Editor's note
What’s more challenging than having a baby is being a parent. While there are plenty of resources to get help from, it is challenging for new parents to entrust their children to popular opinions, experiences, and beliefs. As scientists we believe in verifiable results. Subhashini, a scientist/ parent herself, brings to you some facts that might make one key aspect of your parenting a tad easier.
Parenting isn’t easy. The sleepless nights, constant diaper changes, the need to comfort your child through the endless cycles of teething and milestones, while priceless, do take a toll on you. One fine day the maternity/paternity leave gets over and it’s time to get back to work. All millennial parents have one thing in common— sleuthing on Google for answers to all kinds of doubts! Googling for answers, unfortunately, also has its downsides. There’s plenty of information around. Which do you choose! The question that most parents grapple with is how to strike a balance between work and family. Do you give up a hard-earned career to raise your child? Or do you manage time and do both? While this decision is ultimately yours to make, a recent review in Nature Reviews Cancer says that sending your kid to day care early in life protects them from Childhood Acute Lymphoblastic Leukemia (ALL).
In healthy children, the bone marrow makes immature cells called blood stem cells, which in turn give rise to myeloid stem cells and lymphoid stem cells. Myeloid stem cells mature into red blood cells (that transport oxygen to all other cells), platelets (which help blood to clot), and granulocytes (that fight infection). Lymphoid stem cells mature into B-lymphocytes (that make antibodies), T-lymphocytes (that make certain immune-signaling chemicals to fight infections), and Natural Killer cells (that kill viruses and cancer cells).
Childhood ALL is a cancer of the blood and bone marrow. In Childhood ALL, too many of the blood stem cells turn into lymphoblasts or B- or T-lymphocytes. These aren’t able to fully retain their function and they cannot fight infection very well. A larger number of lymphoid stem cells also means that there aren’t enough myeloid stem cells, resulting in lower numbers of red blood cells, platelets, and granulocytes. This leads to anemia, easy bleeding, and an increase in infections. There is a marked peak in the incidence of ALL in 2-5 year olds . Although cure rates for ALL are pretty high (~90%), it is the most common childhood leukemia. It is therefore important to discover what causes it and what can be done to prevent it. Recent findings suggest that one form of ALL, called B-cell precursor ALL (BCP-ALL; named after the cell lineage that turns cancerous), is in fact, preventable.
When scientists discovered that leukemia in animals can be caused by viruses, they wondered if the same was true of humans too. However, no leukemia-causing viruses have been discovered so far. Two hypotheses that were formulated in the ’80s have shed more light on the role of infections in leukemias. One of these, the “delayed infection hypothesis”, proposed that our immune systems have evolved to expect high exposure to microbes in infancy and “learn” the correct response to infections at an early stage. In the absence of early exposure, the immune system is unable to deal with subsequent infections in an appropriate manner, leading to BCP-ALL. This hypothesis also proposed that ALL develops in two steps: the first mutation occurs in utero (in the mother’s womb) and the second mutation occurs sometime after birth, leading to full-fledged BCP-ALL.
All new-born babies have their heels pricked for blood to test for genetic diseases. These neonatal blood spots, also known as Guthrie cards, are samples of dried blood collected from these heel pricks. Scientists used these stored blood spots to see if kids who developed BCP-ALL were born with any of the mutations commonly seen in BCP-ALL. They found a particular gene fusion (a hybrid gene formed from two previously separate genes) between the genes ETV6 and RUNX1 in 75% of the samples, proving that the first mutation is in utero. If the majority of ALL-affected children have this first mutation, the question remains how many children are born with this mutation and how many get ALL later. Using a large number of unselected blood spots, they found that nearly 1% of all new-borns have the same gene fusion. But incidence rates for ALL are 1 in 10,000. This means that of the 1% of new-borns that have the first mutation, 99% don’t get the cancer. What is the factor that then triggers the cancer in the remaining 1%?
The UK Children’s Cancer Study Group set up a case-control study to figure out if BCP-ALL could be caused by radiation, chemicals, and other exposures. One of the factors they inferred was early exposure to infections, using day care attendance and social activity in infancy as a proxy. They found that attending day care (a loose definition that includes once-a-week play groups and mother-toddler groups in addition to regular full-time day care centers) in the first year of life significantly reduced the risk of a child contracting ALL later in life. This protective effect was even stronger in babies who attended the day care in the first three months of life. The infant does not have to suffer from the symptoms of an infection; simply exposing them to a variety of microbes will do the trick.
The UK study has been corroborated by studies conducted in California , France, and Denmark. Studies also found an increased risk of ALL in first-born children compared to third-borns, with first-borns having presumably lower microbe exposures than their siblings. Vaccinations don’t seem to have the same effect on ALL risk that actual infections do, except in one case – the Hemophilus influenzae B vaccine that has a protective effect. Other factors that affect ALL risk are also ones that affect exposure to microorganisms: C-sections increase ALL risk, whereas breastfeeding past 6 months of age decreases the risk by 19%.
So how does the lack of exposure to microbes lead to cancer? The answers come from studies in mice. Normally, B-lymphocytes undergo a process of recombination in the antibody genes, making each B-cell specific to a particular antigen. This involves the timed activity of recombination proteins, RAG1 and RAG2 (acting early in the process) and AID (acting later in the process). However, in the presence of common pathogens, these proteins can sometimes act accidentally at the same time, causing recombination events in other genes, leading to cancer. When mice containing pre-leukemic cells were exposed to infections early in life, they used up both normal and pre-leukemic B-cell precursors, reducing their risk of developing ALL later. When mice containing pre-leukemic cells were exposed to TGF-ß (a chemical that the immune system releases during an infection), they developed further mutations in immune system cells, leading to BCP-ALL.
One cannot perform such studies in humans for obvious reasons, but there is compelling evidence in the form of space-time clusters. These are clusters of patients diagnosed with the same disease in a narrow time-frame, living in the same area. Between 1957 and 1960 in a suburb in Chicago, USA, eight patients (of whom seven attended the same school) were diagnosed with ALL. This cluster was observed to be linked to an outbreak of streptococcal fever. A recent cluster in Milan, Italy, occurred in a four-week window between December 2009 and January 2010 . Seven patients were diagnosed with BCP-ALL of which three went to the same school and a fourth lived in the same neighborhood. All seven tested positive for antibodies against AH1N1. An outbreak of this pandemic swine flu had occurred only a few months before the BCP-ALL “outbreak”. Of course, these are mere associations and one cannot rule out the role of chance, especially in cancer.
The details of the exact molecular pathways are yet to be discovered, but the inverse association between exposing kids early in life to a variety of microbes and the risk for developing ALL later in life has clearly been demonstrated. This association only exists for a particular subtype of BCP-ALL that has the ETV6-RUNX1 gene fusion. Causal mechanisms for development of three other types of ALL have not yet been elucidated.
What does this imply for new parents? Exposure to microbes isn’t necessarily a bad thing for babies. It helps develop and boost their immune systems. It’s okay to let your kids mouth their toys, play on the ground, or enjoy on the grass. Don’t fall prey to the routine use of anti-bacterial soaps and sanitizers. Go enjoy that hard-earned career, and don’t be wary of day cares or parks or playgroups. Enjoy your parenthood. You’ve earned it.
About the author:
Subhashini has a Ph.D. in Molecular Biology from the Max Planck Institute for Developmental Biology, Tübingen, Germany. She received her Master’s degree from the Indian Institute of Science, Bangalore and her Bachelor’s degree from St. Xavier’s College, Mumbai. She truly believes that Science and Technology will solve most, if not all, problems, if only their value is communicated in the right way at the right time. She spends her free time reading books on her phone and spending time with her family. She now worries about not having sent her kid to a daycare when he was a baby.
Cover Image: Bhrugu Yagnik, PhD
Bhrugu Yagnik is a Postdoctoral Fellow at Emory Vaccine Centre, Yerkes National Primate Research Centre, Emory University, Atlanta, GA and works on the development of a HIV/AIDS vaccine. His doctoral research focused on development of vaccines against Shigella using food grade Lactococcus lactis as an antigen delivery vehicle. Bhrugu has many awards to his credit. He is passionate about communicating science in creative ways. In his free time, Bhrugu indulges himself into the spirituality where he attempts to bring amalgamation of science and spirituality. Follow him on Twitter or connect with him on LinkedIn or ResearchGate.
Editors: Dolonchapa Chakraborty, PhD and Paurvi Shinde, PhD
Dolonchapa Chakraborty, PhD is a biologist by training, a freelance consultant, and a wannabe athlete! She recently joined the NYU School of Medicine as a Postdoctoral Fellow, and is also CSG’s NYC Chapter Rep. She unwinds from her several roles by baking, blogging, and boxing. She believes in the power of technical storytelling as an effective tool for scientific outreach, and looks forward to practicing this art as an editor at Club SciWri.
Paurvi Shinde did her PhD, Immunology from Uconn Health and her expertise lies in T/B cell biology and activation pathways. She currently works as a Post Doc Fellow at Bloodworks Northwest in Seattle, where she studies the mechanism of alloimmunization to certain human ‘Red Blood Cell antigens’. Apart from science, she’s loves editing scientific articles to convey the message behind it, in a clear and concise form. Follow her on Linkedin.
Blog design: Dolonchapa Chakraborty, PhD
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