Twin peeks: Stanford inherits twin registry, expanding research options

Studies of identical versus fraternal twins reveal the relative contributions of heredity and the environment to numerous human traits. Now, Stanford has its own twin registry.

Larry and Lloyd Smith in 2010. Larry is on the left. The twins are members of the Stanford Twin Registry.
Courtesy of the Stanford Twin Registry

The Institute for Immunity, Transplantation and Infection at Stanford has adopted twins — well over 1,000 of them — in the form of a registry.

The Stanford Twin Registry is essentially a glorified Rolodex that contains contact information for thousands of twins who have signed up to join it. Registries such as this make it easier to find people with certain characteristics or diseases and contact them about whether they’re interested in participating in a study.

The institute wants to alert Stanford’s scientific community to this windfall. It is also scouting for more twins to join the registry, and making enrolling easy. It has a website and a catchy sales pitch — “Sign up and win a cup” (a free mug) — to welcome participants, old and new, into the family. 

Until recently, the registry was housed at SRI International, in Menlo Park, California. The nonprofit research center began life in 1946 as the Stanford Research Institute, affiliated with the eponymous university. 

Studying twins helps scientists learn more about the contributions of genetics and the environment to a variety of conditions, including autism, addiction, autoimmune disease, cardiovascular disease and cancer.

But twins are hard to find. About 3% of all new babies are fraternal twins; just 0.3% are identical twins. Once you’ve got a list of thousands of them, you don’t want it to fall by the wayside. Which might have happened, had the registry not changed hands.

Rebuilding the registry

SRI’s registry listed more than 6,000 twins as of early January 2019, when negotiations concerning its transfer to the ITI institute began. That handoff took place in November 2019, requiring all registrants to sign new consent forms and update their contact info. 

“The registry is now all ready to be of use to Stanford investigators,” said institute director Mark Davis, PhD, who led Stanford’s takeover of the registry. But there’s been attrition because of deaths and participants losing touch with the registry’s overseers. So, the Stanford team must now rebuild the registry’s numbers.

It’s well worth the effort, said Davis, professor of microbiology and immunology and the Burt and Marion Avery Family Professor.

Twins are a natural experiment. All twins occupy the same womb at the same stage of their mother’s life. If they were raised in the same home, it’s a good bet their environments while growing up were pretty similar, too. Identical twins have virtually identical genes, although differences can arise through mutations originating in one or another bodily cell during their lifetimes. On average, about half the genes in fraternal twins are the same.

Larry and Lloyd Smith with their mother, Ruby Smith, in 1947. Lloyd is the one with an arm in a sling.
Courtesy of the Stanford Twin Registry

Twin studies compare similarities and differences between identical twins with those between fraternal twins. Stronger similarities between identical twins than between fraternal twins are assumed to be rooted in their genes. Significant differences between twin siblings, whether identical or fraternal, point to environmental influences.

Understanding the environmental versus the genetic contribution is a leg up in a long climb. If you find genetic influences dominate, you can drop your search for environmental causes and go after the genes responsible. If there’s only a weak genetic basis, you can skip the gene hunt and start tracking down suspected environmental causes. Either way, you save time and money.

Born 25 years ago

It was that economy that spurred the creation of the SRI Twin Registry 25 years ago. 

In 1995, SRI researcher Gary Swan, PhD, initiated the registry to further his nicotine metabolism, addiction and cessation research.

“Finding more effective ways to help smokers quit has been a major theme of my career,” said Swan, who for many years directed SRI’s Center for Health Science. “Relapse rates following smoking cessation can be as high as 70% among smokers who want to quit.” 

Now an adjunct lecturer affiliated with the Stanford Prevention Research Center, Swan has authored or co-authored hundreds of papers tied at least in part to the study of twins. These studies allowed him to show, among other things, that about 50% of addiction is genetic, suggesting that treatments to aid smoking cessation can be tailored to individuals’ rates of nicotine metabolism. 

Several Stanford scientists have used the SRI Twin Registry. About a decade ago, Martin Angst, MD, professor of anesthesiology, perioperative and pain medicine, wanted to know whether patients’ responsiveness to the analgesic effects of opioids varied because of genetic influences. Angst recruited participants from the registry to find out. In a couple of papers published in 2012, he concluded that of five distinct dimensions of opioids’ action — analgesia, euphoria, nausea, respiratory depression and addiction — only one of them, nausea, varied in degree largely due to genetic influences. 

Meanwhile, Angst told Davis about the SRI Twin Registry. Davis was contemplating a study on the relative contributions of the environment and genes to immune responsiveness.

The twins in the registry ranged from infancy to 90 years old. This allowed Davis to see whether similarities the researchers observed in the immune responses of young twins were stronger than those found in older twins, which would indicate that twins’ diverging environments, as they moved away from home and from each other, affected their immune response to influenza vaccination.

In 2015, Davis reported in Cell that the environmental contribution in many ways dwarfed genetic factors. 

While there are larger twin registries in the United States — and one in China with half a million registrants — it’s the only twin registry in Northern California. 

Registry moves to Stanford

But with Swan’s retirement in 2014, SRI gradually deprioritized the twin registry. In January 2019, with Swan’s blessing, Lisa Jack, a senior project manager at SRI, asked Davis if he could take over the registry. He responded enthusiastically. 

By November, the transfer was a done deal, and the ITI Institute was actively recruiting twin pairs. In late October, the institute sent emails to most of the intact twin pairs from the SRI registry, offering them a mug emblazoned with a colorful logo: “Stanford TwinRegistry.” 

“But only if they sign up,” Davis said. 

So far,  600 individuals from the SRI registry and about 500 brand-new recruits have climbed aboard. 

Davis wants to get the word out to other Stanford researchers, too. In mid-2019, Philip Grant, MD, assistant professor of infectious diseases and the Stanford Twin Registry’s newly appointed director, sent out an anticipatory notice alerting the institute’s faculty of the registry’s impending transfer. 

 “That was a trial run,” Davis said. “We want to reach the whole community.” 

Having the registry reside on campus should mean reduced overhead and less paperwork, making it easier for Stanford scientists of all stripes to explore genetic versus environmental influences on all sorts of human traits and outcomes.

“There’s a lot of value in having it here,” said Michael Snyder, PhD, professor and chair of genetics and the Stanford W. Ascherman, MD, FACS, Professor in Genetics. “Having the registry at Stanford will put it right in front of our researchers’ faces.” 

 “You never know all the possibilities until people show up and start doing things,” Davis said. “People will find all kinds of ways to study twins that they haven’t thought of yet.”



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