Please describe the research questions of your lab.

The Nichols lab is primarily interested in the genetics of pulmonary hypertension with a secondary interest in the genetics of Parkinson disease. Specifically, we are investigating factors that contribute to the genetic susceptibility to Pulmonary Arterial Hypertension (PAH). Dr. Nichols guided his lab to playing an instrumental role in identifying the first gene (BMPR2) associated with the disorder. Since then, studies have been ongoing to search for other genes responsible for PAH pathogenesis and also modifier genes that could affect the severity or onset of PAH.

In the Nichols Lab, our studies on the genetics of PAH make use of human samples as well as mouse/rat models of pulmonary hypertension:

• The National Biological Sample and Data Repository for PAH (PAH Biobank): The PAH Biobank is an NIH/NHLBI funded effort to bank biological samples, genetic data, and clinical data for over 3,000 WHO Group 1 PAH patients. This collection is a resource to be utilized by the research community to further discoveries and breakthroughs on both the cause and possible treatment of PAH. Currently, 39 enrolling centers across the US and Canada provide the patient samples and clinical data. Genetic data generated using the patient DNAs includes SNP genotyping for ~5 million markers and coding sequence for 12 different genes. Over 2600 patients have been enrolled to date.
• Genetic Analysis of Murine Chronic Hypoxia-Induced Pulmonary Hypertension:  This project utilizes a three tiered approach to search for new genes responsible for PAH and also genes that can modify PAH severity in mice
• Development of Rat Genetic Models of PAH:  Using CRISPR/CAS technology, several different rat lines carrying different BMPR2 mutations have been generated.  These lines are currently being analyzed for development of PAH and offer the potential of a more robust small animal model of the disease.

What genetics/genomics techniques do you utilize in your lab?

We utilize many genetics/genomics techniques in the lab including Sanger sequencing, Next Gen Sequencing, High throughput SNP genotyping using Illumina HumanOmni5 beadchips, analysis of Next Gen Sequencing data using NextGENe software, CRISPR/CAS, QTL mapping, gene dosage by MLPA

Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?

One of the key techniques utilized in the lab is the Next Gen Sequencing.  We are currently utilizing this to interrogate the coding regions of 12 different genes suspected to play a role in PAH.  The amount of time needed as well as cost compared to Sanger sequencing all of these genes is significantly less and allows the generation of large amounts of data in a very quick fashion. 

At what point in your life did you decide you wanted to be a scientist/physician?

I knew sometime in high school, maybe as early as freshman year that I wanted to be a scientist.

In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?

While I am likely biased, the discovery of mutations in BMPR2 as the most common genetic risk factor for PAH is one of the most important discoveries in the field of respiratory disease.  Certainly, the cloning of the CFTR gene for cystic fibrosis is also one of the most important discoveries that was dependent on genomic techniques. The novel techniques used in the discovery of the CFTR gene by Dr. Francis Collins revolutionized the genetics field and lead to the discovery of hundreds of disease genes.

Please describe your favorite publication involving genomics/omics that you were involved with.

My favorite publication involving genetics in which I played a major role is “Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII” (Cell 83:61-70, 1998). As the title suggests, this paper describes our efforts to identify the gene causing combined factors V and VIII deficiency.  This is the first disease gene I played a role in identifying.  It was also my first foray into the field of “positional cloning” i.e. cloning a disease gene based solely on its position in the genome.  We had mapped the gene to the long arm of chromosome 18 using a technique known as homozygosity mapping.  This is used in families in which the affected individuals arose via consanguineous relationships, usually first cousin.  When I was doing this, there was no human genome sequence.  There was a physical map of the human genome and very little sequence data.  We first had to build a physical map of bacterial artificial chromosomes across the region and identify any potential genes/transcripts in the region.  After completing the BAC map, there was only one full length cDNA already known to map to our region: the gene for ERGIC-53, an ER transport protein.  We had identified 2 different haplotypes segregating among our families we had used for the mapping: one in the Ashkenazi Jewish families and a different in the Middle Eastern/Sephardic Jewish families.  I bet my boss we would find two different mutations, a different one for each of the two haplotypes.  He disagreed.  We had to determine the intron/exon boundaries of the ERGIC-53 gene to enable sequencing of the individual exons.   Much to my delight, we did indeed find two different mutations that segregated perfectly in the two different haplotypes.  To this day, this remains likely my most gratifying scientific discovery.  Playing an instrumental role in discovery of mutations in the BMPR2 gene in PAH was also extremely gratifying and I continue working on genetics of PAH to this day.

What is your favorite aspect of ATS?

Clearly the collaborations is my favorite aspect of ATS.  While I communicate quite often via E-mail with my collaborators, the opportunity to meet with them at ATS is invaluable.  This is the only opportunity to meet with many of them either via private meetings or at the PC Assembly meeting.  Many of the collaborators are the clinicians who recruit patients for my studies so these face to face interactions are extremely important especially or a Ph.D. like me.

How could your research assist scientists and clinicians in other assemblies at ATS?

Certainly our PAH Biobank is an extremely useful resource to the PAH research community to provide biological samples, clinical data, and genetic data on one of the world’s largest cohorts of PAH patients.  The resource is unique in that it was built for use by the research community, not just for use in my research. The rat genetic models we are developing will hopefully be very useful to the research community as well.

Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?

I am always open to collaborations with GG and/or non-GG scientists and clinicians. I do not currently have any funded, open positions but happy to explore that with anyone.

William Nichols (Bill.Nichols@cchmc.org)