damage at the root of aging.

One of the major contributors to aging is the accumulation of senescent cells, often referred to as “zombie cells.” These cells have stopped dividing but remain metabolically active, secreting pro-inflammatory factors that damage surrounding tissues and contribute to age-related diseases. Senolytic drugs are designed to selectively eliminate these senescent cells, effectively clearing out the harmful cells that accelerate tissue degeneration.

For instance, Unity Biotechnology’s lead candidate, UBX1325, targets the protein Bcl-xL, necessary for the survival of senescent cells but not for healthy cells. By inhibiting this protein, UBX1325 effectively clears out senescent cells without harming surrounding tissues. In phase 2 clinical trial for diabetic macular edema – which is not typically classified as an age-related disease but shares with these conditions the prevalence of senescent cells – patients treated with a single injection of UBX1325 showed significant improvements in vision over 18 weeks.

Another promising avenue in anti-aging research is CRISPR-based gene editing, which precisely alters DNA and could correct genetic mutations that contribute to aging and age-related diseases. Researchers are exploring ways to target genes regulating telomere maintenance through CRISPR but this is still in the early stages. Telomeres protect the ends of chromosomes, and their shortening is closely linked to aging.

CRISPR-Cas9 is also being explored to target and eliminate senescent cells by modifying senescence-related genes, such as p16INK4a. In doing so, CRISPR could potentially remove these cells or rejuvenate them. This research is still emerging, but there is growing evidence that selectively clearing or reprogramming senescent cells could provide therapeutic benefits for age-related diseases.

What could Shift Bioscience represent for age-related diseases?

The field of possibilities is currently wide open for the British biotech company. “Ahead of mapping the translatability landscape and selecting an age-linked disease on that basis, we will also be assessing our gene-based interventions for genetic linkage to age-linked diseases. Many of the cell types we are using to assess interventions are also more strongly linked to therapeutic applications than fibroblasts, so we’re open to following the data,” said Ives.

But one thing is certain, Shift Bioscience’s platform holds significant promise for therapeutic applications, particularly in the treatment of age-related diseases. By targeting the aging process at a cellular level, their gene-based interventions have the potential to address a wide array of conditions, including hearing loss, cardiovascular disease, and osteoarthritis. These are just a few examples of the diseases caused by the aging of cells, which Shift Bioscience’s technology aims to counteract by safely rejuvenating cells.

The key success that will determine the fate of the cellular reprogramming field as a whole is yet to come. “The biggest challenge is to demonstrate the first clinical and commercial success of a drug targeting the biology of aging. This could be achieved through more powerful interventions, but could also be achieved by better patient stratification. For instance, it’s been shown that different people have different ‘ageotypes’, and therefore an intervention may require some degree of personalization.” 

While the company doesn’t intend to rush things, Ives is prepared to see this first success happening sooner rather than later. “There is external interest in accessing our capability to screen single molecules and combinations of molecules for their ability to reverse the age of cells. It would be amazing if one or more clinical-stage molecules could be used to create a first-in-class therapy in a much shorter time frame.”

With $16 million in seed funding, Shift Bioscience plans to accelerate the development of its AI platform, allowing it to discover safer rejuvenation genes and bring its therapies closer to clinical trials.

The short-term goals include expanding their experiments from human fibroblasts to other human cell types and testing their interventions in animal models. These steps are crucial in demonstrating the real-world therapeutic potential of their interventions. The company is also focused on mapping the translatability landscape of these age-linked diseases to identify the safest and most promising paths for drug development.

Looking at the next steps for Shift Bioscience, Ives said, “My long-term goal for the round is to demonstrate the approach can significantly impact multiple mouse models of human age-linked disease, setting us up for preclinical therapeutic development.”

Shift Bioscience’s current interventions are gene-based, and therefore therapeutic applications gated by gene-delivery. That’s why Ives told Labiotech he was excited by the recent data published by Entos Pharmaceuticals, which showed widespread gene delivery across the body in primates, with five organs, including the heart, receiving more genes than the liver.

In the race to reverse aging, Shift Bioscience is worth watching, and we’ll be following its progress closely.