For Your Cells, Four Genes Hold the Key to Rebirth
Written by El Hebert '24
Edited by Alyssa Steinbaum '23
Could we get back the endless potential that lets our whole bodies grow from just one cell? Dominicus Johannes Bergsma, 2021, hosted on Wikimedia Commons.
Every human starts from a simple, hollow glob of cells. To make a living, breathing person, they harness the subtle superpower of pluripotency - the ability to become anything: heart, nerve, skin, you name it. But when all your organs are arranged and your body assembled, your cells lose their pluripotency and settle into their jobs for good. From then on, there’s only so much these cells can do to repair and regenerate as the clock on your biological lifespan starts ticking.
Still, even settled body cells hold a full complement of DNA - enough instructions to build any body part, seemingly shelved away and ignored. Many nonhuman animals can dust off their old body blueprints to regrow lost limbs. When a baby sea star is sliced in half, silent genes from early development suddenly “turn on” again, marking the injury with body-mapping signals, just like a growing embryo. Some cells even shift their identity to replace their lost comrades; skin gives rise to neurons, and a week or two later, the regenerated critter barely seems shaken . Now, wouldn’t it be nice if we could do that?
In 1962, scientists got the first inkling that, with the right technology, we potentially could. Dr. John Gurdon replaced the pluripotent nucleus of a frog egg with that of a settled intestinal cell, and watched as the transplant produced a healthy tadpole anyway . Later, this same technique was famously used to spawn Dolly, the cloned sheep. Frogs and sheep, of course, sit much closer to humans on the tree of life than sea stars do. Even in these familiar animals, latent pluripotency can be called to action.
However, though promising, these success stories yielded little practical use for humans. Swapping single nuclei is about as inefficient a lab technique as one can imagine, not to mention the personal and political turmoil that surrounds any work with human embryonic cells.
Then, in 2006, researcher Shinya Yamanaka made a groundbreaking discovery. His work revealed a set of genes that could reprogram mature cells back to their ancestral state of limitless potential.
Originally, Yamanaka and his lab had screened reprogramming candidates one by one, working through a list of genes found to be uniquely active in pluripotent cells. To the team’s disappointment, none of the candidate genes, when re-introduced and activated in mouse cells, could make them budge. But then, as practice for a genetic screening procedure, Yamanaka’s colleague, Kazutoshi Takahashi, introduced all 24 candidates at once. Pluripotent colonies sprung forth.
After scrambling to whittle their laundry list of factors down to the essentials, the lab isolated four critical genes: Oct3/4, Sox2, c-Myc, and Klf4. They’re all transcription factors, genes responsible for coordinating the cell’s use of many other genes downstream . Today, these chosen four are known as the Yamanaka factors, and the cells they create are called induced pluripotent stem cells (iPSCs). Like the “stem” of a plant, they can sprout into anything. Expose them to the right signals, and behold: cell differentiation, generating the precursors to muscle and nerve, skin and bone.
iPSCs offer a wellspring of medical discovery. Researchers can propagate their colonies into any new cell type they need to study, without having to sample them from living people in invasive procedures. Some lineages are widely available for testing - such as the iPSC-derived heart cells that drug companies use to check for side effects  - but scientists can also reprogram cells from a specific patient. For example, at the Center for iPS Cell Research and Application in Kyoto, Naohira Egawa and his team used reprogramming technology to study ALS, a fatal genetic disease that affects motor neurons. Instead of extracting tissue from their patients’ spinal cords, as past research would have required, they simply sampled a few skin cells, reprogrammed them, and re-created fresh neurons on their culture plates. Since these new neurons showed all the abnormalities associated with ALS, the lab can use them to quickly test potential therapies .
The cutting-edge work with such custom iPSC lines often sounds more like science fiction than science fact. Today, thousands of people wait, with their lives hanging by a thread, for organ transplants compatible with their immune systems. But iPSCs already match their progenitor’s own body perfectly. On the forefront of medicine, biomedical engineers are developing the techniques to essentially 3D print organ-like tissue on demand . The power of the sea star may lie within reach for us bipeds.
In the past few years, the story got stranger - and even more tempting. What if, several researchers wondered, you activate the four Yamanaka factors only briefly, delivering a pulse of renewed life without causing cells to lose their identities? The results have been astonishing. Partially reprogrammed cells seem to shake off the dust of time. Faltering repair mechanisms come to life again.
In 2016, Juan Carlos Izpisúa Belmonte, working at the Salk Institute, made a critical genetic edit to a strain of mice. These mice were afflicted with progeria, a mutation that causes premature aging. Izpisúa Belmonte modified this mouse lineage to express the four Yamanaka factors when exposed to the drug doxycycline. After two days of doxycycline treatment, and Yamanaka expression, the mice regained youthful function in their major organs . Izpisúa Belmonte’s lab later replicated this effect in non-diseased mice who were simply naturally aging . It wasn’t just a few cells on a culture plate, but a whole living body.
Now, a slew of new companies are diving into partial reprogramming research for anti-aging in humans, receiving billions of dollars in initial financing. However, as promising as the field is, the Yamanaka factors aren’t miracle cures. We still don’t understand the steps of their complex genetic ballet, and if they’re used with anything other than the utmost care, they make their risks clear .
Limitless potential may be an exciting research prospect, but your body can only survive if all your cells adhere to their roles together. With four days of reprogramming treatment, rather than two, Izpisúa Belmonte’s mice began to die as their organs lost their identities . Even resettled cells, derived from iPSCs, can occasionally revert back to pluripotency . And when that happens, the limitless cells may run amok on a bizarre sort of rampage known as a teratoma, meaning “monster tumor.” Essentially, it’s a miniature attempt at a new body, but with no organization. Like preschoolers making macaroni art on a fancy tablecloth, the pluripotent cells express their creativity exactly where it’s least wanted, generating growths that mingle muscle, skin, hair, and even teeth .
With caution, respect, and much more research, though, the cellular reprogramming system will certainly change human lives for the better - potentially even everyone’s lives. Pluripotent cells make a powerful tool for investigation and an even more powerful potential therapy. It’s a window into what makes our bodies human, with our limitations and our strengths; it’s a reminder of the endless potential that lurks within us all.
 Zheng M, Zueva O, Hinman VF. Regeneration of the larval sea star nervous system by wounding induced respecification to the sox2 lineage. Elife. 2022 Jan 14 [cited 2022 May 4];11:e72983. DOI: 10.7554/eLife.72983.
 Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Development. 1962 [cited 2022 May 24];10 (4): 622–640. DOI: 10.1242/dev.10.4.622.
 Yamanaka S. The winding road to pluripotency (Nobel lecture). Angewandte Chemie (International edition). 2013 Dec 23 [cited 2022 May 24];52(52):13900-9. DOI: 10.1002/anie.201306721.
 Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, Aoi T. Drug screening for ALS using patient-specific induced pluripotent stem cells. Science translational medicine. 2012 Aug 1 [cited 2022 May 24];4(145):145ra104-. DOI: 10.1126/scitranslmed.3004052.
 Noor N, Shapira A, Edri R, Gal I, Wertheim L, Dvir T. 3D printing of personalized thick and perfusable cardiac patches and hearts. Advanced science. 2019 Apr 15 [Cited 2022 May 24];6(11):1900344. DOI: 10.1002/advs.201900344.
 Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cel 2016 Dec 15 [Cited 2022 May 24];167(7):1719-33. DOI: 10.1016/j.cell.2016.11.052.
 Browder KC, Reddy P, Yamamoto M, Haghani A, Guillen IG, Sahu S, Wang C, Luque Y, Prieto J, Shi L, Shojima K. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Nature Aging. 2022 Mar 7 [Cited 2022 May 24];2(3):243-53. DOI: 10.1038/s43587-022-00183-2.
 Eisenstein M. Rejuvenation by controlled reprogramming is the latest gambit in anti-aging. Nature Biotechnology News. 2022 Jan 19 [cited 2022 May 24]; 40:144-146. DOI: 10.1038/d41587-022-00002-4.
 Choi HW, Kim JS, Choi S, Hong YJ, Kim MJ, Seo HG, Do JT. Neural stem cells differentiated from iPS cells spontaneously regain pluripotency. Stem cells. 2014 June 4 [cited 2022 May 24];32(10):2596-604. DOI: 10.1002/stem.1757.
 Gutierrez‐Aranda I, Ramos‐Mejia V, Bueno C, Munoz‐Lopez M, Real PJ, Mácia A, Sanchez L, Ligero G, Garcia‐Parez JL, Menendez P. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem cells. 2010 Jul 16 [cited 2022 May 24];28(9):1568-70. DOI: 10.1002/stem.471.