Research Excellence

The Future of Healthcare: Personalized Medicine

Prof Ho studied microfluidics and aerodynamics before turning his attention to personalized medical treatments

This February, US President Barack Obama hosted a summit at the White House on his Precision Medicine Initiative, which aims to develop tailored treatment and prevention strategies based on individual differences in genetics, environment and lifestyle. This national initiative is proof that medicine is moving toward a new paradigm in which patients will receive customized therapy instead of the same treatment as everyone else.

Chih-Ming Ho, IAS Visiting Professor and the Ben Rich-Lockheed Martin Chair Professor at the University of California at Los Angeles, has long been pursuing the systematic optimization of personalized treatment. With the public’s attention on precision medicine, he foresees accelerated progress in developing personalized treatments for patients, and some of those not involving new drugs may even be available in a year’s time.

The current landscape

Existing cancer and infectious disease therapies often use a combination of multiple compounds to improve treatment outcomes. A typical multi-drug design is usually achieved through additive dosing, where the maximum doses tolerated by the human body are combined based on past patients’ average response rates.

“The patient response rates to chemotherapy can be as low as 25% and 10% for lung cancer and liver cancer, respectively, due to human diversity and cancer heterogeneity. Rational combinatorial treatment design must move beyond maximum tolerated dosing,” said Prof Ho.

Recent technological advancements have made it possible to divide patients into groups by measuring their genetic variants. Guided by the patients’ sequence database, doctors can use genotypic personalized medicine (GPM) to improve response rates. However, GPM is undermined by varying genetic and environmental factors, which disrupt genotype-driven treatment. Drug resistance can also increase the difficulty of designing better or alternative GPM courses.

All of these challenges piqued Prof Ho’s curiosity. He began to question whether a simple solution might exist amid the complexity of biological systems. He applied engineering concepts to develop the Feedback System Control (FSC) technology, which later evolved into a different concept that made phenotypic personalized medicine (PPM) possible. Unlike GPM, the revolutionary approach of PPM does not require complex and time-consuming analysis of a patient’s genetic information. Instead, it produces a personalized drug therapy based on a person’s phenotype—biological traits that produce a measurable physiological response to treatments. Another benefit of PPM is that the drug dosages can be recalibrated in real time to adapt to changes during treatment, such as when a person undergoes surgery or develops an infection.

Trial run in post-transplant care

Post-transplant immunosuppressive drugs such as tacrolimus are often prescribed to patients to prevent their bodies from rejecting the organ. As doctors need to find the right balance between effective dosage and minimal toxicity for these drugs, there is a clear need for personalized post-transplant treatments to prevent adverse events and ensure the long-term survival of the organ and the patient.

Building on the PPM approach, Prof Ho and his team developed the parabolic personalized dosing (PPD) platform, which takes into account clinical data such as the blood concentrations of tacrolimus—the primary phenotypic information for immunosuppression efficacy.

\\  Rational combinatorial treatment design must move beyond maximum tolerated dosing.  \\

PPD is so named because it can produce a personalized graph in the shape of a parabolic surface for individual patients, which represents precisely how each person responds to treatment. Doctors are then guided by the person’s unique curve to determine the optimal doses of medicine.

In a pilot trial, the team compared four patients who were treated with tacrolimus using PPD after liver transplants with another four control patients treated with the traditional therapy. Treatment success was evaluated based on how often the amount of tacrolimus in each patient’s body remained in the ideal range. The results showed that those who were treated following PPD spent as much as 50 percent less time outside the ideal range than those who were treated using the standard approach.

“Our ability to calibrate how individual patients respond to treatment and to use that information to robustly guide their regimen based on the parabola-based approach has made personalized medicine a reality,” said Prof Ho.

What makes PPD even more groundbreaking is that it is independent of any disease mechanism and can be applied to cancer and other infectious and physiological diseases. In addition, a pool of 14 drugs was used to search for the optimal drug combination to treat tuberculosis. Less than 1,000 tests were performed and the best four-drug combinations could be identified from out of 6 billion possible drug-dose combinations, which is well beyond what any lab can currently achieve in a reasonable period of time.

An engineer in medicine

Originally trained as an aerospace engineer, Prof Ho moved his research focus to customized therapy for specific patients through a pure coincidence. Since then, he has devoted himself to applying engineering principles to optimize treatment results in biological systems.

“Nowadays, major research breakthroughs almost always happen in the interdisciplinary areas. Collaboration with experts in other fields is a must for scientific progress, and all of my projects in the past were accomplished by working with others,” he said.

Prof Ho is no stranger to HKUST. As an IAS Visiting Professor since 2011, he was awarded an HKUST honorary degree in 2014. He has been working for the past few years with Prof Karl Tsim of Life Science and Prof Yi-Kuen Lee of Mechanical and Aerospace Engineering at HKUST on the optimization of an ancient traditional Chinese medicine, Danggui Buxue Tang (當歸補血湯). Using feedback system control, they have so far reduced the required doses by one tenth and increased the efficacy by three times.

Prof Ho is also collaborating with Prof Nancy Ip of Life Science to optimize the combination of active components in traditional Chinese medicine for neural protection and stroke treatment. Along another line of study, he is working with Prof Yang Wang of Mathematics on a novel method that can substantially reduce the required time and costs of testing the toxicity and effectiveness of drug combinations, demonstrating how “a small step in mathematics can lead to a giant leap in medicine.” This exciting project has already attracted the participation of research teams from UCLA, HKUST, National University of Singapore and Shanghai Jiaotong University. This summer, Prof Ho will return to HKUST as one of the chairpersons for the prestigious Gordon Research Conference on personalized medicine. For more info:

PPD Patient
Control Patient
The patient treated following PPD (top) had the tacrolimus blood level inside the ideal range (shaded area) much more often than the control patient (bottom)
From “Individualizing Liver Transplant Immunosuppression Using a Phenotypic Personalized Medicine Platform” by Ho et al. Science Translational Medicine. Vol.8, issue 333, Apr 6, 2016. Reprinted with permission from AAAS.
\\  ...a small step in mathematics can lead to a giant leap in medicine.  \\