The US government is giving a private research outfit $37 MILLION to find a way to rejuvenate the thymus. What’s all this about? Read on …
By Dona Suri
Here’s interesting information about your thymus …
BOR-RING! Change the channel.
Try again …
The US government is giving a private research outfit $37 MILLION to find a way to rejuvenate the thymus.
BIG BUCKS! What’s this all about?
We have your attention? Thank you. Now here’s something you should know about …
On August 29, the National Institutes of Health (an agency of the US Department of Health and Human Services) announced that it is granting $37 million tax-payer dollars to a Cambridge Massachusetts biotech start-up, Thymmune Therapeutics.
Thymmune’s ambition is to restore normal immune function by producing iPSC-thymic cells.
The founder and CEO of Thymmune Therapeutics is Dr Stan Wang and the Chief Scientific Officer is Dr Bing Lim. They have created a machine learning-enabled thymic engineering platform that mass produces iPSC-derived thymic cells. With enough of these cells they think that they can restore immune function through a non-invasive approach that can be replicated at high quality and at scale. It will become possible to repair immune systems have become frail, either from radiation or chemo therapy or from age.
If they succeed, it will be a revolution in immunology.
Thymmune … thymic … thymus …
You probably can’t recall the last time that you thought about your thymus. Maybe you have never thought about your thymus … or knew that you had a thymus.
And what is a thymus anyway?
Put your finger about two inches below the spot where your collar bones almost meet. Right under that spot, sitting behind the sternum and in front of your heart, is your thymus. It’s your Number One lymphoid organ.
The ancient Greeks knew that this little organ existed and they named it. But until 1961, nobody knew the true function of the thymus and even after 1961, scientists didn’t appreciate how important it is. Initially, it was thought that the thymus didn’t contain ‘true’ epithelial stem cells, but only progenitors arising in fetal development. Doctors supposed that the thymus was nonfunctional in adults, and during cardiac surgery it was a common practice to remove it so as to get at the heart and major blood vessels.
We know better now.
The thymus is jam-packed with thymocytes and epithelial cells; it takes in stem cells from your bone marrow and trains them to become killer T-cells. These are the cells that patrol your body, searching and destroying bad actor foreign cells. T-cell production is tightly regulated. The thymus sees to it that you have just enough to fight infections but not so much that the T-cells wind up attacking your body’s own cells.
The peculiarity of the thymus is that it melts away. An infant’s thymus is a robust and busy little thing but by the time you are 50 years old, your thymus has degenerated into tiny islands of fatty tissue, and when you turn 75, your thymus weighs no more than 6 grams – a mere 16 percent of the 37 grams it weighed when you were young. Degeneration starts from Birthday Number 1; our thymus gets smaller and less active every year. Remember how it was during covid? Elderly people were at highest risk. That was because age had weakened their immune systems and their thymuses were in no condition to turn out T-cells in sufficient numbers to make an effective fighting force. Plus, self-reactive T cells that ought to have been filtered out, were still doddering along in the blood stream and potentially causing trouble instead of busting trouble.
The big crisis for the thymus comes at puberty. An increased production of sexual hormones accelerates the decrease of thymocytes at a rate of 3 to 5 percent every year. With increasing age, there is a loss of fresher T cells and an increase in memory T cells. There is also a decrease in the diversity of the T cell repertoire. If it weren’t for the fact that T cells survive for a good 20 years, we would all drop dead before we turned gray.
The young thymus is highly sensitive to damage, but in the early years it can repair itself. This ability fades with age. For a long time, it was believed that degeneration of the thymus is inevitable and cannot be reversed. Over the past 30 years, one study after another has gradually disproved that idea.
Wang and Lim have not spun the idea of thymic regeneration out of nothing, all by themselves. They are standing on the shoulders of many equally brilliant scientists.
It was 37 years ago that an immuno-physiologist working at the University of Illinois at Urbana-Champaign, set out to find out more about the relationship between age and immunity. Dr Keith Kelley knew that the ability of animals and humans to withstand infections fades as they age, but he wanted to know what happens exactly. Specifically, did a decline in the production and release of pituitary-derived growth hormone result in decline in immune function?
He implanted GH3 pituitary adenoma cells in one group of two-year-old rats and gave the same treatment to a group of 18-month-old rats. (Rats that old are senior citizens.) Pituitary adenoma cells secrete growth hormone and prolactin. Two other groups of rats (18 months and two years) got nothing. Two months later, Kelley autopsied the rats and was amazed to see that the treated 18-month-old rats had regrown their thymuses – complete with distinct cortical thymocytes and medullary epithelial cells. The two-year-old rats had failed to fully regrow their thymuses but, even these rats had more cortical thymocytes and fewer fat vacuoles than the control groups. The control groups still had the geriatric, shriveled up thymuses they started out with.
Kelley’s experiment showed that an ancient, wasted thymus could be REGROWN! IN THE BODY! And REVERSE immunity loss that occurs with aging. (At least in rats.) The experiment, a world first, was published in the prestigious Proceedings of the National Academy of Sciences and it made a lot of other scientists start thinking.
Since then, pathbreaking work has been done in many places. Scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiberg, Germany have been major contributors. Their big breakthroughs are:
- Identifying processes that control the development and composition of thymic tissue throughout life.
- Finding the genetic switches required for T cell maturation in the thymus.
- Understanding how age-related thymus shrinkage can be slowed.
Underlying the research that produced these results is a field of study that lies at the intersection of mathematics, theoretical physics and bio-informatics. It’s called Quantitative Single Cell Biology, and it is concerned with the problem of which cell does what.
It was known that two main types of thymic epithelium arose from bipotent progenitor cells, but was there only one type of progenitor? Or were there many types? Or one type with many subforms? Figuring this out required a new method of investigation. Dr Dominic Grün, a physicist by training, pioneered a method called Molecular Family Tree Analysis. He developed algorithms that made highly accurate guesses about differences in the gene activity of individual cells and from this it became possible to identify potential precursor cells.
The next step was to experimentally verify the probabilities worked out by Grün’s algorithm. To do this, Dr Thomas Boehm invented a “barcoding” system using CRISPR gene editing. A molecular signature was assigned to precursor cells; all cells that emerged from a particular precursor had the same unique signature.
This gave scientists the “family tree” of all the epithelial cells in the thymus – a what a variety that turned out to be.
The next step forward was to connect information from the phylogenetic tree with the molecular characteristics of individual cells. Drs Anja Nusser from the Boehm lab and Sagar from the Grün lab, have spent the past ten years doing this. Thanks to their work, (published in May 2022) for the first time it became possible to study the development of thymic epithelium at different ages in exquisite molecular detail. Immunologists have hailed this project because it gives them a clear picture of the ever-changing thymus at each of its life stages.
Rapid organ growth and massive T-cell production are characteristic of the early developmental stages. But then, year by year, functional thymic epithelial cells are gradually lost and T-cell production wanes, which means reduced immune function. It happens because one kind progenitor cell in the thymus takes over from another kind of progenitor cell.
Nusser and Sagar identified these two bipotent progenitor populations and tracked their activity:
An “early” progenitor population dominates thymus formation during embryonic development.
A few weeks before you are born and in the first year of life, mainly cortical thymic epithelial cells are formed, which primarily contribute to the production of T cells.
Later, during childhood, a “postnatal” progenitor population determines thymus formation and continues doing this into adulthood.
In this stage, the primary output is from medullary thymic epithelial cells. They ensure that no self-reactive T cells are released from the thymus into the body. This prevents autoimmune conditions from developing.
Meanwhile, in the University of Edinburgh’s Center for Regenerative Medicine, Dr Nicholas Bredenkamp and his colleagues were investigating the mechanism regulating the degeneration of the thymus. They zeroed in on a gene called FOXN1. It’s a transcription gene which means that it provides instructions for making a protein that attaches to specific regions of DNA and regulates the activity of other genes. They compelled the thymic epithelial cells to upregulate their FOXN1 function. (How they did this is really complicated.)
By 2014, they could confidently announce that they had succeeded in completely regenerating the kaput thymuses of aged mice. The mouse thymuses were back on the job, turning thymocytes into mature T cells.
Fast forward to barely two months ago, August, 2023, researchers at the Francis Crick Institute in London announced that they had discovered that all the complex cells in the thymus epithelium could be produced from a single stem cell. By using state-of-the-art techniques to map gene expression in single cells and tissue sections, they found that the thymus’s stem cells (which they have named polykeratin cells) express a variety of genes that allow them to give rise to many cell types not previously considered to have a common origin.
They isolated thymus stem cells and then showed that:
These cells be extensively expanded,
All the complex cells in the thymus epithelium can be produced from a single stem cell.
The polykeratin cells can develop into epithelial as well as muscle and neuroendocrine cells. The polykeratins cluster underneath the fibrous capsule of the thymus and around blood vessels in the central part (medulla).
And there they sit, generating thymocytes from thymic epithelial cells. From the thymocytes come T cells, the commandos of your immune system.
Another highly significant aspect of this work is that the researchers were NOT looking at enthusiastic little baby thymuses. They found the polykeratin cells in lazy, blasé adult thymuses. Actually, it turns out that the adult thymus is not so lazy and blasé after all – it continues to play a productive role. This advance opens up enormous possibilities for restoring immune function through regeneration.
The research team at The Crick was led by Dr Roberta Ragazzini.
For Ragazzini, the surprise was that “stem cells in the thymus – an organ which reduces in size as we get older – regenerate just as much as those in the skin – an organ which replaces itself every three weeks. The fact that the stem cells give rise to so many different cell types hints at more fundamental functions of the thymus into adulthood.”
What if the secret of restoring a fatty, wasted HUMAN thymus is discovered? What if a way is found to make thymus regeneration an affordable real-world treatment for everyone who needs it? An advance like that would mean a whole new ballgame.
Restored thymus, bursting with youthful vigor -> amped up immune system -> goodbye to a long list of ailments.
That’s the idea behind the Wang-Lim mass produced bio-engineered thymic cells.
So we ask you … is their project worth $37 million?
You bet it is.