In this episode, we explore some of the major scientific findings – like discovering DNA – that set the stage for the development of gene therapy and its groundbreaking potential when it comes to the treatment of genetic diseases.
The very idea of gene therapy wouldn’t be imaginable had two pairs of pioneering scientists not bonded decades earlier. In 1951, a young chemist named Rosalind Franklin and her colleague Maurice Wilkins at King’s College in London were using X-ray crystallography to try and perceive the properties of a theoretical molecule known as deoxyribonucleic acid.
At the time, many scientists believed that all the genetic information about living organisms was contained in a molecule called DNA. But no one had figured out exactly what it was, or what it looked like.
After attending a presentation by Franklin, James Watson – who was also studying the topic – connected with Francis Crick. Crick had been studying the concept of base pairs – the idea that nucleic acid is composed of chemical bonds between not one but two sets of molecules, each supporting the other, much like the two sides of a ladder support the rungs in between. Excited by their shared passion, Crick and Watson in Cambridge began to build models of possible DNA structures, trying to figure out just how all the pieces fit.
Eventually, Franklin, Wilkins, Watson and Crick’s efforts joined, and DNA was discovered. Then, in the 1970s, DNA was successfully transferred from one life form to another.
Less than 50 years after Crick, Franklin, Wilkins, and Watson first showed us what this molecule looks like, genetic engineering gave us the ability to reprogram it when it isn’t working.
Scientists and doctors began to dream big: could this technology eventually cure all genetic diseases?
There was still work to be done. But, like a tiny plasmid loaded up with recombinant DNA, we were on our way.
For more education on gene therapy, visit www.genetherapynetwork.com.
DDx SEASON 4, EPISODE 1
A Brief History of Gene Therapy and the Discovery of DNA
RAJ: This season of DDx is brought to you by Novartis Gene Therapies.
KIM: In the summer of 1990, a four-year-old girl named Ashanthi de Silva travelled with her family to the National Institutes of Health, or NIH, in Bethesda, Maryland.
It was a rare outing for the brave little girl.
Ashanthi had been born with a genetic disorder called Severe Combined Immunodeficiency, or SCID, which made her body unable to fight off infections. As a result, she almost never left home or played with other children. Her life was constantly at risk.1,2
Most of us are born with a healthy immune system in which an enzyme called Adenosine deaminase, or ADA, plays an important function.3
There is a single, specific gene in our DNA that holds the blueprint for producing the ADA enzyme, and when Ashanthi was born, that gene was mutated: the blueprint was missing a step. The condition was typically fatal. So the little girl’s parents were willing to try almost anything.1,4
At the NIH hospital in Bethesda, a team of geneticists led by Dr. French Anderson had a radical idea: to replace the function of Ashanthi’s mutated ADA gene that causes disease with a healthy one. They called it “gene therapy,” and while it had been tried previously on plants and microscopic organisms, it had never been attempted in humans.1-3
Little Ashanthi was about to become the first.
RAJ: This is DDx, a podcast from Figure 1 about how doctors think.
I’m Dr. Raj Bhardwaj. This season I’m joined by co-host Kim Handysides as we take a deep dive into gene therapy.
Today we’re going to talk about some of the major scientific discoveries that set the stage for the development of gene therapy and its groundbreaking potential when it comes to the treatment of genetic diseases.
KIM: The very idea of gene therapy wouldn’t be imaginable had two pairs of pioneering scientists not bonded decades earlier.
In 1951, a young chemist named Rosalind Franklin, working at King’s College in London, began using X-ray crystallography to try and perceive the properties of a theoretical molecule known as deoxyribonucleic acid.5,6
At the time, many scientists believed that all the genetic information about living organisms was contained in this molecule, better known as DNA. But no one had figured out exactly what it was, or what it looked like.7,8
Franklin and her King’s colleague Maurice Wilkins were getting close to the answer. Franklin gave a lecture that year in which she presented some of her initial findings, which implied that DNA might take the shape of a coil, or helix. In the audience was a young research fellow named James Watson, who shared Franklin’s passion for solving the riddle of DNA.9,10
Soon afterwards, Watson left London for Cambridge, where he met a graduate student who was building models of protein structures to try to figure out DNA. This was Francis Crick. Crick had been studying the concept of base pairs—the idea that nucleic acid is composed of chemical bonds between not one but two sets of molecules, each supporting the other, much like the two sides of a ladder support the rungs in between. Excited by their shared passion, Crick and Watson in Cambridge began to build models of possible DNA structures, trying to figure out just how all the pieces fit. Meanwhile, in London, Franklin and Wilkins continued to use X-ray diffraction to reveal the hidden form of DNA.8,11,12
Crick and Watson were stuck, until Wilkins shared a confidential report that included one of Franklin’s diffracted X-ray images. The image, known as photograph 51, revealed a pattern of DNA nucleotides in the shape of a coil.13
For Crick and Watson, this was a eureka moment. At last, there was one model that checked all the boxes: base pairs, repeating sequences, a ladder in the shape of a coil—DNA was shaped like a double helix!7,14
Crick and Watson, with an assist from Franklin and Wilkins, had officially discovered DNA.9
Crick and Watson received most of the fame, but Rosalind Franklin was the unsung hero in the discovery of DNA. She passed away in 1958, just 37 years old, after a battle with ovarian cancer that many believe to have been caused by her repeated exposure to X-rays.9,15
She made a very personal sacrifice for the sake of science.
Crick, Watson, and Wilkins shared the 1962 Nobel Prize for what is widely considered one of the greatest scientific discoveries of the twentieth century. Franklin was neglected, in part because the Nobel committee by tradition didn’t give posthumous awards. Today, the scientific community is working to restore the honor she deserves.7,15
KIM: After Crick and Watson showed us the structure of DNA, it fell to a new generation of researchers to isolate specific segments of this genetic code—and find out if they could be replicated.
For that achievement, we can thank another pair of scientists and their unlikely bond.
In the early 1970s, Stanley Cohen was part of a team of geneticists at Stanford University who were investigating plasmids.16,17 Cohen realized that plasmids could potentially be a vector for delivering any gene—including one that was cloned in a lab.16
In order to edit the software that runs all of human life, he had to find a way to cut a gene from one place, and paste it somewhere else.
But Cohen didn’t yet know the key to isolating a particular gene. He had the means to paste, but not the tools to cut. Meanwhile, across town at the University of California at San Francisco (UCSF), Herbert Boyer was working on just that tool.18
Amazingly, although their labs were separated by only 30 miles of the Santa Cruz Mountains, Cohen and Boyer didn’t meet each other until they attended a plasmid conference in Hawaii, in the fall of 1972.19
It didn’t take long for their bond to gel: less than a year later, on November 1, 1973, Cohen and Boyer successfully transferred DNA from one life form to another.20
Genetic engineering had just been born. It was another milestone on the journey toward gene therapy.
KIM: A new era dawned following the great discoveries of the early 1970s at Stanford, UCSF, and Johns Hopkins. A gene mutated by chance could be corrected by science. Thousands of lives might be saved and countless more would be changed.16
Back in Bethesda, at the National Institutes of Health, the geneticist W. French Anderson was working on SCID—the genetic immune deficiency that afflicted Ashanthi. He knew the disease was caused by a specific gene variation. And as rare and deadly as it was, it seemed like a worthwhile candidate to finally try gene therapy on humans.21 With his colleague Michael Blaese, an immunologist, the pair set a goal to clone a healthy ADA gene and hitch it to the wagon of a viral vector. They spent several years developing precise clinical protocols for approval by the NIH and FDA, long before they met the four-year-old girl who would change their lives as they tried to save hers.1,4,22
Finally, in 1990, Anderson and Blaese had permission to find a patient.4
Ashanthi’s parents faced a choice: watch their little girl struggle to live a healthy life, or submit her to an audacious experimental therapy that had never been tried before.
It was an agonizing decision, but one her father, Raj, says came down to a belief his daughter’s life could be saved. The DeSilva family arrived in Bethesda on September 2. Ashanthi settled into a hospital room for a treatment procedure.4,22
Anderson, Blaese, and their colleague Kenneth Culver removed some of Ashanthi’s blood and isolated her white blood cells in their lab. They cut a section of a healthy ADA gene from recombinant DNA and then, using a viral vector, pasted it onto the helix of Ashanthi’s DNA in the T-cells in her blood. Finally, they returned the blood to Ashanthi’s body 12 days later and waited. Back in her bloodstream, Ashanthi’s new, corrected white blood cells divided, and divided again. They spread throughout her body, replenishing her T-cell count with every division, replacing the function of mutant ADA genes with every division.1,22
After about six months, Ashanthi’s levels of ADA had risen to the level of a normal, healthy child.4,23
It wasn’t a cure. Even after the successful procedure, Asthanthi remained on a program of synthetic ADA therapy to ensure her disease didn’t slowly return.4,22,23
But it was hope. It was promise.
KIM: Less than 50 years after Crick, Franklin, Wilkins, and Watson first showed us what our DNA software looks like, genetic engineering gave us the ability to reprogram it when it isn’t working.
Scientists and doctors began to dream big: could this technology eventually cure all genetic diseases?24
There was still work to be done. But, like a tiny plasmid loaded up with recombinant DNA, we were on our way.
Show Extro and Sponsorship Disclosure
RAJ: Special thanks to Dr. Peter Kannu, chair of the University of Alberta’s Department of Medical Genetics and leading expert in genomic medicine, for sharing his expertise in the research of this episode.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, co-host and story editor of DDx.
You can follow me on Twitter at Raj Bhardwaj MD.
Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.
This episode was brought to you by Novartis Gene Therapies.
For more education on gene therapy, visit gene therapy network dot com.
Thanks for listening!
- Panno J. Gene Therapy: Treating Disease by Repairing Genes. Facts On File, Inc. 2005.
- Gene Therapy: The Comeback Kid of Hematology Treatments? ASH Clinical News. Published May 1, 2021. Accessed September 16, 2021. https://www.ashclinicalnews.org/spotlight/feature-articles/gene-therapy-comeback-kid-hematology-treatments/
- Whitmore KV, Gaspar HB. Adenosine Deaminase Deficiency – More Than Just an Immunodeficiency. Front Immunol. 2016;7:314.
- Naam R. “More than Human.” Published July 3, 2005. Accessed September 19, 2021. https://www.nytimes.com/2005/07/03/books/chapters/more-than-human.html
- Glynn J. The Art of Medicine: Remembering my sister Rosalind Franklin. The Lancet. 2012;379:1094-1095.
- Rosalind Franklin: Biographical Overview. NIH – U.S. National Library of Medicine. Accessed September 14, 2021. https://profiles.nlm.nih.gov/spotlight/kr/feature/biographical
- Portin P. The birth and development of the DNA theory of inheritance: sixty years since the discovery of the structure of DNA. J Genet. 2014;93(1):1-10.
- Francis Crick: The Discovery of the Double Helix, 1951-1953. NIH – U.S. National Library of Medicine. Accessed September 14, 2021. https://profiles.nlm.nih.gov/spotlight/sc/feature/doublehelix
- Elkin LO. Rosalind Franklin and the Double Helix. Phys. Today. 2003;56(3):42-48.
- Gann A, Witkowski J. The lost correspondence of Francis Crick. Nature. 2010;467(7315):519-524.
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.
- Francis Crick: Biographical Overview. NIH – U.S. National Library of Medicine. Accessed September 14, 2021. https://profiles.nlm.nih.gov/spotlight/sc/feature/biographical-overview
- Latychevskaia T, Fink HW. Three-dimensional double helical DNA structure directly revealed from its X-ray fiber diffraction pattern by iterative phase retrieval. Opt Express. 2018;26(23):30991-31017.
- Zanchetta G, Cerbino R. Exploring soft matter with x-rays: from the discovery of the DNA structure to the challenges of free electron lasers. J Phys Condens Matter. 2010;22(32):323102.
- Benderly BL. Rosalind Franklin and the damage of gender harassment. Science. Published August 1, 2018. Accessed September 20, 2021. https://www.science.org/content/article/rosalind-franklin-and-damage-gender-harassment
- Berg P, Mertz JE. Personal reflections on the origins and emergence of recombinant DNA technology. Genetics. 2010;184(1):9-17.
- Plasmid. NIH – National Human Genome Research Institute. Accessed September 19, 2021. https://www.genome.gov/genetics-glossary/Plasmid
- Roberts RJ. How restriction enzymes became the workhorses of molecular biology. Proc Natl Acad Sci USA. 2005;102(17):5905-5908.
- Russo, E. Special Report: The birth of biotechnology. Nature. 2003; 421:456–457.
- Cohen SN. DNA cloning: a personal view after 40 years. Proc Natl Acad Sci USA. 2013;110(39):15521-15529.
- Mukherjee S. The Gene: An Intimate History. Scribner. 2016.
- Philippidis A. Making History with the 1990 Gene Therapy Trial. Genetic Engineering & Biotechnology News. Published April 1, 2016. Accessed October 12, 2021. https://www.genengnews.com/magazine/269/making-history-with-the-1990-gene-therapy-trial/
- Mak T, Saunders M, Bradley J. Primer to the Immune Response, 2nd Edition. Academic Cell, 2014: 377-421.
- Vaiserman A, De Falco E, Koliada A, et al. Anti-ageing gene therapy: Not so far away? Ageing Res Rev. 2019;56:100977.