Greek hero Heracles, who defeated the multi-headed Hydra by cutting off each of the beast’s nine heads and cauterising the remaining stumps so they couldn’t grow new heads, would have had a far tougher fight if his mission had been to vanquish Earth’s real-world Hydra. This freshwater creature may be only half a thumb tall, but it is almost indestructible. Strip it chemically of all the glue that makes this animal’s cells stick together and it will eventually reassemble like the Terminator. Even cutting it into three won’t condemn the creature to death. Instead, it just regrows the missing parts.

This incredible ability for regeneration has long fascinated scientists—not just biologists but also those who have been tackling some of the most pressing human health problems—with its promise of being able to replace or restore damaged or missing cells, tissues, organs and even entire body parts.

Unlike a Hydra that draws its super regenerative powers from a vast pool of powerful stem cells, which account for about half its cells, an adult human’s body relies on the dwindling number and strength of its stem cells to repair any damage. Often, the injury is just too great for the body to fix, leaving only the option of organ transplantation.

  
“But for some organs and tissues, there is no good way to transplant them. One example is the human brain, which uses a very complicated wiring system,” said Professor Zhang Suchun, Director of Duke-NUS’ Neuroscience and Behavioural Disorders Programme, whose long-term goal is to be able to rebuild ageing or diseased brains from within by using specially reprogrammed cells.

“If you have brain degeneration, the nerve cells get damaged and the wiring system gets affected. Often, we cannot just take a pill and resolve it. In this case, we can apply regenerative strategies to repair, replace or regenerate these nerve cells to restore and regenerate the brain function. This makes regenerative medicine crucial and a great boon when it comes to treating brain disorders,” he added.

Zhang’s colleague from the Neuroscience and Behavioural Disorders Programme, Professor Jonathan Crowston, is also looking for ways in which he can turn back time to reverse nerve damage. For Crowston, who is also the Director of the Duke-NUS’ Centre for Vision Research, the nerve in question is the optical nerve.

 
“Many patients who have lost a substantial amount of their vision come to us, and we would love to be able to regrow their optic nerves and give them full vision back,” said Crowston who is also a glaucoma consultant at the Singapore National Eye Centre.

He likens regenerative medicine to getting a car serviced, adding, “It is not just the matter of fixing what was wrong but potentially making it better. Regenerative medicine is a way by which you could turn your old car that is breaking down into a new car.”

But even in disease areas where organ transplantation is possible, regenerative medicine has huge potential. Long transplant lists often place donor organs beyond reach, so having a cell-based therapy that the body can use to repair the damage itself would bring hope to many people with damaged hearts and other injured organs. Investigating regenerative therapy options in these areas is the life mission of Professor Karl Tryggvason and his team at Duke-NUS’ Cardiovascular and Metabolic Disorders Programme.

“Using matrix proteins called laminins, we have successfully developed fully humanised, chemically defined, highly reproducible, non-tumorigenic differentiation protocols to make human embryonic stem cell-derived cell types. We foresee that the use of such methods can become important tools in the development of robust methodologies that can impact the development regenerative medicine,” said Tryggvason who is also the Tanoto Foundation Professor in Diabetes Research.
 

Coming together to speed up regeneration

With its vast potential to transform medicine, two researchers from the SingHealth Duke-NUS Academic Medical Centre realised that creating a space—if only virtually—where like-minded experts can meet and exchange ideas would be a boost to transforming the field’s potential into tangible improvements to patient care for Singapore and the world.

Professors William Hwang and Teh Bin Tean, Medical Director and Deputy Medical Director of Research of the National Cancer Centre Singapore, respectively, hit on the idea during a fishing trip in 2020.

“We talked about how cardiovascular disease, kidney disease, cancer and stroke are increasing rapidly in our ageing society and how regenerative medicine is expected to have a significant impact on reducing the burden of these diseases,” said Hwang, also a professor at Duke-NUS who has spent years studying blood stem cell regeneration and its use in the treatment of blood cancers. Over the years, he has worked with collaborators from across the SingHealth Duke-NUS Academic Medical Centre, many of whom are pursuing regenerative medicine-based solutions in different fields.

“The idea of bringing together all the expertise we had under one roof in SingHealth in an institute came to me—we could harness our collective strengths and do cutting-edge science, allowing us to develop novel clinical applications that will offer better health and overall quality of life.”

This proposal led to the formation of the SingHealth Duke-NUS Regenerative Medicine Institute of Singapore, which Hwang and Teh lead, in May 2021. The new institute harnesses the potential of regenerating diseased cells, tissues and even organs to develop research, regenerative therapies and tools to tackle age-related diseases and chronic conditions.

The prime focus of the institute is on seven disease areas, which include cardiovascular diseases, neuro-sensory diseases and eye disorders. Together with the SingHealth Duke-NUS Cell Therapy Centre, it aims to take cellular and gene regenerative therapies and tools into clinical trials and translate them into clinical applications that will benefit patients.

“We are working towards developing strategies to regenerate and transplant bone marrow, cardiac muscles and retina cells and hope to improve treatment outcomes for these debilitating conditions. Once we have developed the cellular therapy products, we will study their safety and efficacy through clinical trials in SingHealth Duke-NUS Cell Therapy Centre’s network,” said Teh, who leads a team studying the underlying causes of muscle wasting associated with advanced cancer and old age.
 

Racing to the crest to unleash large-scale benefits

With the campus’ resources united, Duke-NUS and the wider Academic Medical Centre are poised to advance the field significantly over the coming years. But challenges remain before this fledgling field can take off exponentially.

“When it comes to regenerative treatments for inherited rare diseases, the big challenge is to scale this up to treat more complex genetic diseases. For example, there are already challenges toto restore vision in families with a retinal disease caused by a single, identical mutation. Moving on to treating diseases with more complex genetics such as glaucoma, which affects many people worldwide, brings substantially more challenges,” said Crowston.

Many gene therapies use viruses as carriers to deliver the gene to the cells. Once these viruses are introduced to the human body, it will kick start immune responses to the virus. Having virus-free gene therapy approaches present certain advantages over viral methods, such as large-scale production and low host immunogenicity.

“We need to also ensure that the stem cells are of good quality and can reliably perform not only in an animal model testing but also in a clinical setting. Then, there is the process of growing them in a good manufacturing practice environment so that these cells are of adequate quality for delivery to patients,” said Hwang.

Stem cell-derived cells aimed for treatment of tissue injuries are defined as drugs, and regulatory agencies like the USA Federal Drug Administration, European Medicines Agency and the Human Science Authority of Singapore require several prerequisites to be met by therapeutic stem cell derived cells.

“These cells must be prepared under strictly reproducible methods that ensure that the cells are devoid of any infective agents; they should not contain any animal derived components; they should be in chemically defined reagents so they always have the same effects in the patient after transplantation,” said Tryggvason.
 

Moving towards a brighter tomorrow

Taking this into his sights, Duke-NUS Assistant Professor Owen Rackham and his collaborators turned to computational methods to help eliminate some of the trial and error as well as to do away with the need for using animal-derived cells to keep these stem cells alive.

“I am a trained computer scientist and I have always been interested in understanding how to control complex systems. Cell therapy fascinated me and I wanted to understand how changing some genes in fibroblasts helps to reprogramme them in to induced pluripotent stem cells,” said Rackham from Duke-NUS’ Cardiovascular and Metabolic Disorders Programme.

The resulting technology, MOGRIFY and later epiMOGRIFY, are algorithms that help stem cells to reprogramme into the desired cell type, improve the culturing of cells in the lab and provide the right environment for the desired cell type to flourish.

“This algorithm tells us what molecules are needed to keep cells healthy in laboratory cultures, which can help accelerate treatments that require growing patient cells in the lab and also allow us to go to the next step of working out how to scale up and manufacture them for therapeutic use,” added Rackham in explaining epiMOGRIFY.

With such multidisciplinary focus, the field of regenerative medicine is set to expand rapidly into new therapy areas.

“I am confident that the future of regenerative medicine is bright. It will still take a lot of effort and each step has to be taken carefully. But in the next five to ten years, we should be able to see regenerative medicine used for some of the diseases such as diabetes and neurological diseases like Parkinson’s,” said Zhang, whose novel stem cell-based therapy for Parkinson’s disease is on the cusp of entering clinical trials.

 
Reflecting on the impact of regenerative medicine, Crowston believes that these therapies will have a tangible impact on the way diseases that lead to loss of function are approached. He said, “Although many of these are, sadly, still a long way from coming to fruition, as a clinician, it is very satisfying to think that you may, one day, have the potential to not only stop disease progression but also to restore function in our patients.”