Dolly's Legacy: In Support of Fundamental Research

Illustration of Dolly Parton with Dolly the sheep in her right hand, and a COVID vaccine in her left hand
Written by Hayley McKay
Illustrated by Jenny Zhang
Every year, Science names one discovery or advancement as the “Breakthrough of the Year.” Sometimes the discovery or advancement contributes to biology or medicine, while other times it tackles questions about physics or outer space.

Back in 1997, Science named Dolly the sheep as the Breakthrough of the Year after scientists successfully cloned her, the first mammal created from an adult cell. Fast forward to 2020 and you can probably guess the breakthrough that claimed the prize: the rapidly developed SARS-CoV-2 vaccines.

At first glance, the connection between Dolly the sheep and the SARS-CoV-2 vaccines doesn’t seem to go any deeper than simply two stories about biotechnological advancements. But both stories hold an important lesson about how science is conducted and supported, and they surprisingly intersect at one famous country-western singer: Dolly Parton.

Dolly the sheep was born at the Roslin institute in Edinburgh on July 5, 1996. She was the first mammal to be cloned from a non-reproductive adult cell. Researchers Ian Wilmut and Keith Campbell wanted to find out if it was possible to produce a clone from a cell that was already in its final phase of development (called a “differentiated” cell). Their team used a technique called “somatic cell nuclear transfer” or SCNT, an experimental method that had never been used to clone a mammal before.

SCNT is fairly simple in theory, but extremely difficult and error-prone in practice. In Dolly’s case, one “mother” sheep donated DNA taken from one of her mammary gland cells. A second “mother” sheep also donated an unfertilized egg cell with its nucleus removed. The nucleus from the mammary gland cell was extracted and implanted into the egg cell, creating a simulated zygote, or fertilized egg, which was cultured in a petri dish. To get the “zygote” to begin developing, it was given an electric shock. Once the cell began dividing and growing like a naturally fertilized egg cell, the researchers implanted this developing embryo into the uterus of a third “mother” who brought the fetus to term, subsequently giving birth to Dolly.

Since Dolly genetically stemmed from a mammary gland cell, the Roslin Institute researchers couldn’t help but name her after the woman in possession of some of the most famous mammary glands out there: Dolly Parton. (She was flattered by their choice, in case you were wondering)

The singer-songwriter’s influence on scientific breakthroughs doesn’t end there. On top of an already long list of philanthropic efforts, Parton donated $1M to Vanderbilt University specifically to help fund research that produced the Moderna SARS-CoV-2 vaccine. After just a year of warp-speed research, multiple viable vaccines targeting the virus that causes COVID-19 have been produced, shedding a glimmer of hope that the end of the global pandemic is near.

Clearly, supporting targeted research like vaccine development is important. Without the many large financial contributions from governments and individuals like Parton, the COVID-19 vaccine production pipeline would be miles away from where it is today. It’s not hard to convince people (as well as governments and institutions) with money to invest in scientific endeavours which have a tangible end result. But what if the resulting scientific benefits aren’t so clear-cut, should the research still be supported and funded? Yes. A resounding yes.

After Dolly the sheep made headlines in 1997, there was immense backlash about the implications of cloning and fears of misuse of this technology. But the aim of the research was never to perfect the technology to clone adult animals. It was fundamental research in embryology; to investigate whether an adult cell could be reverted to a stem cell-like state. In fact, Ian Wilmut later denounced the use of SCNT for anything other than research, acknowledging that it was rife with error and often produced disfigured embryos that couldn’t survive to term.

While fear-mongers dreamed up wild scenarios of mutant clone armies taking over the world, other developmental biologists started investigating exactly how it was possible that Dolly was able to be created. Normally, specialized cells like heart or skin cells are derived from an undifferentiated cell called a stem cell. It was thought that once a cell reached its fully mature, differentiated state, it could not revert back to a stem cell. However, Dolly’s successful cloning proved otherwise. Since Dolly, a fully formed organism, was created from an adult mammary gland cell, differentiated cells (like the mammary gland cell) must be capable of reverting back to their original stem cell state!

Many scientists came to this conclusion after learning about Dolly in 1997, including stem cell biologist Dr. Shinya Yamanaka, who quickly began experimenting with adult cells to turn them back into stem cells. After nearly a decade of research in mice, Yamanaka and his colleagues identified four factors and the genes by which they’re encoded that together reprogram differentiated adult cells into undifferentiated stem cells. The discovery of these factors, called Yamanaka factors, was ground-breaking, and led to Yamanaka receiving a Nobel Prize in 2012 for his research.

The fundamental stem cell research started to morph into research with a tangible end result. Eventually, a method was developed to efficiently and safely reprogram adult human cells back to undifferentiated stem cells with the ability to differentiate into any kind of body cell. These artificially reprogrammed cells, called induced pluripotent stem cells (or iPS cells), have the potential to solve a lot of problems when it comes to the field of stem cell therapy.

Stem cells are currently used to treat a wide variety of diseases, most often degenerative tissue diseases like ALS, Parkinson’s, Alzheimer’s or type 1 diabetes, but also spinal cord or other neuronal injuries as well as cancer. The goal of using stem cell therapy is to promote the generation of new, healthy tissue derived from stem cells to replace the damaged tissue that’s causing the disease or injury.

However, stem cells are hard to come by. Adult stem cells do exist, but they are few and far between; usually they’re harvested from the bone marrow via an invasive and painful procedure, and they don’t give rise to every cell type in our bodies. Stem cells with the ability to differentiate into any type of cell (called “pluripotent stem cells”) can be harvested from young human embryos, but this method comes with major ethical concerns. Additionally, stem cells that don’t come from the patient’s own body are likely to be rejected by their immune system, negating the entire point of the treatment.

But, iPS cells have the potential to solve all of these problems: targeted research is underway to develop a therapeutic method to take a sample of a patient’s skin (or other adult) cells and reprogram them into undifferentiated iPS cells with the Yamanaka factors. Then, these iPS cells with the same genome as the patient can be re-introduced to treat the disease or injury they are suffering from, without the risk of immune rejection.

Without the creation of Dolly the sheep, would stem cell research be where it is today? Probably not. Fundamental research always has the potential to be applied to solving problems in the real world, but sometimes it takes time, and often, serendipity. Science is about asking questions to better understand the world we live in. More often than not, the most impactful scientific breakthroughs ride on the backs of fundamental research that wasn’t directly related to the advancement. So, we can’t afford to shun open-ended fundamental research in favour of targeted research. Fundamental research is essential for the targeted research to happen down the line.

Scientists aren’t the ones who need to be convinced of this. Governments and public funding agencies need to acknowledge the need for fundamental research and spend accordingly. Public support of fundamental research will also help, and that goes hand in hand with improving science education and literacy.

Having public figures like Dolly Parton who support science and education with their chequebooks and their messaging is always great to see. Leading by example can have a big impact on the progress of science. Millions of people watched Parton receive a taste of her own medicine a couple weeks ago when she got her first shot of the Moderna vaccine. Her endorsement of the scientific breakthrough certainly convinced at least a few of her followers to get a COVID-19 vaccine, and that’s no small feat.