The name Emma peaked in popularity in the late 1800s, declined precipitously through the first half of the 1900s, then shot back up to be one of the most popular names of the early 2000s. Linda peaked somewhere in the late 1940s and Daniel in the mid-1980s. But each rise in popularity was followed by an equally steep decline.

So, what’s in a name — or, at least, what’s in a baby name trend? University of Michigan evolutionary biologist Mitchell Newberry has found that the more popular a name becomes, the less likely future parents are to follow suit. Same goes for popular dog breeds: Dalmatians today are a tenth as popular as they were in the 1990s.

Newberry, an assistant professor of complex systems, says examining trends in the popularity of baby names and dog breeds can be a proxy for understanding ecological and evolutionary change. The names and dog breed preferences themselves are like genes or organisms competing for scarce resources. In this case, the scarce resources are the minds of parents and dog owners. His results are published in the journal Nature Human Behavior.

Newberry looks at frequency-dependent selection, a kind of natural selection in which the tendency to copy a certain variant depends on that variant’s current frequency or popularity, regardless of its content. If people tend to copy the most common variant, then everyone ends up doing roughly the same thing. But if people become less willing to copy a variant the more popular it becomes, it leads to a greater diversity of variants.

“Think of how we use millions of different names to refer to people but we almost always use the same word to refer to baseball,” Newberry said. “For words, there’s pressure to conform, but my work shows that the diversity of names results from pressures against conformity.”

These trends are common in biology, but difficult to quantify. What researchers do have is a complete database of the names of babies over the last 87 years.

Newberry used the Social Security Administration baby name database, itself born in 1935, to examine frequency dependence in first names in the United States. He found that when a name is most rare — 1 in 10,000 births — it tends to grow, on average, at a rate of 1.4% a year. But when a name is most common — more than 1 in 100 births — its popularity declines, on average, at 1.6%.

“This is really a case study showing how boom-bust cycles by themselves can disfavor common types and promote diversity,” Newberry said. “If people are always thirsting after the newest thing, then it’s going to create a lot of new things. Every time a new thing is created, it’s promoted, and so more rare things rise to higher frequency and you have more diversity in the population.”

Using the same techniques they applied to baby names, Newberry and colleagues examined dog breed preferences using a database of purebred dog registrations from the American Kennel Club. They found boom-bust cycles in the popularity of dog breeds similar to the boom-bust cycles in baby names.

The researchers found a Greyhound boom in the 1940s and a Rottweiler boom in the 1990s. This shows what researchers call a negative frequency dependent selection, or anti-conformity, meaning that as frequency increases, selection becomes more negative. That means that rare dog breeds at 1 in 10,000 tend to increase in popularity faster than dogs already at 1 in 10.

“Biologists basically think these frequency-dependent pressures are fundamental in determining so many things,” Newberry said. “The long list includes genetic diversity, immune escape, host-pathogen dynamics, the fact that there’s basically a one-to-one ratio of males and females — and even what different populations think is sexy.

“Why do birds like long tails? Why do bamboos take so long to flower? Why do populations split into different species? All of these relate at a fundamental level to either pressures of conformity or anticonformity within populations.”

Conformity is necessary within species, Newberry says. For example, scientists can alter the order of genes on a fly’s chromosomes, and it does not affect the fly at all. But that doesn’t happen in the wild, because when that fly mates, its genes won’t pair with its mate’s, and their offspring will not survive.

However, we also need anticonformity, he says. If we all had the same immune system, we would all be susceptible to exactly the same diseases. Or, Newberry says, if the same species of animal all visited the same patch of land for food, they would quickly eat themselves out of existence.

“Life is this dance of when do we have to cohere, and when do we have to separate?” he said. “Natural selection is incredibly hard to measure. You’re asking, for an entire population, who lived, who died and why. And that’s just a crazy thing to try to ask. By contrast, in names, we literally know every single name for the entire country for a hundred years.”

As the first-of-its-kind platform, the Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) approach employs nanocomplexes combined with microbubbles to effectively deliver cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an immunotransmitter involved in anticancer immunity, into antigen-presenting cells (APCs). Inside the APCs, the microbubbles release cGAMP to activate the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which stimulates type I interferon responses that are essential for priming tumor-specific T cells.

In the preclinical study, the MUSIC strategy demonstrated a complete tumor eradication rate of 60% when administered as monotherapy in breast cancer models. When combined with an anti-PD-1 antibody, MUSIC significantly improved antitumor responses with minimal toxicity effects, including enhanced primary tumor control and decreased systemic disease progression. In addition, the combination therapy demonstrated superior survival benefit, with a 76% increase in median survival compared to either therapy alone.

“By investigating the mechanisms of action in producing a robust STING activation, we identified a new strategy to activate both the innate and adaptive antitumor immune responses,” said Wen Jiang, M.D., Ph.D., assistant professor of Radiation Oncology and the study’s co-senior author. “Our findings show that the MUSIC strategy is capable of paving the way toward novel image-guided strategies for targeted cancer immunotherapy.”

Immunotherapy has transformed cancer treatment, offering clinical benefits for patients with treatment-refractory metastatic cancers such as melanoma, non-small cell lung cancer and renal cell cancer. However, not all patients respond to immune checkpoint blockade. Therefore, developing a more effective immunotherapy strategy to benefit larger numbers of cancer patients with localized and metastatic disease remains an unmet clinical need.

“Although the majority of cancer immunotherapies have focused on boosting the adaptive branch of the body’s immune system, there has been a growing realization that both the innate and adaptive branches of the body’s immune system need to be engaged to generate optimal antitumoral immunity,” Jiang said. “This understanding has led to the development of new immunotherapies that target the regulators of innate immune systems, including the cGAS-STING pathway.”

Natural agonists, such as cyclic dinucleotides, activate the cGAS-STING pathway, but concerns over poor cytosolic entry, serum stability and systemic toxicity have been major limitations for clinical translation. To overcome these challenges, Jiang and his collaborators developed MUSIC as the first-ever image-guided cancer immunotherapy strategy that uses antibody targeting to activate STING in APCs through delivery of molecular drugs.

Because the microbubbles also serve as contrast agents for ultrasound, the researchers use ultrasound scanners to image the tumor and to precisely identify the location where the microbubbles have accumulated. After confirming the microbubbles are bound to the tumors, the researchers activate ultrasonic frequencies, which cause the microbubbles to oscillate and burst, creating transient pores in the cell membrane that allow nucleic acids to be transferred directly into the cell cytosol. This technique, called sonoporation, previously has been used on tumor cells, but the MUSIC platform is the first to bind nanocomplexes to microbubbles to deliver cGAMP immunotransmitters directly into APCs.

“The beauty of our platform is that ultrasound machines are already clinically available in many outpatient settings and microbubbles are FDA-approved contrast agents for ultrasound imaging,” Jiang said. “Therefore, we expect there is a very real opportunity to translate MUSIC into a clinic application to benefit cancer patients.”

The same concept and design principle behind the MUSIC platform’s microbubble technology could be readily translated to nanoscale systems for targeted systemic delivery and activation of innate immune sensors under image guidance for cancer immunotherapy applications, Jiang added.

“Our MUSIC platform is exciting because it provides a new framework for developing image-guided immunotherapy by using acoustically responsive biomaterials to enable efficient, targeted and robust immune activation to produce potent antitumor effects while minimizing systemic toxicity,” Jiang said. “The versatility of the MUSIC platform could potentially be applied to targeted delivery of other immune-stimulating agents, such as nucleotide-based vaccines, mRNAs and other gene therapies for multiple human diseases.”

The study was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT), Department of Defense and the National Cancer Institute. The study’s co-corresponding author is Jacques Lux, Ph.D., assistant professor of Radiology at The University of Texas Southwestern Medical Center.

However, past research has uncovered associations between the two diseases. Women with diabetes, for example, have a 20 to 27 percent increased risk of developing breast cancer. Insulin resistance — a key characteristic of diabetes — has been associated with breast cancer incidence and poor survival. Population studies suggest diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20 percent higher in breast cancer survivors than in age-matched women without breast cancer.

But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In a new paper, publishing May 30, 2022 in Nature Cell Biology, a research team led by scientists at University of California San Diego School of Medicine describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth.

“No disease is an island because no cell lives alone,” said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UC San Diego School of Medicine. “In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.”

Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine. Olefsky is co-senior author of the study with Wang.

The culprit, according to Wang and Olefsky, are extracellular vesicles (EV) — hollow spheres secreted or shed by cells that transport DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system.

In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. Wang said when vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo and damage the islets’ critical function in maintaining a normal blood glucose level.

“Cancer cells have a sweet tooth,” Wang said. “They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.”

The research was conducted using mouse models, which found that slow-releasing insulin pellets or a glucose-lowering drug known as an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumor, which in turn suppressed the tumor’s growth.

“These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,” said Wang, noting that an inhibitor of miR-122, developed by Regulus Therapeutics Inc. in San Diego, is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumor growth in mouse models of breast cancer.

“These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,” Wang said.

Co-authors include: Minghui Cao, Roi Isaac, Wei Yan, Xianhui Ruan, Li Jiang, Yuhao Wan, Jessica Wang, Christine Caron, Donald P. Pizzo, Xuxiang Liu, Andrew R. Chin, Miranda Y. Fong, Oluwole Fadare, Richard B. Schwab, Wei Ying and Jack D. Bui, all at UC San Diego; Dorothy D. Sears, Arizona State University; Steven Neben and Denis Drygin, Regulus Therapeutics, Inc., San Diego; Xiwei Wu, Joanne Mortimer, Yuan Yuan and Susan E. Yost, all at City of Hope, Duarte, CA; Ziting Gao, Kaizhu Guo and Wenwan Zhong, all at UC Riverside.