Jeff Bezos’ dream or can we really rejuvenate by reprogramming our cells?

Jeff Bezos' dream or can we really rejuvenate by reprogramming our cells?

Rejuvenation through cell reprogramming has recently fantasized billionaires like Jeff Bezos, the ex-CEO of Amazon, or the Russian tycoon Yuri Milner, probably in search of immortality.

Three billion dollars were thus raised by the biotechnology company Altos Labs, founded by Milner and officially launched on January 19, 2022, attracting the most eminent scientists including Shinya Yamanaka the Japanese discoverer of cell reprogramming, but also Juan Carlo Izpisua Belmonte from Salk Institute for Biological Studies in La Jolla. The official goal is “to transform medicine through cellular rejuvenation programming.” Bezos has invested heavily in the company.

With the expertise of these top scientists, the biotech Altos Labs would like to extend cellular rejuvenation to the revitalization of the whole body, in order to prolong human life.

What is behind this technique? Where are we really?

What are the implications for human health?

Human cells have a programmed lifespan and their main characteristic is to divide in a controlled way to ensure the survival of our tissues and organs. An aging cell or in a state of senescence is a cell that no longer divides and will be eliminated by apoptosis (cell death).

Such is life…

But in 2006, the work of the 2012 Nobel Prize in Medicine, the Japanese researcher Shinya Yamanaka, opened up hitherto unthinkable fields of research, based on the possibility of rejuvenating our cells. The introduction of four specific genes into the genome of any adult cell (skin cells or blood cells for example) causes it to rejuvenate at an embryonic stage which is called induced pluripotent stem cell and which will be called induced stem cell for simplicity.

The stem cell thus induced regains the pluripotent properties of embryonic stem cells, ie it can differentiate into any type of adult cell, for example a neuron, a cardiac cell or an epithelial cell. This suggests that in the future, it will be possible to repair or manufacture any type of organ or tissue from these induced stem cells.

The first tissue repair trials using retinal epithelial cells from induced stem cell differentiation have been successfully carried out in Japan to treat age-related macular degeneration.

A pioneer in the field, Japan has set up a bank of immunologically characterized induced stem cells which correspond to each immunological type of a potential recipient in order to avoid rejection of this cellular treatment. In these first regenerative medicine trials, healthy epithelial cells were obtained by differentiation of human induced stem cells showing optimal immunological compatibility with the recipient patient. Despite these promising first trials, we are only at the dawn of the use of induced stem cells in regenerative medicine to treat more complex tissues than the eye, such as the heart, brain or pancreas.

Indeed, the rejuvenation of the adult cell involves the reintroduction of genes called transcription factors which, when they are active, will modulate the expression of other genes characteristic of stem cells normally inactivated in the adult cell. Among these transcription factors, some are said to be oncogenic, ie they can induce cancer.

Similarly, it is not without risk to use adult cells from the differentiation of induced stem cells to regenerate an organ or a tissue. Thus, it is difficult to really control the state of differentiation of these adult cells, because we do not know if they have all lost their pluripotency. Isn’t it possible that a residual induced stem cell hides within these adult cells, and, having kept its property of pluripotency, differentiates anarchically into different types of adult cells resulting de facto in the formation of a teratoma (tumour made up of pluripotent cells)?

Towards new drugs

Imagine, thanks to cellular reprogramming, neurons, pancreatic cells, hepatocytes (liver cells)… that can now be obtained from the differentiation of human induced stem cells.

This technology has greatly facilitated the development of cellular toxicological tests for drugs, but also has simplified the analysis of the therapeutic effects of new molecules on previously inaccessible human cells such as hepatocytes.

These induced stem cells also make it possible to obtain what are called “organoids”, 3D mini-organs which are tending to replace animal experimentation. Thus this major discovery that is cellular reprogramming is of great benefit to the pharmaceutical industry.

new therapies

To go further, not only the different types of so-called “normal” adult human cells are accessible, but also those from patients. Thus it is now possible to generate cellular models mimicking diseases. The latter make it possible to understand the physiopathological mechanisms at the origin of the disease, but also to develop new, more targeted therapies.

The first example is that of cellular modeling of Fanconi anemia which, thanks to cellular reprogramming, has made it possible to understand and correct the defect in the production of blood cells, which is one of the characteristics of this disease.

In addition, induced stem cells from patients suffering from genetic diseases are excellent cell models for testing new therapies such as genome editing. The idea is to specifically correct the genetic defect within the patient’s induced stem cell in order to be able to subsequently reinject the corrected cell. The proof of concept of this approach has been validated in a rare genetic disease of innate immunodeficiency called chronic granulomatosis.

Our laboratory is also developing a new therapeutic approach to this disease, a protein therapy. Chronic septic granulomatosis is a rare disease caused by a deficiency in a key enzyme in the defense against bacterial infections, called NADPH oxidase or NOX, it is located in the membrane of white blood cells such as macrophages or neutrophils. Thanks to this NOX enzyme, these white blood cells produce molecules to kill bacteria or fungi responsible for infections in our tissues or organs. The prevalence of this disease in France and worldwide is one case per 250,000 individuals.

Since the first cause of death for these patients is severe pulmonary infections, the idea is to artificially produce the deficient enzyme NOX incorporated into a lipid envelope which will ultimately be administered as a nasal aerosol to restore the enzymatic activity of pulmonary macrophages. of the patient. For this, we have generated cellular models mimicking chronic granulomatosis, ie macrophages deficient in NOX, derived from induced stem cells obtained from patients suffering from this disease. The proof of concept of the effectiveness of this therapeutic approach was carried out in our pathological cellular model. Proving its effectiveness against lung infections in mice will be the next step.

Immortality is coming soon ?

The major problem with this technique is that it not only rejuvenates the cells, but also changes their identity. Indeed an adult epithelial cell for example will become a stem cell by cell reprogramming then, it is only in a second time that it will be differentiated into a cell of interest (a heart cell for example).

Going through the stem cell stage entails a significant risk of tumor development. This is illustrated by the work of Juan Carlo Izpisua Belmonte published in 2016 on extending the lifespan of mice suffering from premature aging by cellular reprogramming. Indeed, although the expected effect was obtained in some mice, others developed tumours.

Cellular reprogramming has enormous development potential to improve human health by facilitating toxicological tests developed by the pharmaceutical industry. It also allows the modeling of diseases with a view to understanding them and to testing new therapeutic approaches. That said, it is clear that fundamental research work aimed at fully understanding the molecular mechanisms of cellular reprogramming is necessary for controlling carcinogenic risks, in order to secure its application in regenerative medicine.

For the moment, no clinical trial in humans is therefore reasonably conceivable. Despite the dreams of the most fortunate, human rejuvenation is not for tomorrow.