December 2014

Brian Iritani and Geneva

BHD Researcher Interview: Brian Iritani is Professor of Comparative Medicine at the University of Washington. Professor Iritani and his team research how immune cells and tumours develop. His team have found that FNIP1 deletion leads to defective B cell and iNKT cell development.

1. How did you get interested in BHD research?

I became interested in BHD research through a “round-about” way.  My laboratory was interested in identifying novel molecules involved in the development and function of immune cells.  In collaboration  with the McLaughlin Research Institute and Celltech R & D, we treated mice with the chemical mutagen ENU and screened for mutations which resulted in altered immune cell composition in peripheral blood samples.  We identified a 32-bp deletion in a putative gene which resulted in the absence of B cells.  This putative gene was subsequently cloned by Baba, Schmidt, and Zbar et al., as encoding a protein which interacts with Folliculin in kidney cells, and was named Folliculin Interacting Protein-1 (Fnip1).

2. What are you currently working on?

We are focusing our efforts on understanding how Fnip1 regulates B and T lymphocyte development, activation, and transformation.  We had previously shown that loss of Fnip1 results in a block in B cell development at the pre-B cell stage, due in part to increased apoptosis associated with the impaired ability to maintain metabolic balance during stress (lymphocyte activation, nutrient deprivation).  We also found that loss of Fnip1 inhibited B cell cancer formation induced by the Myc oncogene and recently published research showing that Fnip1 is important for the development of invariant Natural Killer T (iNKT) cells.   We are continuing these studies to understand the signaling pathways that are regulated by Fnip1 and whether the Fnip/Folliculin complex is important for survival of certain types of cancer cells.

3. What would help current research (equipment, technique etc.)?

Because Folliculin and Fnip1 appear to act as signaling adaptors in pathways involved in cell metabolism, having more efficient and less costly systems for assessing cell signaling and metabolism (proteomes, phosphoproteomes, and metabolomes) in small numbers of cells would be very helpful. Also, systems for inducibly activating the Folliculin/Fnip pathway in primary cells would be very useful.

4. What recent developments in the field have interested you most?

The two studies by the Ferguson and Sabatini labs showing how Folliculin regulates mTOR recruitment to the lysosomes are quite interesting. I am intrigued by the idea that the Folliculin/Fnip complex regulates recruitment of signaling molecules to intracellular sites of activation or repression.

5. Do you have a favourite research paper?

There are many wonderful research manuscripts.  Some of my favorites include the classic cellular immunology experiments in mice by Zinkernagal and Doherty which demonstrated MHC restriction of T lymphocytes, and studies by Bevan and Fink describing how T cells are selected to recognize self MHC during T cell development.  In the BHD field, the manuscript by Baba et al describing the cloning of Fnip1 and its interactions with Folliculin and AMPK is a landmark study.

6. What are your short/long-term goals?

I would like to make headway in understanding how Folliculin/Fnip complex normally controls immune cell survival, function, and transformation.  Over the long-term, I see myself focusing the latter part of my career on disease-directed questions.  For example, focusing on the basic aspects of developing therapies for BHD or perhaps selected cancers.

7. How do you see the field developing in the next ten years?

Honestly, I think scientists have made great progress on understanding BHD and Folliculin. I really like the utilization of unique scientific approaches using different systems such as mice, flies, and worms to understand how Folliculin functions. I suspect that either new or combinations of known therapies (such as drugs targeting mTOR) will have a big impact in the BHD field.

8. What’s your favourite book/film/music?

Tough question- I have many favorites. A couple of my favorite classic books are “Old man and the sea” and “A river runs through it”-great literature on subjects I love.

9. What did you want to be when you were younger?

My hobby as a child was collecting insects. I was also fascinated with marine biology and thought I would study sea-life as an adult.  I still prefer living near the ocean and one of my favorite pasttimes outside work is fishing with my children.

10. Where do you see yourself in ten years?

I am still trying to figure out what I want to be when I grow up.

11. What’s the best advice you’ve been given?

“Hard work beats talent when talent does not work very hard”.

12. Do you have a scientific hero, dead or alive?

I liked Linus Pauling when I was in college (even the Vitamin C bit).   As a molecular immunologist and cancer biologist, I have always been a fan of Fred Alt.


BHD Personal Story: Geneva is from the USA and was diagnosed with BHD in 2013.

1. When and how did you first get diagnosed?

The first collapse occurred in 1992;  3 months after giving birth and 6 weeks after a flight to Boston.   I had a bleb stapling and doxycycline pleurodesis on my left lung.  In 2005, my right lung collapsed for the first time; I had a mechanical pleurodesis and my surgeon said that I probably had something wrong with my collagen.

Several months after that surgery, I was having some shortness of breath and it was suggested by a pulmonologist that I see a cardiologist to rule out Marfans, though I didn’t have the  real obvious Marfan’s signs.  In 2006 I saw a cardiologist and they didn’t find any aortic enlargement.  So the search for a cause stopped there for a while.

Then in 2008 my right lung collapsed for a second  time and I had a bleb resection and doxycycline peurodesis.  In 2013, my right lung collapsed for the third time. Before I had surgery, I went to a pulmonologist and he mentioned BHD as a possibility and suggested that I should go to a hospital on the East Coast to get evaluated.

When I researched BHD, I knew that’s what I probably had  because it was the only explanation that fit my particular symptoms .  Later,  I had the good fortune to come across someone who was able to give me the name of the only doctor in my city that evaluated adults for genetic diseases.  I went to the genetic doctor and had a blood sample drawn, several weeks later I was diagnosed as having BHD and given additional counseling.

2. What symptoms prompted the BHD diagnosis?

Multiple lung collapses.  History of  congenital blebs on both lungs.  I don’t have the fibrofolliculomas nor the kidney tumors.

3. What impact did the diagnosis have on you?

It came as a relief because I knew something other than my 15 year history of smoking was causing my lung collapses.

4. Have you explained BHD to family members?

My father and my sister both have numerous white skin bumps that look suspiciously like fibrofolliculomas.  I explained BHD in depth to my sister who wants to be tested when she gets the money for the genetic test.  My brother has decided not to get tested at this time.   I haven’t explained it to my parents as they are quite elderly (father is 93 years old).

5. What implications do you think it has had on your family?

Numerous stays in the hospital for long periods of time.  Loss of income.   Emotional stress for my husband caring for me in a hospital in another city.  More work for my husband doing housework that I can’t do because of limited use  of my right arm and side after my third surgery on the right lung.

6. Where did you go for more information on BHD syndrome?

Internet and BHD Foundation website.

7. Do you have advice for people who are looking for a diagnosis?

Locate a genetics doctor who sees adult patients and get the blood test.

8. If you have children, has BHD affected you as a parent? E.g. telling your children, starting a family, genetic counselling.

My son was an adult when I was diagnosed and he decided to have the test, fortunately he is negative and has been told he cannot pass it on.

9. Do you have tips and advice for caregivers?

Don’t assume that our  collapses will re-expand on their own, mine never have.  Don’t do a spirometry test with a  partially collapsed lung as it caused my right lung to go from 25% to 50%  within 48hrs.  Don’t take chest tubes off suction less than 4 days post op pleurodesis.  With the  first surgery on my right lung they discontinued suction on the 3rd day and my lung  re-collapsed in the hospital with the chest tube still in place  so they re-started suction and I had to stay in the hospital a lot longer.  I have to wonder if that event caused the further difficulty that my right lung has had in staying stuck against the chest wall (more scarred tissue that doesn’t adhere).  Recognize that the protocol for treating BHD lung collapses is different than other spontaneous lung collapses .

10. What are your current symptoms?

The third surgery on my right lung involved a partial pleurectomy, mechanical pleurodesis and two large chest tubes. Later they had to insert a small chest tube anteriorly to resolve an air leak.  Only with this last surgery have I had chronic pain on my right side.  My pulmonologist says that I have some restrictive breathing because of the scar tissue.  I do get short of breath when I’m in pain.  The only way I can get out of pain is to lie down.  Apparently this shortens the volume my lung has to stretch.  I can’t lie on my right side for long without pain or discomfort.  I can’t thump up and down like on a horse or motorbike.  Walking on hard surfaces is difficult.  Housework and yard work is limited: can’t rake, mow, vacuum, etc. I can’t stand up for long periods of time.  I’ve had to adjust my life to my abilities, but I do make a little progress as time goes on.

11. What treatment are you having, and have you had?

Other than the surgeries, I’ve had physical therapy.  First time I tried in it in January  they overworked my right arm and side and that set me back pain-wise.  In July I saw a PhD physical therapist and was able to get some  stretching exercises that have really improved my quality of life.  I do a series of stretches and light exercises that allow me a decent range of motion on my right side. Also I am advised to get an MRI of my kidneys every three years to check for tumors.

12. How did you find a doctor?

The first surgeon I had I was referred by my primary care MD.  The next surgeon was on call when my collapse occurred.  After my third lung surgery, I went to Houston and asked a nurse on a hospital floor who she thought was a good Cardiothoracic surgeon and got two referrals.

A year later, when my fourth collapse occurred, I was instructed by my pulmonolgist to go to an academic hospital in Houston to receive treatment as there was no surgeon experienced in doing multiple lung collapses in Austin and my previous surgeon had encouraged me to treat my lung collapse as a chronic conditon.  I went to an academic hospital ER in Houston with a 50% collapsed lung, told the ER doctor not  to insert a chest tube and to please contact one of the two cardiothoracic surgeons I had been referred to, he sent in a resident cardiothoracic surgeon who knew both my referrals.

The resident located both surgeons in the hospital, talked with them about my case, and came back with the one who happened to do more lung surgeries and he fit me into his schedule the following Thursday. Considering what he had to work with and the complications that were overcome, this surgeon did an excellent job.

After I got back to Austin I spoke with  someone who had a different genetic disease and she told me about her genetics doctor.  I called and made an appointment with the genetics  doctor and was diagnosed in April 2013. Most recently I found a  pulmonologist PhD doctor at the LAM center in Houston, so if I have any further issues I can call on him.

13. What has been your experience of the healthcare system and healthcare professionals?

The cardiothoracic surgeons who perform the lung surgeries generally have no knowledge of BHD and that puts those of us with the disease at a disadvantage in that the protocol for our lung collapses is different than those with other spontanous pneumothoraces.  Also when I was in the hospital in Houston with my fourth collapse I kept asking the pulmonologists who rounded on me to further explore a possible genetic cause for my collapses but no one ever did which was disappointing.

14. Has BHD has any health insurance implications for you?

I receive insurance through my husband so I’m fortunate but the medical care costs of a $80,000 surgery (I’ve had four) and long hospital stays add up to a few thousand dollars out of pocket.

15. What are your thoughts for the future?

I’d like to see more people being counseled to get the genetic test who have frequent lung collapses.

16. What advice would you give to someone who has just been diagnosed with BHD?

Read all you can especially about your particular BHD manifestation.  If you have blebs and especially if you have had a collapsed lung, find the best doctor for doing surgery on LAM patients preferably one in a large metropolitan area.  Also find a Cardiovascular surgeon that operates on a lot of lungs not just hearts.  Locating the LAM centers (look at the BHD site) could put you in touch with one. If you have blebs and especially if you have had surgery don’t valsava manuver: ie hold your breath and bear down, don’t blow up balloons, no weight lifting or pressure masks. For those with multiple surgeries,  stay off long flights and unpressurized cabins, and if multiple surgeries, then avoid air travel all together if your surgeon suggests it . Watch high altitudes, don’t dive below the water surface more than a few feet.  Don’t lift more than 10 lbs.