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Rare Disease Geneticist: A Profile of Uta Francke

The Stanford University human geneticist identified the genes and genomic abnormalities underlying numerous rare diseases, including Rett  syndrome, and advanced the field of molecular diagnostics. 

May 1, 2018
Anna Azvolinsky

UTA FRANCKE
 Professor of Genetics, Emerita, Stanford University  
    School of Medicine
 Professor of Pediatrics, Stanford University School  
    of Medicine
 Past President, American Society of Human Genetics
    (1999)
 Past President, International Federation of Human
    Genetics Societies (2000-2002)
 March of Dimes/Colonel Harland Sanders Lifetime
    Achievement Award in Genetics (2001)
 William Allan Award, American Society of Human
    Genetics (2012)
 Association for Molecular Pathology Award for Excellence in Molecular Diagnostics (2014)
COURTESY OF STANFORD CHILDREN’S HOSPITAL
Before moving her lab from the University of California, San Diego (UCSD), to Yale University in 1978, Uta Francke learned how to fly. “I thought, where could you go from New Haven if you are very busy and don’t have much time? It’s hard to do with a car and even the train, so I got a license to fly a small plane and joined a flying club in New Haven,” says the professor emerita of genetics and pediatrics at Stanford University School of Medicine.

In her Piper Comanche plane, Francke would zoom off to Martha’s Vineyard or Nantucket for weekend excursions or to institutions in the northeast to give invited seminars on her research. “I would agree to give talks if the institution was within flying distance. And then the researchers would take me out to dinner, and what they mostly wanted to do was talk about my flying the airplane,” she says.

But Francke had much to discuss in addition to her experience as a pilot. She trained as a physician in Germany, initially driven by her interest in pediatrics. In the U.S., she entered—and helped define—the new field of medical genetics, becoming an expert in human cytogenetics and pioneering molecular diagnostics techniques. 

Her scientific accomplishments include being among the first to map specific genes to their chromosomal locations and, with that information, contribute to a detailed map of the human genome. Francke and her team also found the genes responsible for Prader-Willi and Rett syndromes, laying the foundation for investigators to discover genes responsible for other rare genetic disorders.

Francke’s research helped set the stage for the Human Genome Project (HGP) that began in the 1990s. What is underappreciated today, according to Francke, are the efforts by researchers like herself—who had generated detailed maps of each human chromosome—that greatly facilitated stitching together the sequences generated by the HGP.

But before molecular diagnostics and her discovery of variants responsible for rare diseases, Francke was a sharp student growing up in wartime Germany with parents who initially discouraged her from following her academic talents.

From her father’s death, an opportunity

Francke was born in 1942 in a small town just north of Frankfurt, Germany. Her father, who had a law degree, fought for Germany in World War II, and her mother was an elementary school teacher. Her parents did not think she and her sister should attend the local school that would put them on a path to a university education, as neither of her parents thought that girls needed much in the way of career options. Instead, the girls went to a local middle school that would direct them to become secretaries or technical assistants.

Then, when Francke was 12, her father suffered what was assumed to be a heart attack at age 46. “It was a total shock for us. I realized that things can change suddenly, that nothing is truly stable,” says Francke.

After her father’s death, Francke informed her mother that she wanted to switch schools, and her sister followed suit. From then on, Francke’s mother let her choose her own way. She chose a science track in which she was the only girl. “I didn’t feel out of place at all,” she says.

I said from the beginning that people should have their genetic information if they want it.

After high school, Francke pursued a career in medicine. She had volunteered at a hospital, doing the unglamorous work of changing patients’ bedpans and sheets, and found the tasks gratifying. “I loved taking care of patients. I wanted to go into medicine because it was immediately useful to people,” she says. At the University of Marburg, Francke settled into a cozy student life of coursework and singing in a choir. But after two years, she realized that small-town life wasn’t preparing her well for the “real world,” so she transferred, in 1963, to the University of Munich, where she completed her clinical training.

Attaining her medical degree required Francke to write a thesis, and she initially inquired about bacteriophage research at the Max Planck Institute of Biochemistry in Munich, where her first husband, whom she’d met in medical school, was working on his thesis. But a professor at the institute discouraged her from molecular genetics work, Francke recalls, likely because she was a woman. Instead, she was advised to pursue a clinically focused thesis. She followed up with patients who had been diagnosed with an appendix tumor to see whether the cancer—identified incidentally by a pathologist when they’d had their appendices removed—progressed in subsequent years. Francke and her surgeon collaborator found that the tumors were not likely to recur or metastasize.

New country, new profession

Francke completed medical school in 1967, followed by two years of postgraduate rotations in various specialties. In 1969, she applied for a pediatric fellowship at the Children’s Hospital of Los Angeles. She wanted additional pediatric training, and her husband was starting a postdoc at UCLA. The Children’s Hospital took a chance on Francke, she says, as she didn’t know much English and didn’t have a US license to practice.  “I knew so little about America. I remember calling a lab and asking someone there to send me test results. After saying, ‘Thank you,’ the person replied, ‘You’re welcome.’ And I thought, ‘I should write down their number, I am welcome there!’ I didn’t know about this expression and many others.”

After that residency, Francke was ready for a change and applied for a new medical genetics fellowship at UCLA. In 1970, she was among the first fellows in the program, making the rounds in the hospital to identify patients with potential genetic anomalies that could be studied. Back at the lab, Francke sat at the microscope manually counting the number of chromosomes in patient samples to spot abnormal karyotypes with more or fewer than 46 chromosomes. In 1971, she found out about a new technique, developed in Sweden, in which chromosomes are stained with a fluorescent dye, quinacrine mustard, resulting in distinct chromosomal banding patterns that allowed for the identification of individual chromosomes.


Greatest Hits
  • Demonstrated that quinacrine mustard staining of human and mouse metaphase chromosomes could be used to identify individual chromosomes and abnormal chromosomal translocations
  • Generated high-resolution banding ideograms for human
  • and mouse chromosomes
  • Developed a noninvasive hair follicle genetic test to detect heterozygous carriers of variants for Lesch-Nyhan syndrome
  • Using positional cloning, discovered the gene underlying Wiskott-Aldrich syndrome
  • Created mouse models for microdeletion syndromes and identified causative genes


Francke got the method to work and started to collaborate with Muriel Nesbitt, a mouse geneticist then also at UCLA. The two published their first paper together in 1971, demonstrating the utility of the technique to identify each mouse chromosome. The same year, the pair also described a translocation involving a chromosomal fragment that moved from an autosome onto the X chromosome in mice.

Francke also began staining intact human chromosomes, usually in metaphase. From the samples of 16 patients, she showed that the technique could be used to identify translocations between chromosomes, including the amount of DNA that was moved. The new approach was both quick and accurate, allowing for better characterizations of  abnormal chromosomes and therefore more-accurate diagnoses and genetic counseling for patients.

Hair follicles to screen disease carriers

At the end of 1971, Francke says, she had “chromosomes coming out of my ears.” She wanted to go back to pediatrics and sought out William Nyhan, a physician at UCSD who had co-discovered Lesch-Nyhan syndrome, a recessive, X-linked disease that causes compulsive self-mutilation, cognitive deficits, involuntary muscle movement, and early death in males. The syndrome is caused by a defective gene that encodes the hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) enzyme necessary for purine metabolism.

As a postdoc in Nyhan’s lab, Francke launched into biochemical genetics to find an efficient way to identify women who were carriers of mutations in the HPRT1 gene. Because blood levels of the enzyme are normal in carriers, blood tests couldn’t identify them. Instead, doctors would take a skin biopsy and grow individual fibroblast clones. The system allowed them to measure enzyme activity, but it was a time-consuming process.

Francke had read that hair follicles are essentially clonal, giving her an idea for a new carrier assay. She developed a test in which she would pluck 30 hair roots from a potential carrier, and run the roots’ dissolved proteins through a gel along with a radioactively labeled substrate, hypoxanthine, to measure activity of the HPRT1 enzyme. The test allowed for more-extensive screening of family members and provided data on inheritance and mutation rates for X-linked conditions, about which researchers knew little at the time.

At UCSD, Francke also learned how to make somatic cell hybrids, combining cells from two different mammalian species, from her colleague Jerry Schneider, a pediatric rare-disease researcher. After fusing cells of an established mouse or hamster cell line to human fibroblasts, human chromosomes are randomly lost from the hybrid cells, allowing Francke to study the activity of individual chromosomes. Francke would look for abnormal human chromosomes with translocations and examine their gene expression. The analysis allowed her to map genes within a single chromosome.

Francke’s expertise in making such hybrids earned her funding from the National Institutes of Health (NIH) to set up her own lab at UCSD. Using the hybridization method, Francke’s lab homed in on a region of chromosome 6, finding that it encodes the major histocompatibility complex—“a bit of a breakthrough for the immunology field,” says Francke.

Improvements to ideograms

In 1978, Francke moved to Yale University, setting up her lab in the department of human genetics. She continued to map genes in both mice and humans and refined a painstaking technique that produces high-resolution chromosome diagrams. Her lab developed ideograms in which each chromosome is represented by its size, shape, and banding pattern.

A dark band resulting from the method’s staining represents dense, largely nonexpressed and repetitive regions called heterochromatin, and lighter bands are enriched for euchromatin, where genes are located. Analyzing chromosomal spreads for hours a day, Francke became an expert at identifying any slight changes to banding patterns representing subtle abnormalities associated with rare genetic disorders. “When you see human chromosome banding ideograms in papers, those are often my ideograms, but no one knows that because their origin doesn’t have to be referenced,” says Francke. A decade later, in 1994, Francke developed a set of digitized ideograms.

During her time at Yale, Francke worked on another X-linked rare disease, Duchenne muscular dystrophy (DMD), which affects mostly boys, causing progressive muscular degeneration and weakness. In 1983, Hans Dieter Ochs, a pediatric immunologist in Seattle, came across a particularly perplexing case of a male patient who was diagnosed with four X-linked disorders, including DMD. Ochs sought out Francke, considered to be among the best cytogeneticists, those who study chromosomes, in the U.S. at the time, for help.

Francke’s lab used high-resolution chromosome banding and what were then novel complementary DNA (cDNA) probes on somatic-cell hybrids made with patients’ cells to identify the deletion on the short arm of the X chromosome responsible for all four conditions. Harvard School of Medicine researcher Louis Kunkel had been trying to identify the gene responsible for DMD since the early 1980s, and Francke’s study provided the material that allowed Kunkel’s lab, in 1986, to clone the gene responsible for the disease.

A window into rare diseases

In 1989, Francke moved to the Stanford University School of Medicine and delved deeper into rare-disease studies. In 1992, a pediatric endocrinologist presented Francke with 20 female patients from Ecuador who had a growth hormone deficiency called Laron syndrome. It is an autosomal recessive disorder, but the girls had normal levels of human growth hormone. It turned out that the mutation was in the growth hormone receptor gene but did not change the amino acid sequence. Francke discovered that the mutation creates a new splice site that causes a deletion of part of the protein.

In 1994, using positional cloning to systematically identify smaller and smaller DNA segments that likely contain the gene of interest, Jonathan Derry, a postdoc in Francke’s lab, and Ochs identified the gene responsible for Wiskott-Aldrich syndrome, an X-linked immunodeficiency. The gene, called WASP, encodes a molecule important for regulating platelet and lymphocyte functions, and was the 11th human gene to be cloned using positional cloning.

In the years before and since, Francke worked on many other rare diseases, including Williams-Beuren syndrome, which, among other symptoms, manifests in a lack of stranger anxiety. Francke also studied the X-linked Rett syndrome, which affects only females. She and colleagues found that the disorder is caused by mutations within the MECP2 gene, which encodes a protein that binds methyl CpGs on DNA. The autism-like disease results, Francke and colleagues determined, when certain mutations in MECP2 affect the ability of its protein to silence certain genes in neurons.

Working retirement

Francke collaborated with her second husband, Heinz Furthmayr, a biochemist at Stanford, to find and characterize the effects of gene mutations responsible for Marfan syndrome, a disease that weakens connective tissue.

Furthmayr, whom Francke met in Colorado while skiing and married in 1986, shared her passion for flight. After 25 years of flying, the couple decided to sell their plane and committed themselves to exploring the world outside of the cockpit. Furthmayr retired in 2005 and Francke decided to close her lab in 2010. But two years later, Francke was still working part-time at Stanford and part-time at 23andMe, a direct-to-consumer genomics company. In May 2012, when Furthmayr was on trek in Nepal, a trip Francke had decided not to join, he collapsed on the trail and died of a heart attack.  

Francke now focuses on outpatient clinical genetics services and consulting for 23andMe. “I said from the beginning that people should have their genetic information if they want it, and I joined the company as a consultant to make sure that the information that is put out is accurate and up to date.” 

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