NIDDK 

Recent Advances & Emerging Opportunities 

January 2024 

Cross-Cutting Science 

U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute of Diabetes & Digestive & Kidney Diseases 

This is a chapter from the NIDDK’s Annual Report. The full Report includes highlights of research on 

these and many other areas across the NIDDK’s mission and is available at: 

www.niddk.nih.gov/about-niddk/strategic-plans-reports/niddk-recent-advances-emerging-opportunities
NIDDK Recent Advances & Emerging Opportunities 2024

CROSS-CUTTING SCIENCE..................................... 8

Delving Into DNA Structure and Repair .................. 9 

Insights Into Cellular Regulation 

of Chromosome “Caps” ....................................... 9 

Molecular Structures Provide Insight 

Into Key Players in DNA Damage Repair .......10

Building Better Research Tools................................10

Improved RNA Detection Technique 

Enhances Ability to Monitor 

Cellular Messages...............................................10

Feature: Pathways to Health for All: 

A New Report From NIDDK’s 

Health Disparities and Health Equity

Research Working Group of Council......................12

Feature: Mentorship and the NIDDK 

Commitment to Increasing 

Scientific Workforce Diversity.................................14

Cross Cutting Sicience TOC 2024
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 8

Health equity means that everyone has opportunities to live long, healthy, productive lives—no matter who they 

are, how they identify, or where they live. NIDDK is committed to advancing health equity by supporting research 

to enable all communities affected by NIDDK diseases and conditions to thrive. To that end, as highlighted in this 

chapter, a new report outlines research recommendations from the NIDDK Working Group of Council on Health 

Disparities and Health Equity Research. These recommendations complement other NIDDK strategic planning 

efforts with high-impact opportunities and equity-focused principles to advance the Institute’s mission and to pursue 

pathways to health for all. 

 
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 9

NIDDK’s research mission is broad and includes some 

of the most chronic, common, consequential, and costly 

diseases and conditions affecting people in the United 

States. Many of these diseases and conditions are 

associated with health disparities, and innovative new 

ways to combat these disparities are needed to promote 

health equity. Additionally, while scientific talent is well 

represented in people of all backgrounds, opportunity 

is not. Thus, NIDDK strives today to promote a steady 

and diverse pool of talented investigators who can make 

tomorrow’s innovative breakthroughs. 

Described in this chapter are examples of NIDDK efforts 

to overcome these critical challenges through research 

and scientific workforce development. In these ways 

and others, NIDDK works toward its goal of building a 

pathway to health for all.

DELVING INTO DNA STRUCTURE AND REPAIR

Insights Into Cellular Regulation of Chromosome “Caps”:

Researchers identified a key regulator of human telomere 

length with potential implications for diseases and 

disorders of telomere biology as well as broadly for human 

health. Telomeres are sequences of DNA found on the 

ends of chromosomes—the structures in which DNA is 

organized within a cell. When a cell divides, a bit of DNA 

sequence from the chromosome end is lost naturally. This 

shortening is counteracted by a protein that synthesizes 

new telomeric DNA, so telomeres act as a “cap” to 

protect the critical genetic information from degradation 

and keep chromosomes stable. Natural telomere 

shortening is a hallmark of aging and is associated with 

increased incidence of disease, including age-related 

diseases, and poorer outcomes. In addition, disruption 

of telomere maintenance (such as through inherited 

genetic alterations) can cause a number of conditions 

including bone marrow failure, cardiovascular disease, 

lung disease, liver cirrhosis, and cancer. Bone marrow 

failure syndromes, also known as telomere biology 

disorders, lead to impaired blood production. Therefore, 

understanding the regulation of human telomere length is 

vital to developing treatments for a variety of diseases and 

disorders and promoting human health.

Using an approach that allowed them to screen a large 

number of genes for effects on telomere length in human 

cells in the laboratory, scientists identified the molecule 

thymidine (one of the building blocks [bases] of DNA), 

and genes that affect levels of thymidine, as important 

regulators. When genes predicted to promote production 

of thymidine were turned off, the scientists observed 

short telomeres in the cells. Conversely, when genes 

predicted to decrease levels of thymidine, such as the 

thymidine-degrading gene SAMHD1, were turned off, 

they found longer telomeres. Interestingly, this regulation 

appeared to be specific and unique to thymidine; altering 

the levels of the other three DNA bases did not have the 

same effect. The researchers also demonstrated similar 

effects when supplementing the cells with thymidine or 

treating the cells with small molecules that decreased 

thymidine production. These results suggest a novel and 

key role for thymidine in regulating telomere length. 

Medical advances are not usually achieved in great, intuitive leaps. More often, new 

prevention strategies, treatments, and cures result from a long, gradual accumulation of 

knowledge from years of scientific research. Insights into fundamental biological building 

blocks and processes—genes, the proteins they encode, the inner workings of cells, and the 

ways cells communicate with each other—can have broad and far-reaching implications. 

Indeed, many significant advances in our understanding and treatment of disease can be 

traced to laboratory studies whose relevance to health could not have been fully known or 

appreciated at the time they were conducted.

Cross-Cutting Science 

Identification of a key regulator of telomere 

length reveals a new potential strategy to 

treat a variety of diseases and disorders.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 10

Given that some current therapies for cancer and other 

diseases alter production of molecules like thymidine, the 

scientists tested whether a similar approach might have 

potential to treat telomere biology disorders. They found 

that supplementation of thymidine in cells from people 

with different telomere biology disorders promoted 

telomere lengthening, suggesting the possibility of a new 

therapeutic strategy. This promising approach will need 

to be studied in animals, including humans, to determine 

whether the effects are similar to those observed in the 

laboratory and to develop further this exciting advance.

Mannherz W and Agarwal S. Thymidine nucleotide metabolism controls 

human telomere length. Nat Genet 55: 568-580, 2023. 

Molecular Structures Provide Insight Into Key 

Players in DNA Damage Repair: New research from 

scientists in NIDDK's Intramural Research Program has 

provided useful insight into the function of proteins 

involved in repair of damaged DNA. DNA is one of 

the basic building blocks of life, providing the genetic 

code to make every cell in our bodies. We encounter 

environments and situations daily that can damage 

our DNA, such as exposure to certain chemicals, UV 

radiation, and errors cells make in replicating their 

DNA. Additionally, some chemotherapeutic drugs 

intentionally damage DNA to effectively kill cancer 

cells. If left unchecked, DNA damage itself can lead 

to genetic alterations that can contribute to the 

development of several inheritable disorders and even 

some cancers. Therefore, the body uses different 

strategies to repair the various types of DNA damage, 

including one strategy called nucleotide excision repair 

(NER). NER involves several different proteins within 

the cell working together to recognize and cut out the 

damaged area of DNA. Understanding the details of 

this process could unlock new ways to treat or prevent 

some disorders and cancers. 

Using synthetic mimics of different types of DNA damage, 

together with proteins known to be involved in NER 

in humans, the researchers created detailed molecular 

images of the protein interactions with the damaged DNA 

site. Detection of damaged DNA in the cell can occur 

through two different pathways: through stalling of the 

process by which cells create RNA copies of DNA, or 

through recognition by a group of proteins that scan the 

genome for potential damage. These proteins are called 

xeroderma pigmentosum complementation group C, or 

XPC, named after one type of condition in which NER 

is compromised, resulting in extreme sensitivity to UV 

light. After recognition via either pathway, a new group of 

NER-related proteins is recruited to the site to take over 

the process of removing the damage. The researchers 

discovered that these proteins work together to separate 

the two strands of DNA, much like unzipping a zipper 

from the center, to create a space—or “bubble”—where 

proteins can confirm the damaged strand of DNA and cut 

it out. 

The findings from this study have revealed key roles 

for several proteins involved in the NER process for 

repairing DNA damage. The importance of these 

proteins in maintaining health is highlighted by cases 

where compromised protein function is associated with 

certain cancers and disorders. NER is also thought to 

contribute to resistance to some chemotherapy drugs. 

This study’s findings could enable the development of 

more effective cancer treatments and potential genetic 

therapies targeting the NER process.

Kim J, Li CL, Chen X,...Yang W. Lesion recognition by XPC, TFIIH and XPA in 

DNA excision repair. Nature 617: 170-175, 2023.

BUILDING BETTER RESEARCH TOOLS

Improved RNA Detection Technique Enhances Ability 

to Monitor Cellular Messages: Scientists have improved 

an existing technique to detect RNA messages inside 

cells, making it faster and cheaper to simultaneously 

track the activity of multiple genes. Messenger RNAs 

(mRNAs) carry protein assembly instructions from genes 

to the cellular machinery where proteins are made. 

Technologies that track which mRNAs are in what cells 

at what time can be powerful, versatile tools. These 

tools can help researchers better understand the roles of 

the proteins the mRNAs encode, especially in processes 

where the activity of many genes changes at once, such 

as when healthy cells are disrupted by disease.

Researchers have now reported on improvements to 

one RNA detection method, called clampFISH. This 

technique uses a series of probes customized to stick 

to mRNAs encoding instructions for a specific protein 

of interest. A large molecular scaffold is then built over 

the mRNA, binding fluorescent dyes that amplify the 

Researchers streamlined a cutting-edge RNA 

detection method to make it cheaper, faster, 

and more flexible.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 11

relatively weak “signal” from a single mRNA so it can 

be detected by microscopy. A weakness of the original 

“clampFISH 1.0” procedure, however, was that it was 

relatively expensive and time-consuming, especially 

when detecting multiple different mRNAs at once. 

To create clampFISH 2.0, the scientists modified the 

structure of the scaffold and streamlined the protocol to 

make it faster and cheaper. They verified that clampFISH 

2.0 still accurately and precisely detected targeted mRNAs 

and that it could pinpoint an mRNA’s location within a cell. 

clampFISH 2.0 also generated a strong enough signal to 

allow imaging by lower-powered microscopes with wider 

fields of view, which allowed researchers to analyze cells 

faster. This feature was particularly useful in studying rare 

events. For example, scientists used clampFISH 2.0 in a 

very large tumor cell sample to measure the simultaneous 

activity of 10 genes, observing for the first time how 

those genes activate together in rare instances that can 

lead to drug resistance. Researchers also performed a 

similar analysis on preserved tumor tissue, such as would 

be generated by a cancer biopsy.

Overall, the streamlined clampFISH 2.0 procedure was 

shown to be a rapid and flexible tool to efficiently detect 

multiple mRNAs at once, allowing the study of research 

questions previously hindered by technical limitations.

Dardani I, Emert BL, Goyal Y,...Raj A. ClampFISH 2.0 enables rapid, scalable 

amplified RNA detection in situ. Nat Methods 19: 1403-1410, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 12

FEATURE

Pathways to Health for All: A New 

Report From NIDDK’s Health 

Disparities and Health Equity 

Research Working Group of Council

In Spring 2023, NIDDK announced the release of 

Pathways to Health for All, a new report from the Health 

Disparities and Health Equity Research Working Group 

of the NIDDK Advisory Council. The Report makes 

innovative recommendations to advance research in 

health equity and health disparities. It also includes 

guiding principles for embedding equity into research 

and tips for researchers, both at NIDDK and externally, 

who plan to engage in robust health equity research. 

Many of the diseases and conditions in NIDDK’s 

research mission disproportionately affect racial 

and ethnic minority populations and others who 

are medically underserved or marginalized. Health 

equity means that people of all backgrounds and ages 

have fair and just opportunities to live long, healthy, 

productive lives. The social and structural drivers of 

health disparities operate in multiple sectors and at 

levels beyond NIDDK’s traditional scope, but research 

can make a valuable contribution toward advancing 

health equity. Importantly, social determinants of 

health—the conditions in which people are born, grow, 

work, live, and age—can be primary contributors to 

health inequities among groups that are socially or 

economically marginalized.

The report presents five overarching research 

recommendations, each with corresponding 

opportunities, for high-impact research and actionable 

strategies:

1. Strengthen community engagement through 

partnership, power sharing, and capacity building 

to improve research

2. Advance research on the mechanisms by which 

biological, behavioral, environmental, and 

structural factors interact to affect health, disease, 

and resilience
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 13

FEATURE

3. Advance research on interventions and studies to 

address racism, health-related social needs, and 

social determinants of health

4. Promote new methods, measures, tools, and 

technologies to accelerate achievement of health 

equity research goals

5. Enhance NIDDK collaboration, structures, and 

programs to support robust research in health 

equity

Community members—including patients, caregivers, 

and others living with or at risk for diseases within 

NIDDK’s mission—were involved throughout the report 

development process as Working Group members who 

shared their lived experiences, perspectives, values, and 

priorities. These insights are featured in call-out boxes 

throughout the report. One member commented, 

“It made me proud and honored that my opinion was 

valued, and it made me want to go out and do research 

in the community to see what is missing or where we 

can help or fill the void to respond to the community’s 

voice or the community’s calling.” Another remarked, “I 

believe participating in this group will facilitate change 

for us that feel we have been left behind.”

NIDDK thanks the Working Group participants, 

including Council members, community members, 

patients, caregivers, NIDDK staff, and external 

researchers across the country, who contributed 

their time, expertise, and perspectives to this project. 

NIDDK research can foster scientific breakthroughs, 

provide the evidence base needed for equitable and 

effective clinical practice, and inform public health 

programs and policies. NIDDK is poised to act—

both within its traditional scope and with innovative 

strategies and collaborations—to implement the 

recommendations in the report to effect meaningful 

change within its research mission.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 14

FEATURE

Mentorship and the NIDDK 

Commitment to Increasing Scientific 

Workforce Diversity

Strengthening biomedical research workforce diversity 

and training is a cross-cutting theme in the NIDDK 

Strategic Plan for Research, and the importance of 

nurturing a diverse, world-class workforce is one of 

the core values described in NIDDK’s report Pathways

to Health for All. This is because research shows that 

diverse teams working together and capitalizing on 

innovative ideas and distinct perspectives outperform 

homogenous teams. Scientists and trainees from 

diverse backgrounds and life experiences bring 

different perspectives, creativity, and individual 

interests to address complex problems. In this way, 

they foster scientific innovation, enhance global 

competitiveness, contribute to robust learning 

environments, improve the quality of research, 

enhance public trust, and increase the likelihood 

that health disparities and the needs of underserved 

populations are addressed in biomedical research. 

Studies also show that robust mentorship is an 

important predictor of success for researchers, 

including the ability to obtain research funding. 

Indeed, effective mentoring is critical for career 

advancement in biomedical research, particularly 

at early career stages and for individuals from 

underrepresented backgrounds. A National Academy 

of Sciences, Engineering, and Medicine report on the 

science of effective mentorship in science, technology, 

engineering, mathematics, and medicine highlights 

mentorship as a catalytic factor in an individual’s 

participation, persistence, and success in these 

fields. They also found that although mentorship 

has a particularly positive effect on individuals from 

underrepresented backgrounds, these individuals were 

also less likely to receive mentoring than were trainees 

from well-represented groups.

For these reasons, NIDDK has a long-standing 

commitment to fostering training and mentorship for 

diverse students interested in research careers and is 

continuously testing new approaches and maintaining 

existing programs, such as the Institute’s flagship 

partnership with the Network of Minority Health 

Research Investigators (NMRI). NMRI has had support 

from NIDDK through its Office of Minority Health 

Research Coordination for more than 20 years, but 

is “owned” by its members. NMRI’s success begins 

with the dedication of senior investigators to mentor 

and serve as role models for junior investigators and 

continues with their ongoing participation and with 

recruitment of new members. 

Testimonials of those members are evidence 

for the power of this approach. For example, 

Deidra Crews, M.D., a professor in the Division of 

Nephrology at the Johns Hopkins University School 

of Medicine said, “NMRI has provided me with 

a network of colleagues across the country who 

are dedicated to improving the health of socially 

marginalized communities and has served as a 

collective source of mentorship and sponsorship 

throughout my career.” Likewise, Susan Brown, 

Ph.D., an associate professor in the University of 

California Davis Department of Internal Medicine 

calls NMRI “a gem. This community of generous and 

accomplished scholars offers a new entry intellectual 

home, where you can bring your whole self. NMRI 

offers a sense of connection and purpose that 

helped sustain me through the critical early years 

of my research career. This has been equally true 

during challenging times of professional transition, 

pandemic, and national social upheaval. It’s an 

honor and a privilege to continue as a member.”
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 15

FEATURE

Lina Huerta-Saenz, M.D., an assistant professor in the 

Department of Pediatrics, Division of Endocrinology 

at the Pennsylvania State University, recalls “a time 

during my career training in the United States when 

nobody looked like me in a room, and it was very hard 

to visualize myself in a future leadership position.... 

Now, I can see myself as a future leader because I 

know it is possible.” This transformation of outlook 

demonstrates why NMRI and other NIDDK scientific 

workforce diversity programs remain so important: 

as NIDDK Director Dr. Griffin Rodgers has noted, 

scientific ability is broadly distributed around the 

country and the world, but opportunity to build a 

successful scientific career is not.

Accordingly, NMRI is just one of the many approaches 

that NIDDK takes to advance scientific workforce 

diversity and mentorship. Others include the Diversity 

Supplement Program, which covers 2 years of costs, 

materials, and salaries for young researchers from 

backgrounds underrepresented in the biomedical 

workforce, and providing travel awards to attend the 

annual conferences of the National Medical Association 

and the National Hispanic Medical Association. 

These efforts are complemented by diversity 

efforts supported by the extramural and intramural 

NIDDK Divisions. Recently, the Institute 

expanded such efforts with Helping to Accelerate 

Research Potential, a program designed to provide 

opportunities and mentorship for current NIDDK 

grantees, especially postdoctoral scholars and 

junior faculty from diverse backgrounds, to enhance 

their skills in areas that are critical for establishing 

and maintaining successful independent academic 

research careers. In addition, NIDDK Investigator 

Awards to Support Mentoring of Early Career 

Researchers from Diverse Backgrounds is an 

initiative designed to provide high-quality mentoring 

to graduate students and postdoctoral fellows 

from diverse backgrounds, including those from 

underrepresented groups, by established, NIDDKfunded scientists. 

Together, each of these programs is helping to advance 

NIDDK’s research mission by developing a scientific 

workforce that realizes the tremendous, untapped 

potential of future scholars from every background 

and region of the Nation.