Decoding the Immune System

By deciphering the DNA of core immune structures, the Human Immunome Program is set to transform disease diagnosis, prevention, and treatment.

By Maureen Salamon featured image Illustration by Mario Wagner

If there were a clock heralding Helen Naylor’s blood donations, it would ring precisely every eight weeks. For the last decade, the 47-year-old genetics researcher has rolled up her sleeves so many times and at such regular intervals that she estimates nine gallons of her O-positive blood have now flowed through other people’s veins. Naylor never knows who receives it, of course — just that it may save or improve someone else’s life.

So it wasn’t a stretch for the Nashville resident to sign up last year for a really lengthy bloodletting — known as leukapheresis — in which scientists extracted all 40 billion disease-fighting white blood cells circulating through her body, funneling the remaining blood components back into her in a four-hour process. With her donation, Naylor became one of the first participants in early international research that aims to decode the human immunome, the so-called parts list of genetic and molecular structures underlying the immune system.

The vast and comprehensive effort is only recently possible because of a potent combination of biomedical and technological advances, including fast and accurate next-generation gene sequencing and massive-scale computer data crunching. If its promise is realized, proponents of this work believe the coming revelations could transform how we diagnose, prevent, and treat diseases.

“As a scientist, I’m in the business of trying to help,” Naylor says. “I’ve been fortunate to be fairly healthy, so I don’t know whether at some point this research will benefit me. [But] we all get sick. It’s probably more likely to help someone else in the short run, which is perfectly fine. That could mean the world to that one person. It’s like giving blood — I don’t know where it goes, but hopefully someone gets it who needs it.”

Mystery dance

Our immune system is both essential and enormously intricate. Indispensable to human survival, it works by identifying foreign invaders — bacteria, viruses, parasites, fungi, even cancers — and producing antibodies and T-cell receptors to rid us of these trespassers. The immune system’s ability to “remember” specific pathogens over time can lead to immunity from various conditions, which is how vaccines can protect us from illnesses.

But sometimes this efficient process goes awry, pegging a normal substance or cell as dangerous when it’s not. This can lead to haywire responses in the form of allergies or autoimmune diseases. At the core of all immune responses — beneficial or not — are T cells and B cells, the two main types of white blood cells that collaborate to make disease-fighting T-cell receptors and antibodies. Despite this fundamental knowledge, the immune system continues to evade perfect understanding.

“White blood cells spend entire lifetimes in our bodies patrolling for viral, fungal, and bacterial pathogens … [but] in no way do we have a firm grasp over which [cells] have control [of this process],” explains Adam Buntzman, an assistant professor at the BIO5 Institute at the University of Arizona in Tucson. “It’s the dawn of immune analysis. The more we understand how this system is put together, the better off we are to make those functions better.”

Thinking big

Enter the emerging global efforts to fill this major knowledge gap. Perhaps most notable is the Human Immunome Program, a venture initiated in June 2016 and led by researchers at the Vanderbilt University Medical Center in Nashville. The program aims to tease out and analyze the enormous collection of genes and their combinations in B-cell and T-cell receptors. The 10-year, 1,000-participant endeavor was launched by the Human Vaccines Project, itself a young initiative, which intends to use revelations about the immune system to speed the development of new vaccines and immunotherapies.

It’s no exaggeration to describe the effort as colossal, with the human immunome’s data output projected to be 100 billion times larger than that of the Human Genome Project, which first mapped the human genome in 2003. The number of variations of immune receptors also far exceeds the 20,000 or so genes in our genome, Buntzman notes.

But just how the immune system is able to generate billions of distinct antibodies from only a small subset of our tens of thousands of genes was a puzzle that had long stumped scientists — until a 1987 Nobel Prize-winning discovery. This work, led by Japanese scientist Susumu Tonegawa, revealed DNA enzymes known as RAGs (recombination-activating genes) that shuffle three types of gene segments into a smorgasbord of variations to recognize microbes. “There’s an extraordinarily big difference between this and all the variation you’d expect to have in all the genomes that existed in all the humans that have ever existed,” Buntzman marvels.

This immense scale had previously thwarted scientists hoping to explain in detail how the immune system adapts to and fights disease, but the Human Genome Project paved the way to this new opportunity, says Wayne Koff, president and CEO of the Human Vaccines Project.

“The Hubble Space Telescope has opened up a new layer of understanding of the origin of the universe, and, frankly, the origin of life,” Koff says. “With the Human Immunome Program, we have the potential to gain the foundational knowledge of what the human immune system actually is, which will give the next generation of scientists new tools and ways of thinking about the prevention and treatment of diseases.”

“It’s a big vision with big impact,” he adds. “It really has the potential to transform the whole future of public health.”

Locks and Keys

Deciphering the common rules of the immune system could pay off in several key areas of medicine, since sequencing immune receptors can determine exactly which receptor is responsible for each disease, allergy, or autoimmune response. It should also be possible to identify new biomarkers — measurable substances signaling disease — that would enable the creation of highly targeted vaccines and immunotherapies for conditions as wide-ranging as Alzheimer’s, AIDS, multiple sclerosis, and cancer, according to James Crowe, lead investigator of the Human Immunome Program.

“The immune system is one tissue that’s everywhere in your body,” Crowe explains. “So, no matter what disease or tissue or process we’re studying, the immune system probably regulates that process.”

With cancer — an area in which immunotherapy treatments have become increasingly important — “the immune system is thought to be suppressed in some ways,” Crowe says. “We don’t know if there are particular types of antibodies and T cells missing during cancer states. If we [come to] know that, maybe we can work toward restoring those features.”

Vaccine and immunotherapy development stands to skyrocket if the immune system’s shared elements are revealed, Koff says. “Ideally we want 100 percent of people getting a positive response to a vaccine,” he says. “For example, if we had a million B-cell receptors, and one was common among all people, we would want to design a vaccine in a way to target that one. Think of a lock-and-key analogy. We’ll have a structural catalog of the universe of locks, and then it’s up to vaccine designers to create a universe of keys. We’re looking for keys that everyone will respond to. That’s the ultimate goal in vaccine development.”

World-Changing Project

Crowe is simultaneously pragmatic about the scope of the Human Immune Program and antsy to plow ahead as rapidly as possible. He is not a dilettante: Crowe has led an independent lab at Vanderbilt since 1996 largely devoted to discovering biological mechanisms vital to developing new vaccines. He also completed five years of postdoctoral training in infectious diseases at the National Institutes of Health.

“I’m looking at the second half of my career and want to do something big and world-changing — something fun and impor-tant,” he says. “When I thought about what would affect not just my field of virus immunity, but all types of immunity, I thought of what we could do now that expands our impact.”

The Human Immunome Program is supported by a range of institutions that includes the J. Craig Venter Institute; the University of California, San Diego; the Scripps Research Institute; and the La Jolla Institute for Allergy and Immunology. And it continues to add others with the necessary skill sets. In April 2017, it joined forces with sequencing giant Illumina, which will provide its technologies and expertise to help process the vast datasets involved in decoding the immunome.

“It’s the dawn of immune analysis. The more we understand how this system is put together, the better off we are to make those functions better.”

But initial steps have been tough going, Crowe says. As of August, three participants’ B- and T-cell immunomes had been comprehensively studied, along with smaller blood volumes from the cord blood samples of 10 individuals. In part, the labored pace can be attributed to the leukapheresis process itself, but it’s also slow “because there’s no standard [scientific] method considered to be proper for doing this,” Crowe says.

Project investigators have tried “as many as 10 scientific approaches and [used] sequencing experts at four different sites,” Crowe adds. “This has allowed us to benchmark various laboratory approaches, which is critical to planning the 1,000-person effort, to make sure we are using the best possible and most efficient, cost-effective approach.”

The 10 approaches have generated billions of sequences. Crowe calls the comparison of these sequences a “pre-pilot phase,” since he and his colleagues will end up choosing one approach based on data quality and cost-effectiveness. The plan is to sequence 100 people each year once this happens; tissue-specific analyses — of lymph nodes or bone marrow — may be added along the way.

Going global

Like Naylor, study participants so far have hailed from the U.S. But that will soon change, since recruiting a diverse base is critical to capture the combination of genetic and environmental influences shaping humans’ immune-system repertoire, Crowe says. Such diversity may also spring from geography and exposure to agents such as parasites, pollutants, foods, and animals, among others.

Global participants will be recruited with the help of wide networks established by the Human Vaccines Project partners, as well as via collaborators from networks established by NIH and other international research and development agencies, Koff notes. All data will likely be open-source so that the worldwide scientific community can access it. Meanwhile, the Human Immunome Program is also seeking major donor support from entrepreneurial philanthropists who “share our vision to conduct this major, big-science initiative because of its high potential to impact all biomedical fields,” Crowe says. Current cost projections are $200 million.

“We don’t know how many sequences an individual even has. But we made a best-guess estimate that it will take 1,000 people from all over the world to find out,” Crowe explains. “I hope it’s [fewer], because then we can pivot to some follow-up questions, like what happens in a disease state or what happens when we immunize someone and perturb the immunome.”