Cutting NIH Support of FlyBase Threatens Preclinical – and Ultimately Clinical – Research

The toppling of health care in the US has begun, and I fear will reverberate for decades to come. It is beginning with vaccine refusal.
• “2 Kentucky Infants Die of Pertussis as Cases Rise” (American Academy of Pediatrics)
• “Two Infants Die of Whooping Cough in Louisiana as Cases Climb Nationally” (CNN)
• “Whooping Cough is Surging in the US – What You Need to Know” (New York Academy of Sciences )

Ahead of pertussis is the more-deadly measles. It’s back, and mostly among the young and unvaxxed. Details are here, from what’s left of the CDC.

While vaccine-preventable deaths get attention, a perhaps larger problem looms: the decimation of preclinical research. Like pulling out a critical block in a game of jenga, cutting funding for research using non-human animals will ultimately topple the foundations of clinical trials that test new treatments in people.

Model Organisms Stand In For Us
Preclinical research tests experimental treatments on non-human animals, on human cells and tissues growing in culture, and, increasingly, in organoids. These are human body parts assembled from cells and tissues and nurtured in the lab, usually from stem cells. For example, liver organoids can be used to test drug toxicity without endangering a person.

Model organisms like the fruit fly have been a mainstay of preclinical research because humans and flies (and mice and rats and even roundworms) are all animals. We share many genes, with only small differences in our genome sequences. Researchers are increasingly using CRISPR to introduce human versions of genes into fly genomes, fashioning “fruit fly avatars.”

Without model organisms, biomedical research would, eventually, grind to a halt. New drug candidates do not just magically appear at the starting gate for a clinical trial.

I began working with the fruit fly Drosophila melanogaster in college. In grad school, I did my PhD research on flies that grew legs where their antennae should be and antennae where their mouthparts should be, thanks to mutations in genes called homeotics.

We have these genes too, as do other animals, plants, and even fungi. In Thom Kaufman’s lab at Indiana University, we probed the genetic controls of early development, as an animal’s body sorts out what goes where.

A fruit fly, early in development, has cells that divide to eventually become part of a leg or antenna, bristle or eye segment. Similarly, in a human body, immature (hematopoietic stem) cells “choose” to follow an unfurling developmental pathway towards a specific type of blood cell – B cell or T cell? Basophil, eosinophil, or neutrophil? A glitch could mean a leukemia or lymphoma, or inability to fight off certain infections.

Flies and humans are multicellular animals with complex bodies, so it isn’t surprising that we, too, have homeotic genes. They lie behind cancers and a few rare diseases, thanks to mutations intervening when a cell has to “decide”which developmental pathway to follow. (See When an Arm is Really a Leg) It makes sense.

Debasing FlyBase
Given my appreciation for basic research, I was alarmed to receive a message from a friend from grad school who worked on those weird flies with me. She told me about this message on the website for a research resource, FlyBase:

“FlyBase needs your help!
Because of recent changes to government funding, the NIH grant that supported FlyBase has been terminated. We are now reaching out to the community for emergency funding.”

FlyBase is the “database of Drosophila genes and genomes.” Since 1992, it has been a clearinghouse of information on research that uses the fruit fly as a model for human diseases.

Scientists at some 4,000 labs use FlyBase, as well as clinical organizations such as the Undiagnosed Diseases Network that has helped people, typically young children, who have sets of symptoms so rare that they do not fit any diagnostic criteria.

Reported NBC News, “Trump’s Harvard cuts threaten a giant in the biomedical research community: A database about the tiny fruit fly.”

NIH support is $2 million a year; cobbled-together interim funding for the database runs out this month.

FlyBase provides research reports, organizes findings and data according to specific genes, and keeps track of genetically modified lines of flies.

Fly Disease Models
Name a condition, and there’s likely a fly for it.

Type “cancer” into FlyBase and 1,867 results appear, highlighting common cancers like blood, breast, prostate, lung, and skin, but also of individual organs in the digestive, reproductive, and urinary tracts, and even the eye and sebaceous glands.

Flies also stand in for cancer syndromes – such as Li-Fraumeni, Costello, Noonan, and Sotos.

Type “hair” and 166 conditions pop up. Hair refers to both bristles and hair cells in the hearing organs of the fly. Their unusual hairs model certain ultrarare human genetic disorders, such as the ultra-kinky hair of Menkes disease, the brittle, woolly hair of people with Carvajal syndrome, and even hair follicle cancer and forms of alopecia (hair loss).

FlyBase lists 64 movement disorders, and several sleep disorders.
Here are some others.
• A “hedgehog” fly, named for its bristles, models a type of skin cancer (basal cell carcinoma) and a brain cancer (medulloblastoma).
• Fly models mirror neurological disorders, including ALS, Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease.
• “Bang-sensitive” flies display seizures, serving as models for epilepsy drugs.
• Flies can be addicted to cocaine.
• Flies engineered to have high uric acid levels mimic diabetes and gout, useful in testing new drugs.
• Flies model many rare diseases, such as DiGeorge syndrome, which is an immune deficiency that also causes cleft palate, heart defects, and affects learning.

Preclinical research is particularly vital for extremely rare diseases.

CODA
Defunding FlyBase today will echo in a drying up of drug and procedure pipelines years from now.

Like slowly chopping down a tall tree at its base until the entire organism comes crashing down. stopping preclinical research is going to reverberate in the clinic, halting development of new diagnostics and treatments. It simply makes no sense. But when biomedical science falls into the hands of political appointees without appropriate knowledge or experience, the patients of tomorrow are going to suffer.