Why Research Matters...

New Tools: Stanford Researcher Unlocking the Language of the Immune System

Howard Chang, MD
Stanford University
School of Medicine;

Professor of Dermatology at Stanford;

Director of the NIH Center of Excellence in Genomic Science: Center for Personal Dynamic Regulome

 

Video Clip:

In this two-minute video Dr. Chang shares is optimisim on the future of scleroderma research and the value of the SRF research program. Click to watch video.

 


"I'm really optimistic about the prospects for scleroderma, because in the last five to 10 years there's really been an increasing pace of understanding about the disease, its subtypes, and also some potential causes. I'm hopeful that maybe in a five-year time frame, many of these ideas will start moving into actual therapies."
- Dr. Howard Chang

An accomplished dermatologist and Director of the Stanford Center for Personal Dynamic Regulomes, Dr. Chang immigrated to the United States with his family when he was 12 years old. From a young age, he was encouraged by his parents to improve his language skills by pursuing debate, and the methodical, thoughtful and analytical process underpinning debate held fast in his mind. “For every topic, you would explore both sides of the facts, it was quite different from other forms of study, and a very different process from other types of learning,” recalls Dr. Chang. “Later I realized that this is what science felt like as well—going back and forth to see which set of facts and data have merit—getting evidence and weighing that versus what is known.”

Dr. Chang was supported by many gifted mentors throughout his years at Harvard, MIT and Stanford. However, it was the bold work of his mentors at Stanford, Drs. Pat Brown and David Botstein (now Chief Scientific Officer of Calico and a SRF Scientific Advisor), that really motivated and challenged Dr. Chang to “think big” in his approach toward seemingly impossible disease-relevant problems, as they had when they sought to map the human genome. It was this kind of foundation that taught Dr. Chang to question how well our current knowledge allows us to understand complex biological problems and what information and new technology might be needed to make n a five-year time frame, .

 

Dr. Chang and his team have pursued a “think big” approach to defining the complexities of how genes are regulated—a fundamental biological question and one that is essential to understanding human health. In this effort, they are developing new tools and techniques to study the regulome, the intricate set of DNA elements, RNA, transcription factors, and larger proteins that dictate the expression of genes.


“If DNA is the hardware for our cells that we inherit from our parents,” explains Dr. Chang, “the regulome is the software programming governing and reflecting the cells' activity, essentially telling our cells—be it muscle, liver or skin—how to react and which program to run. As with a computer, it is easy to see and examine the hardware, but not always simple to understand which bits of code are responsible for what function; what the software is doing that leads cells to a disease process. Cells have a series of genes that switch on or off, regulating activity: some of the switches are always on, some always off and sitting unused for years at a time, while others are turned on and off with high frequency. Deciphering the state of switches doesn’t lead to a perfect understanding of all the cell functions, but it is significant progress in that direction.”

 

This quest to better understand the regulome led Dr. Chang, Dr. William Greenleaf and their teams at Stanford to develop a new technique called ATAC-seq, for studying the complex system of gene regulation. Different cells use different genes and therefore different parts of DNA; similarly, environmental stimuli cause different genes to be activated or turned off within a cell. Because the DNA in one cell would be two meters long if fully stretched out, inside a cell it exists in a compacted form and only those genes that are in a non-compacted or “open” conformation are accessible to be activated by other components of the regulome. ATAC-seq gives researchers information about which genes are in an “open” conformation, and it reveals other information about what other regulome components are involved in the genes’ regulation. Dr. Chang and his team are using the technique to better understand the immune system and scleroderma.

 

The research and the technique are quite promising, and with ATAC-seq, Dr. Chang already has some interesting findings. Among them were distinct differences in gene expression in the immune system of men and women. In a study evaluating healthy subjects, Dr. Chang and his team took blood samples from 12 volunteers to measure how genes switched off and on, and how the activity varied from individual to individual. Dr. Chang’s team also looked at how much change occurred at different times in the same volunteers, looking exclusively at T cells, a critical cell of the immune system.


The study found that a small number, 7% of the genes, were switched on in different patterns from person to person. When the team measured gene activity levels from 30 of the top 500 gender-influenced genes, researchers found that women and men use different switches to activate and deactivate many immune system genes. These genes may have particular value in understanding scleroderma, where four out of five patients are women.

“Since autoimmune diseases have a female-male bias, we’ve long believed that there was something going on in the immune system, and we now have a clue that there are differences in the immune system, and that gives us an entrée into the problem,” says Dr. Chang.

 

With a better understanding of scleroderma, Dr. Chang and others may identify a therapeutic vulnerability, providing opportunity for a tailor-made approach aimed at the one or two types of "bad-acting" cells.  

As a heterogeneous disease involving multiple types of cells, understanding the normal state for cells is important, and observing changes over time with a disease like scleroderma would provide clinicians with tremendous insight into how and why changes occurred. To accelerate the analysis of scleroderma genes, Dr. Chang’s team is searching for sets of monozygotic twins— one with and one without scleroderma. The twin analysis would make it possible for Dr. Chang and his team to compare people with identical DNA whose cells have different switches turned on and off or, to use Dr. Chang’s analogy, the twin analysis allows researchers to compare people who have identical hardware, but whose cells may be running different software, leading to disease in one twin while the other remains healthy. This type of analysis vastly simplifies their search, and the hope is that it will quickly identify the disease-specific differences.

One of the benefits of the ATAC-seq technique is that it lets researchers sample living cells in real time, using extremely small samples of blood or tissue. Prior to ATAC-seq, researchers had to take large samples from patients, or use cell culture to grow enough material to analyze, vastly increasing the potential for error. The ATAC-seq process is a million-fold more sensitive and a hundred times faster than previous methods. This improved sensitivity and efficiency means that the technique can be used to study rare cell types and that it someday may be amenable to clinical use.

Optimism surrounding ATAC-seq and Dr. Chang’s SRF-funded research projects stems from some tantalizing potential outcomes: understanding and effectively predicting the progress and impact of disease, and using the switches and their processes as a potential diagnostic or therapeutic target.

Dr. Chang has made progress in identifying cell switches and “bad-acting” cells in other diseases, including asthma and leukemia. And, in the coming years, we anticipate additional insights from this groundbreaking technique. ATAC-seq is not only a robust research tool, but also has broad clinical and drug development application so Dr. Chang has co-founded Epinomics, a company devoted to making ATAC-seq available to the widest range of researchers and companies to improve clinical development, clinical trials, and to ultimately benefit the greatest number of patients.

Following his mentors, who paved the way for his research, Dr. Chang is tackling perhaps among the most difficult, complex and challenging diseases of all in scleroderma.

“It’s far easier to research a system when we use cells grown in culture or animal models because we can control all the variables and do a very beautiful experiment that way,” says Dr. Chang. “But when you look into a problem in human health, you are forced to confront disease process and many elements you can’t control in human studies. That aspiration, that goal, solving disease-relevant problems—that is inspiring to me.”

And like his early mentors, “the SRF acts boldly,” says Dr. Chang. “They find the best scientists with fresh perspectives and provide an environment where interesting ideas can get off the ground… The SRF has the flexibility to immediately pursue the ideas that are at the forefront of science. As a result, the community is in a much stronger place and progress is happening in an accelerated fashion.”