Sometimes scientific medical breakthroughs even stun the researchers themselves. That’s what happened to Dr. Hakonarson and his colleagues at Children’s Hospital of Philadelphia (CHOP).
They discovered a surprising cure for a boy about to die.
The story of how medical researchers saved Daniel by genetically engineering his disease onto zebrafish embryos until they found a medication that worked has profound implications for genetic research.
It suggests how precision medicine could be the wave of the future, how the least likely gene may be the culprit, and how genetic techniques could save 1 in every 4,000 newborns every year with lymphatic malformations.
Daniel's Medical Miracle
Before the age of 10, Daniel ran a 5K event in 25 minutes, but at 10, his legs started swelling and breathing became increasingly difficult.
Two years later, his parents rushed him to the Children’s Hospital of Philadelphia (CHOP) because his lungs were filling up with lymph fluid.
At the hospital, doctors drained the lymphatic fluid building up around his heart, but it continued to leak in — and things looked grim until researchers found a novel genetic therapy to save his life.
Born with a complex genetic defect that affected the proper circulation of lymphatic fluid in his body, Daniel’s health condition in the hospital became increasingly worse.
Because his belly and legs swelled and his lungs filled with fluid, lymph drainage only gave him temporary relief. His situation became so dire he had to rely on an oxygen tank to gasp for breath.
Since his health was getting rapidly worse, Dr. Hakon Hakonarson, the pediatric lung specialist and director of the Center for Applied Genomics at the children’s hospital, thought he would die.
Saved by Fast Research
Fortunately, as reported by STAT News, the doctor and his colleagues saved Daniel using zebrafish for quick lab research.
First, the medical team found the mutation causing the lymphatic vessels to propagate at an accelerated rate to leak copious amounts of fluid into his lungs.
Then, they replicated the mutation into zebrafish, the translucent fish often used in genetic research, and waited for them to develop a version of the disease.
Next, after testing many drugs, they found that Trametinib, a drug by Novartis for melanoma, stopped the fast-expanding network of vessels.
Finally, after getting approval from the Food and Drug Administration (FDA), they used the medication on Daniel to reverse his health condition.
The Power of Precision Medicine
Historically, the standard way of working out the efficacy of a drug has been trial and error.
This has not worked well.
Doctors relied on trial and error for centuries. They leaned on it despite the medical establishment having long recognized that people react in dissimilar ways to any drug. What works for some does not work for all.
Daniel’s medical miracle illustrates that this model of medicine may be about to change.
His physician saved his life because he deployed a new, emerging medical model called “precision medicine.”
Precision medicine stems from the field of pharmacogenomics, the study of how genetic differences influence how people respond to a medication.
Here at Your DNA, we’ve noticed that the use of genetic tests for improving treatment decisions is becoming much more acceptable. People recognize that they respond to medications in different ways because they have different genetic differences.
Today, precision medicine is becoming more readily available across many diverse areas of healthcare.
Precision medicine offers three remarkable benefits:
- It usually works more effectively.
- It often reduces negative side effects.
- It frequently cuts healthcare costs.
An Unlikely Suspect: the ARAF Gene
In Daniel’s case, if it were not for precision medicine, doctors would not have found the gene responsible for the proliferation of lymphatic vessels that caused his lymph fluids to leak into his lungs.
When Dr. Hakonarson and his team sequenced Daniel’s exome, the protein-producing part of his genome, they initially only looked at genes associated with lymphatic abnormalities.
Baffled by their inability to find any mutations, they researched other genes and stumbled upon an unlikely suspect, the ARAF (A-Raf Proto-Oncogene, Serine/Threonine Kinase) gene. It did not look normal.
The ARAF gene is a protein-coding gene on the X chromosome. It makes an enzyme called serine/threonine kinase which adds molecules to cellular proteins.
The genetic researchers did not suspect this gene because genetic researchers had never linked it to lymphatic anomalies, only to diseases like Pallister-Killian Syndrome.
After stumbling upon the mutated ARAF gene, they wondered if this was causing the fast-paced growth of lymphatic vessels flooding the body with lymph fluid to cause life-threatening congestion and swelling.
They verified their suspicions by genetically engineering the embryos of the zebrafish to carry the mutation.
The Future of Genetic Research
Besides discovering ARAF mutations can cause lymphatic vessels to propagate out of control, the Applied Genomics team at CHOPS also discovered an excellent reason researchers should start using genetic techniques to investigate the cause of lymphatic malformations that affect one in every 4,000 newborns.
The lymphatic system integrates seamlessly with the cardiovascular system to absorb and return fluid from various tissues back to the veins. Although primarily recognized as a system that supports the immune system, the lymphatic system also transports fat and protein.
Daniel’s anomalous lymphatic flow went undiagnosed until fluid started to accumulate in his chest and abdomen, leading to breathing difficulties, abdominal swelling, and swelling in his arms and legs.
Daniel’s scientific miracle using zebrafish points the way to the value of mutation-specific therapies. In fact, researchers are already exploring technologies like CRISPR/Cas9 to edit genes.
The future of medicine certainly looks bright from where we're standing.
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