TS Digest Issue | October 2024, Issue 1 | Why Do People Have Different Blood Types?

Cartoon of a cell with blue chromosomes and gold telomeres. One chromosome is zoomed in in a callout, and gold DNA is extending out of the telomere.

Article

Going to New Lengths to Measure Chromosome Ends

A novel sequencing-based method revealed chromosome-specific telomere lengths, challenging prior models.

Shelby Bradford, PhD

and

Priyom Bose, PhD

Oct 1, 2024 | 2 min read

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Telomeres protect crucial functional regions of DNA, however the regulation of their length remains poorly understood. One model suggests that all telomeres are maintained around an average length but another model points to chromosome-specific lengths. This discrepancy is in part due to the difficulty in accurately measuring telomeres.

To overcome these limitations, one group adapted nanopore sequencing to quantify individual telomere lengths. The new method, Telomere Profiling, and study findings, published in Science, demonstrated that telomere lengths are specific to chromosomes and not globally maintained.¹

“It's very exciting because it gives us an inroad into understanding new mechanisms that might be involved in telomere length regulation,” said Carol Greider, a molecular biologist and geneticist at the University of California, Santa Cruz and study author.

Greider’s team isolated all telomeres from peripheral blood mononuclear cells (PBMCs) from volunteers spanning a range of ages using biotin-labeled tags, sequenced them, and quantified the distance from the chromosome end to the subtelomere region. They observed that telomere lengths varied in an age-dependent manner. When they compared Telomere Profiling to two other telomere measuring techniques, Southern blot and flow cytometry fluorescent in situ hybridization, and observed similar measurements.

The researchers then measured individual chromosome telomeres in a cell line with a reference genome and identified chromosome-specific length distributions. They found a similar trend when they applied Telomere Profiling to PBMCs from 147 volunteers. Additionally, they observed that certain chromosomes were consistently shorter or longer than others and that these lengths were present at birth.

“[This method] will allow more detailed studies of these length differences,” said Peter Lansdorp, a stem cell biologist at the BC Cancer Research Centre and cofounder of Repeat Diagnostics, a telomere testing service for medical professionals. He said that the method could be more accessible than other techniques and more accurate than quantitative PCR, a currently used approach. “[This approach] opens up new avenues for trying to understand where these chromosome-specific differences in telomere length come from.”

Reference

Karimian K, et al. Science. 2024;384(6695):533-539.

Just Curious| Article

Why Do People Have Different Blood Types?

Humanity’s microscopic foes may be to blame for the ABO polymorphism.

Hannah Thomasy, PhD

Oct 1, 2024 | 2 min read

Image Credit:

Modified from © istock.com, Tetiana Lazunova, VikiVector, Rujirat Boonyong

Although researchers began performing blood transfusions in the 1600s, ABO blood groups were, unfortunately for patients, not discovered until 1901.¹ Despite the decades of study that followed, scientists are still working out why blood types exist in the first place.

Alex Rowe wears a grey sweater and rests her head on her hand.

Alex Rowe studies host-parasite interactions to better understand factors that contribute to the severity of malaria.

Graham Stone

“There’s lots of evidence that ABO genotype can influence a whole variety of infectious diseases,” said Alex Rowe, a malaria researcher at the University of Edinburgh. For example, Rowe and others demonstrated that people with type O blood develop severe malaria symptoms less often because infected type O red blood cells (RBCs) are less likely to form large clumps—called rosettes—with uninfected RBCs, which then block small blood vessels and damage organs.²

However, Rowe doesn’t think malaria drove the evolution of different blood types. While the timelines are still somewhat contentious, many researchers believe Plasmodium falciparum, which causes the vast majority of malaria deaths, only jumped from gorillas to humans about 10,000 years ago.³ ABO blood groups on the other hand, likely evolved about 20 million years ago.⁴

The association of blood groups with disease susceptibility goes far beyond malaria. ABO antigens are found not just on RBCs, but also on white blood cells and most epithelial cells, including those lining the gastrointestinal tract. Indeed, ABO types are associated with different levels of susceptibility to many non-RBC infections, including cholera, tuberculosis, hepatitis, and Helicobacter pylori.⁵

“Some of the infectious diseases going back into human ancestry millions of years are likely to have been the selective pressure that led to the evolution of the ABO system,” said Rowe. Currently, however, it’s not known exactly which disease—or diseases—is the culprit.

What makes you curious? Submit a question for us to answer in future “Just Curious” columns.

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References

Bertsch T, et al. Clin Lab. 2019;65(6).
Rowe JA, et al. Proc Natl Acad Sci U S A. 2007;104(44):17471-17476.
Sharp PM, et al. Annu Rev Microbiol. 2020;74:39-63.
Ségurel L, et al. Proc Natl Acad Sci. 2012;109(45):18493-18498.
Abegaz SB. Biomed Res Int. 2021;2021:6629060.

Image of female scientist crouching as she collects samples in a cave.

Interview| Article

Spelunking for Microbes

Hazel Barton studies cave microbiomes and leverages their properties for unique applications.

Laura Tran, PhD

Oct 1, 2024 | 2 min read

Image Credit:

modified from © istock.com, jemastock, robuart, Anna Pogrebkova, Tasha Vector; designed by erin lemieux

Hazel Barton, a geomicrobiologist at the University of Alabama, fell in love with caving at the age of 14 during an outdoor program. Caving and microbiology remained separate passions until Norman Pace, her postdoctoral advisor and fellow caver, urged her to leverage her unique skillset. More than 30 years later, Barton continues to explore caves to find answers to ecological and biological questions.

How has your caving experience influenced your research?

I’ve always taught my students that our decisions are driven by science, so our direction is dictated by the scientific question. Although many cave microbiologists usually work within half a mile of an entrance, my students and I can reach areas that are days away from an entrance. These deep caves are like a big, underground jungle gym. You’ll see some wild stuff there. Cavers tend to be super inquisitive people, exploring to see where the cave goes, so they make great scientists.

Where have your projects taken you, and what have you learned from these cave microbes?

My students and I studied antibiotic resistance in Lechuguilla Cave, one of the longest caves in the world.¹ Because of how the cave formed, microbes were isolated from the surface for millions of years. If the use of antibiotics led to antibiotic resistance, we wouldn’t expect to see any in the cave microbes. However, we saw every kind of natural antibiotic resistance in a cave bacterium, demonstrating antibiotics’ ancient origins.²

In Borneo, the caves are enormous—just black in every direction—and full of birds. Isotope data suggests that ammonia from bird droppings enlarges the cave as microbes convert it to nitric acid, contributing to the pitting and sculpting of cave passages. Not only that, but bird poop also degrades the nylon ropes we use to climb in the cave. We’re now harnessing this mechanism to compost and recycle nylon.

This interview has been edited for length and clarity.

References

Bhullar K, et al. PLoS One. 2012;7(4):e34953.
Pawlowski, A, et al. Nat Commun. 2016;7:13803.

Technology Highlight| Article

Starting Strong for Successful mRNA Therapeutic Development

Standardized and scalable in vitro transcription reagents allow researchers to enhance and accelerate cell-free mRNA synthesis.

Oct 1, 2024 | 2 min read

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Created in collaboration with

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Decades of research contributed to successful RNA therapeutic development, beginning with scientists first demonstrating mRNA delivery into living systems. Today, mRNA technologies continue to hold the spotlight in translational and clinical research. They are notable for rapid development, manufacturing, and deployment times, and hold promise to revolutionize the therapeutic field for a wide range of indications.¹

cGMP-grade in vitro transcription reagents for mRNA therapeutic manufacturing workflows help scientists accelerate the transition from benchtop to bioreactor.

promega

Drug development challenges related to workflow quality, consistency, scalability, and flexibility, and shifting quality compliance landscapes may impede the transition from bench to bioreactor and beyond. As the first step in many workflows, in vitro transcription (IVT) has quickly emerged as an essential part of successful mRNA therapeutic manufacturing processes, optimizing and accelerating production for simple, scalable, cell-free mRNA synthesis.

Researchers aiming for safe and effective final therapeutic products must start with good manufacturing practice (cGMP)-grade raw materials that meet strict quality standards, perform consistently, and can be easily scaled up for commercial production, including IVT reagents.

For over 40 years, scientists have used RiboMax™ in vitro transcription reagents from Promega to synthesize large quantities of high-quality capped RNA in a short amount of time. The RiboMax™ in vitro transcription reagents are animal origin free and cGMP-manufactured to meet strict quality standards and improve scalability. Between custom capabilities and dependable raw materials, these IVT reagents support a wide variety of translational mRNA synthesis workflows.

Learn more about raw materials for mRNA therapeutic manufacturing.

How do you make your in vitro transcription experiments scalable?

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Reference

Youssef M, et al. Biomolecules. 2023;13(10):1497.

A baby rhesus macaque against a forest backdrop.

Citizen Science Corner| Article

White Blood Cells, Hurricanes, and the Monkeys of Cayo Santiago

Citizen scientists help monitor monkey immune cells, providing a foundation for future work on stress, sociality, and aging.

Hannah Thomasy, PhD

Oct 1, 2024 | 2 min read

Image Credit:

Lauren Brent

Just off the east coast of Puerto Rico lies the diminutive island of Cayo Santiago. The island boasts about 1,500 inhabitants and—since it is only 0.05 square miles—it is lucky that almost all of them are 15-pound monkeys.

Julie Horvath smiles against a background of laboratory equipment.

Julie Horvath studies primate genetics and immunological aging.

Matt Zehrer

All of these free-ranging rhesus macaques are descendants of animals brought over from India in 1938 to establish a behavioral research colony. When Julie Horvath, a comparative genomics researcher at the Renaissance Computing Institute, joined the group more than a decade ago, she hoped to study associations between genes and behaviors. “But now,” she said, “we’ve realized that this is really challenging, because there isn’t just one gene that controls one behavior.”

Horvath, along with several collaborators, then became interested in how gene expression patterns in blood changed as the monkeys aged and how environmental factors might affect these transcription profiles. Since neither red blood cells nor platelets have nuclei, these patterns largely reflect gene expression in the various types of white blood cells.

“But depending on which cells you have more of in your blood, you're going to have different genes turning on or off,” said Horvath. Therefore, researchers need to determine the proportions of these different cell types to help make sense of differences in gene expression changes measured in blood. With thousands of blood smear images for each monkey, researchers are enlisting the help of citizen scientists to categorize the different cell types via the Monkey Health Explorer project.

In 2022, the team published their findings on how exposure to Hurricane Maria accelerated aging-like changes in immune system gene expression.¹ Now, said Horvath, they want to know whether factors like social connectedness can normalize these patterns, bringing them back in line with the monkeys’ chronological age. Understanding the factors that speed up or slow down age-related changes in gene expression could one day provide insights into healthy aging strategies for humans.

Do you have your own citizen science project? Share it with us.

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Reference

Watowich MM et al. Proc Natl Acad Sci USA. 2022;119(8):e2121663119.

A cross section of the pistil of <em>Arabidopsis thaliana </em>plant. Pollen grains are labeled with fluorescent markers and sit at the top of the structure. Fluorescently tagged pollen tubes penetrate the plant’s ovary where the ovules (small, curved structures) are located.

Science Snapshot| Article

The Hidden Dance of Plant Fertilization

A new method enables clear visualization of the dynamic changes during angiosperm reproduction.

Mariella Bodemeier Loayza Careaga, PhD

Oct 1, 2024 | 2 min read

Image Credit:

Yoko Mizuta

In the flowering plant world, reproduction means an intricate succession of events. It begins when a pollen grain that carries the sperm cells lands on the top of the pistil, the female reproductive structure of a flower. The pollen grain then germinates into a tube that guides the male reproductive cells to the depths of the ovary, picking up signals along the way that reveal the location of an ovule. Blocking signals prevent polytubey—the fertilization of an ovule by more than one pollen tube—to maximize offspring formation.¹

Plant biologist Yoko Mizuta studies fertilization of flowering plants and hopes to apply this knowledge to improve seed production.

Yoko Mizuta

Yoko Mizuta, a plant biologist at the Nagoya University, became fascinated by this attraction-repulsion dance over a decade ago. Yet the available imaging techniques did not allow Mizuta to visualize pollen tube guidance over time. Determined to solve this problem, Mizuta and her colleagues developed a new method for live imaging pollen tube dynamics in plant ovaries.²“With this live imaging technique, we can analyze each pollen tube journey to the ovule,” she said.

The team hand-pollinated Arabidopsis thaliana plants using a mixture of fluorescently labeled pollen grains. Using a tissue clearing method that they previously developed, the researchers turned the carefully-dissected pistils transparent while preserving the fluorescent labels in the pollen grains and ovary tissue.³ Using time-lapse imaging microscopy, they captured snapshots of the structure, which were stacked for 3D reconstruction.

After years of optimization, the researchers obtained images that reveal the complexity of pollen tube guidance. As shown above, fluorescently tagged pollen grains elongate their pollen tubes and form a colorful bundle that penetrates the ovary in search of one of the hanging ovules. Using their method, the team discovered that polytubey blocking first employs weak repulsion signals, followed by strong ones.² Next, Mizuta hopes to identify the molecular mediator of this repelling system, unveiling another mystery of plant fertilization.

References

Higashiyama T, Takeuchi H. Annu Rev Plant Biol. 2015;66:393-413.
Mizuta Y, et al. EMBO Rep. 2024;25(6):2529-2549.
Kurihara D, et al. Development. 2015;142(23):4168-4179.

Tip Box| Infographic

Best Pipetting Practices

Correct pipetting techniques allow scientists to instantly improve experimental accuracy.

Oct 1, 2024 | 2 min read

Created in collaboration with

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	Temperature Equilibrium If possible, ensure that the pipette, tips, and liquids are at room temperature. Pre-wet to equilibrate temperature differences and humidity inside the pipette and tip.	Optimize Volume Pipette within 35–100 percent of the nominal volume range for air displacement pipettes. When dispensing multiple aliquots, discard the first and last dispense of the series.
	Pre-Wet After loading tips, aspirate and dispense the nominal volume 3 times to pre-wet. Without this step, the first few dispenses may deliver less volume.	Tackling Tricky Liquids Pipette viscous liquids slowly and volatile liquids quickly. Reverse pipette to avoid volume loss; aspirate the selected volume plus an extra discardable dispense.
	How to Pipette Hold the pipette at a consistent angle ≤20 degrees. Immerse the pipette tip 2–3mm below the liquid’s surface and touch off after each dispense.	Calibration Calibrate pipettes based on liquid density. When working with nonaqueous liquids, recalibrate the pipette if the liquid has a considerably different density than water.
Learn more tips for proper pipetting.
What is your biggest pipetting pain point? Submit your Answer

Cartoon of three people helping each other climb up stairs.

Perspectives| Article

How Can Researchers Be Good Science Mentors?

Two scientists weigh in on what makes for a successful mentorship experience.

Shelby Bradford, PhD

Oct 1, 2024 | 3 min read

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Good mentorship in science and academic training can propel trainees into successful careers. Additionally, researchers at multiple career stages can be instrumental advisors to younger students. However, every person has different needs and goals, so how can one individual provide guidance to multiple mentees? Two scientists, a principal investigator and a graduate researcher, share their mentoring insights.

Felipe Santiago-Tirado, a cell biologist at the University of Notre Dame, stands in front of a university backdrop in a navy jacket and white and blue plaid shirt. He is smiling and has square-framed glasses.

Felipe Santiago-Tirado is a group leader at the University of Notre Dame. He mentors trainees ranging from undergraduate students to postdoctoral researchers.

Matthew Cashore

Felipe Santiago-Tirado
My goal as a mentor is to make sure that when trainees leave my lab, they can be successful. To do this, the first thing I ask students about is their goals, so that we can plan to help them prepare for what they want to do in their career. That could be helping them publish more papers, connecting them with resources, or encouraging them to participate in conferences and professional development events. My approach as a mentor is to encourage independence, but I do have an open-door policy, so trainees can come talk to me whenever they need advice or assistance. However, mentoring isn’t a one size fits all, so if a mentee tells me they would like more involvement from me, I will provide that extra support. I also emphasize that they can have more than one mentor.

Ivan Alcantara is a neuroscience graduate student at the National Institute of Diabetes and Digestive and Kidney Diseases. He is smiling in the photo and wearing a beige jacket and rounded glasses.

Ivan Alcantara is a neuroscience graduate student at the National Institute of Diabetes and Digestive and Kidney Diseases. He is both a mentee and a mentor to postbaccalaureate students in his lab.

Cassandra Alcantara

Ivan Alcantara
The purpose of a mentor is to help your trainees achieve their professional goals, so open communication is one of the most important features in a mentoring relationship. As a mentee, I told my advisor my goals and what help I needed to accomplish them, and I’ve also turned to him for advice. Now that I’m looking for postdoctoral positions, I’m asking potential mentors what their advising style is so that I can find the mentorship that works best for me. Then, as a mentor, I have the same conversation about goals and mentoring styles with my mentees to learn their needs and understand how I can help them. Sometimes it involves career paths; other times, it’s writing letters of recommendation. In the lab, it’s often troubleshooting failed experiments to help them improve their approach.

This interview has been edited for length and clarity.

What do you think? What are the makings of a good mentor?

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