Lynch Syndrome Awareness Day: What is Lynch Syndrome?

Lynch Syndrome is a hereditary condition caused by germline mutations that inactivate at least one of the major DNA mismatch repair (MMR) genes. Individuals with Lynch Syndrome have an elevated risk of developing several cancers, especially colorectal, uterine and endometrial. Approximately 1 in 279 individuals in the United States is Lynch-positive, but most people are unaware of their status.

Lynch Syndrome results in highly elevated risks of several cancers.

Lynch Syndrome can be diagnosed following screening by microsatellite instability (MSI) analysis or immunohistochemistry (IHC) for the MMR proteins. For some patients, MMR gene sequencing is as easy as an oral “swish.” However, the genetic basis of Lynch Syndrome and its clinical relevancy are relatively recent discoveries. Long before modern sequencing methods simplified testing and diagnosis, a seamstress in Ann Arbor, Michigan correctly predicted her own Lynch Syndrome status based only on her family history. Talking with Dr. Alfred Scott Warthin in the late 19th century, she said that since so many of her family members had died of several specific cancers, she believed that she would follow the same path. Several years later, she unfortunately proved herself right.

Dr. Warthin took interest in the story and began studying the woman’s family. At the time of their conversation, five of her nine siblings had already been diagnosed with uterine, stomach or “abdominal” cancer. Warthin concluded that the family, which he dubbed “Cancer Family G,” did, in fact, have a predisposition to cancer. Warthin and other researchers continued studying the family for several decades. They found that cancers of the colon, uterus and stomach were most common, and that many members of the family were diagnosed at extraordinarily young ages.

In the 1970s, Dr. Henry T. Lynch organized a family reunion for Cancer Family G and subsequently published a report on “Cancer Family Syndrome.” By this time, 95 members of the family had developed one of the expected cancers. Dr. Lynch still didn’t have the technology to determine the molecular basis of the disease, but he noticed that it followed an autosomal dominant inheritance pattern.

In the mid-1990s, three labs simultaneously discovered microsatellite instability and its connection to colorectal cancer. It had been established in bacteria and yeast that inactivating mutations in DNA mismatch repair genes resulted in mutations in microsatellite sequences, so several labs began racing to clone the human homologs of the DNA MMR genes. Within a few months, two labs had cloned the MSH2 gene and found mutations that were present in members of Lynch-positive families who developed cancer.

Around this time, the name “Lynch Syndrome” was adopted to apply to families carrying germline mutations in a gene associated with the condition. Further research established four genes (MSH2, MLH1, MSH6, PMS2) as “Lynch Syndrome Genes,” and researchers began working on guidelines for diagnostic testing (See “The History of Lynch Syndrome” below for further reading).

Today, over two decades later, many researchers are pushing for the adoption of universal tumor screening for Lynch Syndrome. One of the widely recommended screening method is MSI analysis. MSI-H status indicates that certain sections of DNA called microsatellites have become unstable because the major mismatch repair genes that correct errors during DNA replication are not functioning properly. MSI status can influence treatment decisions, based on the 2015 discovery that MSI-H tumors respond well to immunotherapy drugs (1).

It’s also important knowledge for a patient’s family. Lynch-associated cancers are among the most preventable, so individuals who know they are Lynch-positive can work with their healthcare providers to develop robust strategies for prevention and surveillance. As one Lynch-positive mother said to her Lynch-positive son, “Your knowledge is power, and it’s going to keep you healthy and safe.”

March 22, 2019 is Lynch Syndrome Awareness Day, and we’re encouraging everyone to join the fight against colorectal cancer. Visit our website to learn more about Lynch Syndrome and colorectal cancer.

 

 

Further reading:

Take the pledge to fight colorectal cancer: During Colorectal Cancer Awareness Month, we’re donating $10 to Fight CRC for every person who takes the pledge.

Life with Lynch Syndrome: Read about what a Lynch Syndrome diagnosis means for Carrie Ketcham and her family

Dreaming of Universal Tumor Screening: Learn how cancer genetic counselor Heather Hampel is advocating for universal tumor screening

The History of Lynch Syndrome: Dr. C. Richard Boland and Dr. Henry T. Lynch provide a broad review of Lynch Syndrome research, starting over a hundred years ago.

 

 

References

(1) Le, D.T. et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair DeficiencyNew Engl. J. Med. 372, 2509–20.

Goodbye to the Most Famous Bird in Maine

When Wisconsin plunged into a deep freeze during last week’s polar vortex, I built a roaring fire in my fireplace and settled into my armchair with a thick blanket and a video game controller. Except for the twenty minutes I spent driving to and from the office, I stayed warm and toasty.

Birds, however, don’t have it quite as easy. To survive freezing temperatures, non-migratory birds have developed many interesting adaptations. Many species grow extra down layers and huddle together for wind protection. Others, like the black-capped chickadee, use a process called regulated hypothermia to drop their resting body temperature by as much as 22°F to conserve energy. I’m particularly fascinated by the process of regional hypothermia—many species of ducks and gulls use a countercurrent heat exchange system to keep vital organs warm while letting temperatures fall in extremities.

Birds that aren’t accustomed to cold weather don’t have these adaptations, though. When a bird—or any animal—ends up far outside of its natural habitat, the consequences can be deadly.

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2019: International Year of the Periodic Table

Periodic table of the elements

From the inside covers of elementary science textbooks to the walls of chemistry labs all around the world, the periodic table is one of the most pivotal and enduring tools of modern science. To honor the 150th anniversary of its discovery, the United Nations General Assembly and UNESCO have declared 2019 to be the International Year of the Periodic Table of Chemical Elements.

As with all scientific progress, Dmitri Mendeleev’s periodic table was the result of decades—centuries, even—of research performed by scientists all over the world. Aristotle first theorized the existence of basic building blocks of matter over 2,500 years ago, which later were believed to be earth, air, fire and water. Alchemist Hennig Brand is credited with discovering phosphorus in the late 17th century, sparking chemists to begin pursuing these basic atomic elements.

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RAIN Incubator Turns Students into Scientists

Judy Nguyen wasn’t looking for an adventure as the Head of Scientific Research at a fledgling incubator for students. She just finished her Ph.D. in molecular biology and neuroscience, and was looking for stable work in scientific research or biotechnology. However, when she arrived in Tacoma, Washington, she was disappointed by the opportunities available to her.

“With Puget Sound, in the Pacific Northwest, so outdoorsy…Most of Tacoma is environmental science, which is not my background,” Judy says. “I had a hard time finding anywhere to fit in.”

Judy finally found a position with an engineering company, but she didn’t feel quite at home. One day, her boss sent her out for an external meeting with a professor who had, she was told, “cool ideas.” She was instructed to establish a connection and return with ideas for how her company could collaborate with the “crazy professor.” As it turns out, that “crazy professor” had an idea for an organization to spark a revolution in the life science community around Tacoma.

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In a Perfect World, Bacteria Wins

iGEM 2018 from aboveLast month, several of my Promega colleagues and I attended the 2018 iGEM Giant Jamboree in Boston, MA. This annual event is the culmination of the International Genetically Engineered Machines competition, in which 350+ teams of high school, undergraduate and graduate students use synthetic biology to solve a problem they see in the world.

The iGEM Giant Jamboree is the closest I have ever come to a scientific utopia. For four days, several thousand students from 45 countries come together to share their experiences and discuss ways that science can change the world. They present impressive projects with real-world applications including human diagnostics and alternative energy. Collaboration and open science are among the core tenets of iGEM, and it’s not unusual to see three or more countries represented on the Collaborators slide at the end of a presentation. Each project also contains a public engagement component, which many teams fulfill with educational programs or partnerships with underrepresented communities. Continue reading “In a Perfect World, Bacteria Wins”

Hey, iGEMers! We’re talking to you!

The 2018 iGEM Giant Jamboree is upon us! This Wednesday, October 24th, thousands of you will flood into Boston, weighed down by posters and presentation materials, but energized by the excitement of a non-stop science-packed conference. Promega will also be attending, with a booth full of helpful giveaways and staff standing by to answer all your questions about science, Promega or future careers. As you make your final plans for the Jamboree, here are a few helpful tips for making the most of this incredible opportunity.

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The 5 Stages of Failed Cloning Grief (and how to get back on track!)

Cloning is a fickle process that can make even the most seasoned bench scientists scream in frustration. By the time you perform a colony PCR and run the gel to check for your insert, you’ve invested several days in preparing these transformed cells. But then, the unthinkable happens. When you image your gel…the target band is missing.

This can trigger what’s known as “The 5 Stages of Failed Cloning Grief.” As you work through each stage at your own pace, just know that scientists all over the world feel your pain and can empathize with you in this difficult time. Continue reading “The 5 Stages of Failed Cloning Grief (and how to get back on track!)”

A Crash Course in Fighting Lab Contamination

When I first started in my undergraduate lab, one of the first things I learned was how to prepare agar plates for growing yeast. My supervisor, a grad student, looked over my shoulder as I added the yeast extract, bacto peptone, and other ingredients. I sealed the pitcher tightly with aluminum foil and autoclaved it until sterile. When I was ready to pour the plates, I carried the pitcher to the “plate-pouring” room, ripped the foil off, and started to pour an even layer of agar into each of the plastic dishes, leaving the lids off so they could cool. After I’d poured a dozen or so, my grad student supervisor burst into the room.

“What are you doing?” she demanded.

“I’m pouring plates,” I stammered back.

She took a deep breath and explained. By fully uncovering the pitcher and leaving my plates uncovered, I had left my precious media at high risk for contamination. The open containers were far too inviting for potential contaminants floating through the air. In the end, we ended up throwing away several of the plates that had been exposed the longest.

Now, I don’t share this story to demonstrate how clueless when I first started in the research lab as an undergrad. We all have those “uh-oh” moments when we realize for the first time that something that seemed so obvious was, in fact, more complicated than we’d expected. However, that day I learned how easily I could sabotage my own work by unwittingly inviting contaminants into my experiments.

Whether you work with yeast, bacteria, mammalian cells or anything else in a molecular biology lab, preventing contamination is crucial to getting desired results. Fortunately, minimizing your risk can be incredibly easy.

Let’s start with your lab bench. Everyone has their own organization system, but if yours is “out-of-control chaos,” you might want to reevaluate. Benchtop clutter makes it difficult to thoroughly clean the bench as often as needed. All those bottles of solutions, empty tip boxes, and wrinkled protocol sheets harbor dust and other unwelcome particles that you want to keep away from your cultures and reactions.

Once your benchtop is tidy (or at least somewhat tidy), make sure you keep the surface as clean as possible. Immediately clean up any spills or drips that happen while you’re working. Wiping your workspace with a 10% bleach solution will sterilize it, and following that up with 70% ethanol will dry it quickly. This wash should be performed at least once a day. Ideally you should also regularly remove everything from your workspace and perform a deeper cleaning of your benchtop, as well as any shelves and containers in your area.

Now that your bench is in good shape, it’s time to gear up . You should always follow standard safety procedures (lab coat and goggles, closed-toe shoes, hair tied back), but above all, make sure you never forget your gloves. Gloves protect you from harmful chemicals, but they also protect your experiments from anything that could be on your hands. Skin can carry reagents, bacteria, and enzymes that are good for your body but bad for your experiments. Change your gloves regularly to prevent potential carryover of reagents or samples between containers. A good rule is, “When in doubt, change your gloves.”

Finally, to guard against airborne contaminants, do your best to keep everything covered when you aren’t immdiately using it. I learned this rule the hard way when several of my yeast plates developed fuzzy patches of mold several days after I poured them. Bacteria and other undesirables floating through the air can affect stock solutions, cultures, plates, tubes, and basically anything else you rely on. Keep your lids on and cover open containers to minimize air exposure to reduce the chances of nefarious particles finding their way in.

There’s no way to guarantee you’ll never experience some form of contamination in your lab, but smart practices can help reduce your risk. Develop an anti-contamination routine that meets your needs and make sure you stick to it every day in the lab.

Working with RNA doesn’t have to be a nightmare

We’re all familiar with the Central Dogma of Molecular Biology: DNA is transcribed into RNA, which is translated into proteins. It’s drilled into our heads from the early days of biology classes, and it’s surprisingly useful when we start exploring in our own research projects. For example, if you’re interested in gene expression, you’ll most likely be working with RNA, specifically mRNA. Messenger RNA (mRNA) is transcribed from DNA and is used by ribosomes as a “template” for a specific protein. The total mRNA in a cell represents all of the genes that are actively being transcribed. So, if you want to know whether or not a gene is being transcribed, RNA purification is a great place to start.

When preparing your RNA samples for a downstream assay, there are several roadblocks and pitfalls that could give you quite a headache. Let’s tackle two of the most common.

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