Rewriting the Code

A high school volleyball player with sickle cell disease once measured her life in hospital visits. Now, she measures it in serves and wins. Another young woman with the same condition, once defined by chronic pain and fatigue, has returned to school, thriving for the first time in years. Both women are now free of the disease that shaped every part of their lives, thanks to gene therapy.

Their stories represent a shift in medicine that’s redefining what it means to treat, cure, and even prevent disease. At Yale School of Medicine (YSM), that transition is being driven by scientists and clinicians working at the intersection of the human genome, data science, and the clinic, turning decades of research into real-world healing.

“This is what precision medicine looks like in practice,” says Lakshmanan Krishnamurti, MD, professor of pediatrics at YSM and chief of pediatric hematology and oncology at Yale Medicine. “It’s not just about targeting a mutation—it’s about restoring possibility to a person’s life.”

Upstream from the clinic, physician–scientists like Yong-Hui Jiang, MD, PhD, are reimagining the genetic foundations that make such therapies possible. Jiang, who is professor of genetics and the Dorys McConnell Duberg Professor of Neuroscience as well as chief of medical genetics at YSM, studies genome and epigenome editing, and sees rare diseases not as scientific outliers, but as powerful guides toward understanding—and eventually curing—a wide range of conditions. “The insights rare diseases provide can transform how we treat common ones,” he says.

Precision medicine at YSM also extends to leveraging modern technology like wearable devices and portable diagnostic tools. According to Rohan Khera, MD, assistant professor of medicine (cardiovascular medicine) and of biostatistics (health informatics), and director of the Cardiovascular Data Science (CarDS) Lab, “We are using wearable devices, portable devices, ECGs, and others to diagnose conditions that typically require more advanced testing, moving diagnosis upstream, automating it, and making it easy and accessible.” This approach captures essential data continuously from real-world environments, thus improving diagnosis and personalizing care.

Together, the work of Jiang, Krishnamurti, and Khera illustrates a new kind of medicine—one that begins with the tiniest molecular edits and ends with lives rewritten.

When the term precision medicine first entered mainstream conversation, it was often framed as a way to personalize treatments for common conditions like diabetes, cancer, or heart disease. But researchers like Jiang believe the true power of precision medicine lies deeper—at the level of rare genetic disorders, in which even a single mutation can reveal the functioning of the human body’s most intricate systems. “Every rare disease is a natural experiment,” Jiang explains. “When one gene stops working, we see exactly what it does, and that gives us clues about how to target more complex diseases.”

In Jiang’s lab, the focus is on rewriting those faulty instructions. Using gene editing tools like CRISPR and base and prime editing, Jiang and his colleagues are exploring ways to correct the DNA “typos” that cause disease. But their work also extends beyond the genome itself. Through epigenome editing, Jiang’s team is developing techniques to fine-tune how genes are expressed—not changing the code, but tuning its activity up or down, much like adjusting a dimmer switch.

Jiang’s lab, working closely with a biomedical engineering lab led by Jiangbing Zhou, PhD, Nixdorff-German Professor of Neurosurgery, is developing this technique as a potential therapy for conditions like Angelman syndrome, H1-4 (Rahman) syndrome, and Prader-Willi syndrome—complex neurodevelopmental disorders caused by the silencing of a critical gene. By using a modified CRISPR system to reactivate the silent gene, they aim to restore normal function without permanently altering the DNA coding the genes.

For Jiang, rare diseases are not a niche area but the perfect incubator for the future of precision medicine. “We use Angelman, H1-4 syndrome, Prader-Willi as a showcase,” Jiang says. “If our approach works there, it can set us up to treat many other diseases.”

That’s because the knowledge gained from studying rare diseases has a ripple effect. Jiang points to the landmark discovery of the genetic basis of familial hypercholesterolemia, an inherited condition that causes dangerously high blood cholesterol levels. “This knowledge helped develop some of the most-prescribed medications, like statins, used to treat high cholesterol, a very common condition,” he says.

This interconnectedness between rare and common diseases has become a cornerstone of modern precision medicine, allowing researchers to leverage insights from studying rare conditions to benefit patients with more prevalent disorders.

“Gene editing technology is advancing rapidly,” Jiang says, “but if we can’t deliver it effectively, it won’t reach patients.” He mentions that Zhou’s group is developing next-generation delivery systems designed to target brain tissues that minimize the harmful immune responses and off-target events.

The goal, Jiang says, is to create a modular platform: one that can be adapted to different diseases quickly and safely, shortening the time between discovery and treatment. “We want to make genome editing not just powerful,” he adds, “but practical.”

Meanwhile, Krishnamurti is seeing breakthroughs come to life in his patients. A global leader in sickle cell disease treatment, he has spent decades working toward what once seemed impossible—a genetic cure. Now, it exists.

The therapy involves extracting a patient’s own blood-forming stem cells, adding a novel non-sickle cell gene to eliminate the faulty hemoglobin gene or editing the gene to activate a fetal version of it, and then reinfusing the cells back into the patient’s body.

Within months, the patient’s bone marrow begins producing healthy red blood cells, easing the painful life-threatening complications of sickle cell disease.

Krishnamurti highlights his work with a young woman with sickle cell disease who experienced chronic severe pain, frequent hospitalizations, and a deep-seated suspicion of the health care system. “There was no belief that anything else was possible for her life,” Krishnamurti says. For this young woman, and many like her, a future free from pain seemed like a fantasy. With the help of a dedicated care team of Yale Medicine colleagues, his patient received gene therapy, and has since attended her prom, graduated from high school, and is enrolled in college.

For Krishnamurti, the transformation is both biological and deeply human. He notes, however, that for many patients, adapting to a life without sickness can be daunting. “We found that many people in such situations cannot wrap their heads around the possibility of a different life due to their past experiences and anxiety about change,” he says. “It’s like winning the lottery,” Krishnamurti says. “Everyone dreams of it, but few are prepared for what happens next.”

Krishnamurti’s clinic has built an interdisciplinary model that includes psychological and social support alongside medical care. Counselors, social workers, and patient navigators help individuals and families prepare for the emotional impact of a cure. The process, he says, is as much about redefining identity as restoring health. “This is a new kind of medicine,” he says. “It doesn’t end with treatment. It ends with transformation of life’s possibilities.”

While gene editing offers transformative potential for individual patients, the future of precision medicine lies in developing scalable solutions that can benefit entire populations. Khera’s work in cardiovascular precision medicine exemplifies this approach, integrating readily available data streams from electronic health records, wearable devices like smartwatches, and such simple diagnostic tests as electrocardiograms (ECGs) to identify at-risk patients before they develop symptomatic disease.

The challenge, Khera notes, is that real-world data are messy. Unlike the clean, curated datasets of a research study, a health system’s data can be fragmented and variable. His team’s goal is to build AI models that can work with this messy reality, harmonizing disparate data streams and understanding their limitations.

The results are already striking. By training an AI model on thousands of cardiac ultrasounds, Khera’s team found they could identify the nascent signs of serious conditions like cardiomyopathy up to two years before a human clinician made the official diagnosis.

“A patient may be short of breath, go to the emergency room, and somebody checks whether the heart’s functioning okay,” he explains. “Our tools are able to deploy tests that are done early in the patient’s disease course. This can be the way to target early identification.”

This power extends beyond the hospital walls. Khera’s lab has developed a suite of smartphone apps, including one that can analyze a 30-second ECG taken on a wearable device, and flag potential heart disorders. The vision is a future in which disease is not something you discover in a doctor’s office, but something your phone warns you about, prompting you to seek care before symptoms even begin.

Ultimately, Khera predicts, “We’ll diagnose people early, we’ll target treatments to a person’s unique profile, and we’ll be able to monitor whether or not they’re receiving appropriate care.” This proactive approach culminates in the concept of a “digital twin”—a rich, dynamic, data-driven representation of an individual that allows clinicians and researchers to simulate how a patient might respond to different treatments before trying them in real life. “We will learn from that other ‘person’ how to provide the best care to this patient.”

What connects Jiang’s, Krishnamurti’s, and Khera’s work is more than the language of genes and data. It’s the vision of a continuum in which discoveries in the lab flow quickly into clinical trials, and insights from patients and real-world data loop back to inform the next generation of research.

At YSM, this cycle is accelerated by new cross- disciplinary collaborations. Jiang’s team is partnering with biomedical engineers and computational biologists to refine editing tools, while clinicians like Krishnamurti and experts like Khera are feeding real-world data and patient outcomes back into research. “The collaboration is essential,” Jiang says. “A therapy is only as meaningful as the life it changes.”

In some cases, the translation from lab to clinic happens in a matter of months. A novel editing technique developed in Jiang’s lab can be tested in patient-derived cells, refined, and then move toward clinical development through Yale’s precision medicine infrastructure—an ecosystem built to close the gap between discovery and delivery. Tackling these multifaceted challenges requires an institutional culture that fosters collaboration, prioritizes ethics, and supports audacious goals. For these three investigators, YSM provides that fertile ground.

Jiang credits the environment for a significant upturn in his research since his arrival from Duke University in 2019. He recounts a serendipitous meeting in a parking lot during the COVID-19 pandemic with Zhou. “He has the new technology, I have the disease,” Jiang says simply. That chance encounter blossomed into a major collaboration to develop new delivery technologies to treat rare genetic diseases. “I’m very fortunate for the environment here and the support from the leadership at every level,” he reflects.

This spirit of collaborative mission-driven science is shaping not only the research of today but the researchers of tomorrow. “We have to create a generation of investigators who think like this,” says Khera, emphasizing the need to train clinician–data scientists who can bridge the worlds of medicine and computation.

The Human Genome Project gave scientists a complete map of human DNA more than 20 years ago. Now, researchers like Jiang and clinicians like Krishnamurti are learning how to rewrite it—carefully, safely, and for the benefit of patients who once had no options. The next chapter of precision medicine, Jiang predicts, will be about genome health—an integrated understanding of how our genetic code, environment, and behavior interact to shape disease and wellness.

“Within the next five to 10 years,” he says, “genome and epigenome editing will be part of standard clinical practice. We’ll be able to diagnose, correct, and even prevent disease with unprecedented accuracy.”

From the first glimmers of hope for a child with sickle cell disease to the quiet promise of a smartwatch algorithm, a new era of proactive personalized medicine is dawning. It is an era built on a foundation of rigorous science, ethical commitment, and the profound belief that the most complex codes—whether genetic or digital—can be deciphered to serve a simple universal human goal: a healthier life. And at YSM, the work is just beginning.

For Krishnamurti, that vision is already taking shape—not just in the lab, but in the lives of his patients. “Gene therapy isn’t just a cure,” he says. “It’s a restoration of possibility—a reminder that science at its best gives people back their futures.”