For Jonathan Han ’21, interacting with patients for his clinical experiments comprises the most deeply satisfying aspect of medical research. “I’m always interested in acquiring a patient’s perspective on our work, to evaluate how our experimental methods affect their experience by understanding what works for them, and what doesn’t,” Han says. “It is, ultimately, the end goal of all patient-orientated medical research.”
During the summer of 2019, Han conducted experimental research and interacted with nephrology patients at Weill Cornell Medicine in New York City. Han is a member of the Iwijn De Vlaminck lab, Biomedical Engineering, at Cornell University in Ithaca. De Vlaminck has been collaborating with John R. Lee, Darshana M. Dadhania, and Manikkam Suthanthiran, Medicine, transplant nephrologists at Weill Cornell Medicine, to improve the diagnosis of post-transplant kidney-related complications. Han worked on the clinical component of his research project alongside the transplant nephrologists.
Diagnosing Complications, Following Kidney Transplants
The Suthanthiran laboratory at Weill Cornell Medicine, Han says, was the ideal location to pursue this research, given their expertise and pioneering work on the development of noninvasive assays, or medical tests, to diagnose and prognosticate kidney transplant functions—using urine mRNA.
Han explains, “Clinical and subclinical rejection by the host are common complications post kidney transplant.” He says that the two current methods for determining the patient’s health the weeks following a transplant, however, are either not accurate enough or are significantly cost-inhibitive. The first method is to examine the amount of creatinine and other waste products in the bloodstream. An excess indicates that the kidney is unable to carry out its primary purpose of filtration. This method, although adept at diagnosing the presence of an issue, cannot help doctors locate the specific type of kidney injury.
“It can only articulate that something’s wrong,” says Han. A biopsy, which can identify specific ailments, requires the physical extraction of a tissue sample from the kidney. The greater effectiveness of a biopsy is compromised by the invasive nature of the process and its significantly high procedural costs.
New Nephrological Diagnostic Tools, Using Cell-Free DNA
In order to formulate an optimized, cost-effective process, Han decided to develop an assay for nephrological diseases, using cell-free DNA in the bloodstream and urine. This method would require a less invasive analysis than a biopsy, while delivering greater accuracy than a simplistic examination of waste secretion patterns.
“I am essentially observing identification patterns relating to diseases, in DNA found in blood and urine,” Han says. “Certain nucleotide bases in the DNA exhibit chemical modifications, which can be detected using genomic technology, such as a quantitative polymerase chain reaction (qPCR) machine.”
The first step of Han’s research involved a substantial amount of data mining, as he combed through records of DNA sequences generated in patients in order to identify patterns that corroborate a specific kidney disease. These patterns help determine the causal pathway for cell deaths. “If, say, x kidney cell dies, there’s a particular pattern that follows as its corroborating methylation pattern is released, thus indicating the x disease-related cell’s degeneration,” says Han.
Following the data-mining phase, Han utilized in vitro samples of DNA to validate the chemical assertions of his assay. Having completed the initial steps of structuring his assay at the De Vlaminck lab in Ithaca, Han performed pilot studies, using patients’ DNA at Weill Cornell.
As Han explains, specific DNA markers appear in patients’ DNA following the diagnosis of certain nephrological diseases. He is trying to reverse-engineer the process, in order to ascertain the specific disease, based on its signature effect on DNA. The process involves inducing a chemical reaction in the DNA sample to effect cytosine methylation. If a cytosine nucleotide exhibits methylation, the modification can be detected by the nucleotide’s inability to convert to thymine, a different nucleotide, after a conversion reaction.
“The idea is that by identifying these signature expression patterns in blood DNA, nephrological diseases can be identified and diagnosed.”
“The idea is that by identifying these signature expression patterns in blood DNA, nephrological diseases can be identified and diagnosed,” Han explains. He has identified several signature patterns relating to complications in the epithelial tissues, as well as glomerular cells in the kidney.
Next Steps to Better Nephrology Diagnostics
Ideally the next step would be a comprehensive study involving more patients. Following that, Han plans to initiate an interventional study, where he can help formulate a treatment regimen for patients, based on the results of his diagnosis—examining the real-world applicability of his process. While there are significant remaining experimental steps to execute before Han’s assay can be utilized in clinical trials, he is confident that the cost-effectiveness of his method will render it a preferable alternative to the prevalent post-transplant diagnosis procedures.
“Because every major hospital already has PCR machines available, the cost for each assay can be as low as $50. A biopsy, on the other hand, costs far more due to the need for a patient to be hospitalized while they undergo testing,” Han says.
Han’s method will also deliver results far quicker than a biopsy, which usually takes a week. Whereas a biopsy is only conducted once kidney-related health complications become evident in a patient, his testing method can be performed pre-emptively, preventing future complications before they arise.
Following the completion of his undergraduate degree, Han plans to pursue medical school. He says that working in the Department of Transplantation Medicine at Weill Cornell Medicine was a highly rewarding experience. “Alongside getting a firsthand understanding of how a patient perceives treatment, interacting with people from a wide range of medical sectors—administrative operatives, researchers, doctors—has given me a comprehensive understanding of life in the medical sciences.”