BHD Researcher Interview: Tim Cash

Tim is a PhD student at the Abramson Institute, University of Pennsylvania, USA, who recently presented his data at the Second BHD Symposium.

1. How did you get interested in BHD research?

I became interested in BHD about seven years ago while working on Tuberous Sclerosis Complex in Lisa Henske’s lab at Fox Chase Cancer Center. I came across BHD in the literature, was struck by the clinical similarities between the TSC and BHD and thought there must be a connection on the molecular level.

2. What are you currently working on?

I’m currently analyzing the effects of BHD on chromatin—specifically at Smad-depedent promoters. I’m also looking for a post-doc where I can pursue new avenues within the BHD field.

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

I think developing model organisms to study BHD would be of great help to the field, because they’re so amenable to genetic screens and unbiased experimentation.

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

I think the work being done on the crystal structure of BHD is the most fascinating thing going on, and will reveal alot about what Folliculin is doing in the cell!

5. Do you have a favourite research paper?

The Cancer Cell paper from Laura Schmidt’s group where they cloned the BHD gene, which started this research for us all.

6. What are your short/long term goals?

My short term goal is to find an academic postdoc which will allow me to continue work on BHD, preferably in a foreign country where I can learn a new language and culture. My long term goal is to figure out what Folliculin is doing in the cell—I hope this goal is not too long-term in nature.

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

I foresee BHD being placed firmly in a signal transduction pathway first. Then I see its direct biochemical function being elucidated. This will inevitably lead to targeted therapeutics for patients.

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

My favorite book is the classic novel, “The Grapes of Wrath” by John Steinbeck because it tells the story of ultimate human perseverance in the face of adversity. I love horror films, especially those from the 70’s and 80’s like “The Shining” and “The Exorcist.”

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

I wanted to be a physician, but realized later in life I was more interested in science.

10. Where do you see yourself in 10 years?

I see myself continuing to do cancer research, hopefully in the capacity of a Principal Investigator in 10 years.

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

I can’t remember where I saw this, but I once read that it’s more important to think about what experiment NOT to do, rather than what experiment to do. I think of this all the time and it helps keep me focused.

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

All the great scientists who have changed the way we think or understand science such as Darwin, Mendel, Watson and Crick.

BHD Personal Story – Ruth, UK.

1. When did you first get diagnosed?

A few weeks ago.

2. What symptoms prompted the BHD diagnosis?

I have had skin lesions since my early twenties to my face, upper body and waist. These have become increasingly worse. I was looking for a way to remove them so I studied the internet to first try and identify what they were. It was the BHDSyndrome. org website which I came across when searching for photographs of different lesions. It was bizarre, I realised immediately that the pictures looked exactly like my skin.

3. What impact did the diagnosis have on you?

I initially felt guilty because I was going to bring so much worry into the lives of my family. I also felt as if I had disappointed my husband (we are recent newlyweds). I felt like ‘faulty goods’.

4. Have you explained BHD to family members?

My family have all been told, as there has been no family history it must have been a shock for them. My mother volunteered to tell them and we made sure that everyone was told on the same day. I had prepared some bullet points to leave with them so that they could think things through rationally later on. We all agreed that there would be little mileage in telling my father due to his own deteriorating state of health. My mother is going to have the gene test to establish which family line it exists in.

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

My siblings (all boys) have been fantastic. Their immediate concerns were regarding my current state of health, they wanted to know that I was OK. All of my brothers have children and therefore they are concerned enough to all want to have the genetic test. I remain hopeful for them all, this is based on the fact that they do not have skin lesions and are all aged between 40 and 50 years of age.

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

As I mentioned previously, the BHD Syndrome website was absolutely great. It is the information from here that I printed off and took to my GP. When I knew that there was a problem, I used the same information to discuss and explain things to my mother.

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

Read the information on the website, take information to your GP to help them to understand your concerns. My GP was pleased that I had done the research.

8. Has it affected you as a parent? E.g. telling your children, starting a family, genetic counselling.

I do not have children.

9. Do you have tips and advice for caregivers?

None.

10. What are your current symptoms?

Multiple skin lesions. I am currently waiting for a detailed MRi scan. Prior to my diagnosis I had a “Lifescan”, this was because I had previously been a smoker and wanted to know that my heart and lungs were ok. The Lifescan showed up two cysts, one on my liver and one on my kidney. Obviously I am anxious to complete the MRi scan to ensure that these were just simple cysts.

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

None, but considering a medical skin peel to see if I can improve my skin for a while (still a bit vain at 45 years old)!

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

My GP was great, she admitted that she had not heard of BHD but was interested and referred me to Mr Bruce Gee a consultant dermatologist at Warwickshire Nuffield. When I met him I was relieved to find out that he knew all about BHD and arranged immediate biopsies. When fibrofolliculomas were confirmed he then referred me to Dr Lim at Birmingham Women’s Hospital. Dr Lim came to see me and carried out the genetics testing. He is an expert in this area and he explained everything I needed to know. He was genuinely interested in how I felt and has been available to talk to if needed.

13. Has BHD had any health insurance implications for you?

I already had insurance in place, so far so good.

14. What are your thoughts for the future?

Just to complete my MRI scan and get on with enjoying the rest of my life.

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

My advice would be to get regular checks and do not spend time worrying about what might happen in the future. Whatever age you live to, it would be awful to look back at your life and realise you wasted your time worrying about something that you could not have changed.

Biography: Eamonn graduated in Medicine from the University of Manchester and after undertaking postgraduate training, moved to a Clinical Lecturer (and then Lecturer) post in Medical Genetics at the University of Cambridge. He took up the Chair of Medical Genetics at the University of Birmingham in 1996. His research is aimed at understanding the genetic basis of inherited diseases, especially those associated with kidney cancer, in order to develop new approaches to diagnosis and treatment.

1. How did you get interested in BHD research?

When I moved to Cambridge I started a project on von Hippel-Lindau disease and this expanded to other forms of kidney cancer. We were collaborating with Dr Bert Zbar, Michael Lerman and Marston Linehan on VHL disease and about 10 years ago Bert mentioned that that he had found an association between kidney cancer and BHD syndrome, so it was a natural step to set up a collaboration on BHD syndrome also.  We maintained an interest in BHD and then more recently we were able to expand our research with funding from the Myrovlytis Trust.

2. What are you currently working on?

We are investigating how the function of the folliculin protein is disturbed in BHD disease, looking for new therapeutic approaches to the treatment of BHD-related kidney tumours and studying the relationship between the genetics and clinical complications of BHD syndrome.

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

A lot of resources have been developed recently and the BHD research community moving forward nicely. One bottleneck is the scarcity of material and cell lines from BHD tumours – it would be very helpful to have more to work on.

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

I think the increasing knowledge of the function of folliculin and the development of mouse models of BHD are exciting. In addition the development of the European BHD Consortium has enhanced collaboration across Europe and is allowing us to share knowledge on the genetics and clinical complications of BHD.

5. Do you have a favourite research paper?

It is difficult to choose just one but the gene identification paper (Nickerson et al Cancer Cell. 2002;2:157-64) provided the basis for all the later studies on the function of the folliculin protein and genetic studies of BHD.

6. What are your short/long term goals?

In the short term, we want to complete our investigations of folliculin interacting proteins and their related pathways and develop potential new drugs for BHD tumours. Our longer term goal is to see the results of the laboratory research translated into new treatments in the clinic.

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

I think we will make real progress in understanding the functions of folliculin, but there are likely to be multiple functions so the field could be very complex. Hopefully some targeted therapies based on our knowledge of the biology of BHD will be shown to be beneficial in a clinical setting.

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

Unfortunately I don’t have much time for leisure reading but I liked “The Glass Bead Game” and enjoy taking my children to the cinema (e.g. Avatar) or watching a DVD (e.g. Rocky) with them.

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

I always wanted to play football (soccer) for Everton – unfortunately I didn’t have the talent and a career in medical science has been a good alternative!

10. Where do you see yourself in 10 years?

Hopefully still learning through my research and seeing families in clinic.

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

Seize the day

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

Many but Professors Malcolm Ferguson-Smith and John Yates gave me the opportunity to build a career in medical genetics and I took a lot of inspiration from them.

BHD Personal Story – Wendy, Australia

Wendy is a registered member of www.BHDSyndrome.org and has kindly taken the time to share her experiences of living with BHD syndrome.

1.   When did you first get diagnosed?

In January 1996 I was diagnosed with Kidney Cancer, BHD diagnosis was many years later after I conducted my own research and requested our Genetic Services to investigate.

2.   What symptoms prompted the BHD diagnosis?

I didn’t have any symptoms except for bilateral kidney cancer, but during the course of my research I realised that I had the whitish bumps on my face and neck consistent with Fibrofolliculomas.  I asked a dermatologist to biopsy one of the bumps, and sure enough I was correct.

3.   What impact did the diagnosis have on you?

I was relieved in a way, to finally put a name to it.

4.   Have you explained BHD to family members?

Yes, my sister who has also had bilateral kidney cancer, a spontaneous lung collapse and fibrofolliculomas has been tested.  Our children and siblings are yet to be tested though.

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

My children will eventually be tested but until then have decided not to start families. They are both informed adults, so I can only give them the information and guidance.

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

No one here in Perth, Western Australia, has ever heard of BHD so my information is gathered from the internet.

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

Yes, read up on it as much as you can.  Regular Renal Ultrasounds and or CT scans are an absolute must.

8.   Has it affected you as a parent?  E.g. telling your children, starting a family, genetic counselling.

Yes, I feel awful that I have unknowingly possibly passed BHD on to my children.

9. What are your current symptoms?

I have been cancer-free for 11 years.  I have many fibrofolliculomas on my face and neck (they seem to increase as I get older.) I have recently had bowel polyps removed.

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

Radical left nephrectomy and partial right nephrectomy.  Colonoscopies and polyp removal.

11.  How did you find a doctor?

I only have a GP and an Urologist.  I haven’t come across a doctor in WA who has any knowledge of BHD.

12. Do you have advice for people living with the BHD?

Be vigilant but get on with the art of living.

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

No health professional has ever shown any interest in BHD, except for the Genetics people. They were very excited to find a new type of mutation.

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

No, not at the moment as I was insured before (and have continued to be) the diagnosis. I don’t know if it would be an issue if I applied for insurance now though.

15.  What are your thoughts for the future?

I hope and pray that I haven’t passed BHD onto my children.  I wanted to live long enough to see my children in to adulthood, now I would like to retire with my husband and be around long enough to enjoy some grandchildren.

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

I hope and pray that I haven’t passed BHD onto my children.  I wanted to live long enough to see my children in to adulthood, now I would like to retire with my husband and be around long enough to enjoy some grandchildren.

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

It’s not the end of the world, just a challenge. Advances in surgical technique now means kidney sparing is possible. Be vigilant and cross your bridges as you come to them, not before.

Biography: Maurice is a dermatologist at the Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, The Netherlands. Dr van Steensel works on congenital dermatological disorders.

1. How did you get interested in BHD research?

I have been interested in molecular genetics, in particular of the hereditary skin disorders, for a long time and am one of the few dermatologists in the world specializing in these disorders. So my department is a referral center for rare disorders and “funny” disorders. And my interest in BHD arose from a chance meeting with someone who had something “funny”. One day, back in 2006, a patient with small facial tumours came into my outpatient clinic to have something done about those annoying bumps. I took a good look and then a biopsy and so found out that my patient had fibrofolliculomas. I had never seen those before and became really curious – hair follicle tumors to the dermatologist are a sign of underlying disorders, often cancer syndromes, but fibrofolliculomas were not on my radar at the time. A little searching then made it quite obvious that he had to have Birt-Hogg-Dubé syndrome and sure enough further screening showed renal cysts. We next sequenced his FLCN gene and found a novel mutation. A bit of reading then quite quickly showed that very little was known about BHD and FLCN’s function and that was when I decided to invest extra time and effort and see whether we could have a stab at building a new research line – here was a promising new field! So we did some initial work to try and work out whether FLCN behaves like a typical tumour suppressor in skin, which we found it doesn’t. So that was pretty surprising and we did not really know where to go from there until I had a casual conversation with my colleague and friend Michel van Geel who is a molecular geneticist. While talking about the phenotype and then hit upon the close similarity between BHD and tuberous sclerosis. We then hit upon the idea that FLCN might be involved in mTOR and HIF signalling. I wrote a grant proposal around that idea and got funded so I could hire a PhD student. A second grant then brought in a post-doc for two years. These initial investments allowed us to build the infrastructure and get the preliminary data needed to go after larger funds which we got fairly recently when I was awarded a major grant from the Dutch Cancer Society to hire a post-doc and a PhD student and fund my own salary so I could spend more time on BHD. The Myrovlytis Trust meanwhile had agreed to fund a clinical researcher for two years to work out clinical management of BHD and conduct the first translational trial. So now we have a group of five people doing nothing but BHD! I’m a lucky man.

2. What are you currently working on?

We spent a lot of time getting up to speed – tooling up, building up our infrastructure and defining our goals for the next five years. Our research is now focused on pretty basic stuff – we have become quite interested in how FLCN responds to various inputs from the outside world and are looking at things like phosphorylation of FLCN after activation of (presumed) upstream inputs. We have started a close collaboration with Andrew Tee in Cardiff and together with his group we are looking at BHD tumorigenesis in a number of systems that we think are relevant to the patients. We also have someone who is working to create three-dimensional tissue culture systems in which to check cell growth of BHD mutant cells and there is a new PhD student who is examining epigenetic changes in hair follicle tumors, including fibrofolliculomas. On the clinical side the Myrovlytis Trust has funded a clinical researcher for us who is setting up a trial of topical rapamycin for fibrofolliculomas – we’re very excited about that. Together with our friends from Birmingham and Amsterdam she is also starting to explore other aspects of BHD, such as the behaviour and biology of metastasizing renal cancers that patients can develop, with a particular view to the type of treatment that patients with metastatic cancer might require. Finally, we act as a referral center for patients and provide FLCN mutation analysis as a free service to researchers and physicians. So, we’re pretty busy!

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

I think the consortium is pretty much on the right track – we have structural biology support and zebrafish models. Still needed are decent fruit fly models and people interested in/experienced with yeast because I think that some aspects of FLCN function may be more tractable in that organism. Rodent models are good but not for understanding the skin phenotype because they do not develop skin tumors. So I would like to have a rodent (mouse/rat) that does develop skin tumors, I have some thoughts about how to go about it but nothing really definitive yet. What’s also very important is to keep up the work on the clinical side- we have just started to define the research questions d have  a lot of work ahead of  us to improve patient care.  Finally, it would be good to have access to high-throughput gear for examining protein-protein interactions.

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

Top on my list is the recent elucidation of the crystal structure of FLCN’s C-terminus. That has given us a LOT of new ideas. Number two would be the Consortium’s first set of guidelines for clinical management, because these will help us to systematically study the clinical behaviour of BHD and to prospectively work out optimal patient management. The mouse data that have been published recently have also given me much to think about.

5. Do you have a favourite research paper?

Not a single one but a load of them. But if I do have to choose, my favourite BHD paper would be the 2007 paper by van Slegtenhorst et al looking at the S. Pombe ortholog of FLCN. It kind of contradicts much of the ideas that for a long time influenced much of the experimental work that was done in BHD and is now providing new inspiration for my group. My favourite biology paper of all time is the Watson& Crick paper – not for its contents per se but for the way it manages to condense a paradigm shift into a single page and end with a masterful understatement.

6. What are your short/long term goals?

My short-term goal is to get a clear sense of where to go with elucidating FLCN’s role in health and disease – there are conflicting insights at the moment. Working on that now. The long-term goal is to understand how FLCN mutations cause BHD and to be able to translate that insight into a drug-screening program and thence into the clinic. Even further down the road I want to understand why the skin tumours in BHD do not become malignant whereas the kidney tumours do. This is a mystery that contains a profound lesson about malignancy. To understand it, I think, will be to understand cancer.

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

We’ll probably make some real progress towards understanding BHD and be able to rationally look for/design medical interventions to prevent malignancies and to treat the outward manifestations. I’m also looking forward to some deep insights into the basics – how the network that FLCN is in functions to manage cell growth and proliferation. There’s some real biological subtlety there and I am going to thoroughly enjoy learning how it works. That, in turn, will help us to understand some other processes that are still mysterious – one being why people with BHD develop hair follicle tumours in their faces. Nobody knows or understands and that applies to related disorders such as tuberous sclerosis, too. There are profound lessons to be learnt and I think that we will learn some of them in the next ten years.

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

My favourite film is Paul Schrader’s Mishima and my fave book is the Ancestor’s tale, by Richard Dawkins. I am a musical omnivore so I find it difficult to give a definite favourite there, but if there has to be one it’s probably la Sonnerie de Sainte-Geneviève, a work by the French composer Marin Marais.

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

A geneticist, so I did not end up too far from my childhood dreams – I count myself lucky.

10. Where do you see yourself in 10 years?

Hopefully leading a couple of thriving research groups working on the absolute cutting edge of my favourite themes. Not sure whether it’s going to be in Maastricht, I’ve had some interesting offers lately. But, generally, doing much the same as I am doing now but on a larger scale and hopefully with a very strong sense of direction.

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

Don’t look back.

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

No real heroes but I do very much like Richard Dawkins for his rationality and passion for all there is to know and experience about life and the living.

BHD Personal Story – Karen, New Zealand

Karen is a registered member of www.BHDSyndrome.org and has kindly taken the time to share her experiences of living with BHD syndrome.

1.   When did you first get diagnosed?

I was diagnosed with BHDS about two years ago.

2.   What symptoms prompted the BHD diagnosis?

I had pneumothoracies on both lungs and a family history of spontaneous pneumothorax (SPs) so enrolled in Dr Christine Garcia’s study of Familial spontaneous pneumothorax. Although my test results could not be disclosed to me, it was recommended that I discuss the link between SPs and BHDS with my family doctor. He then referred me to a dermatologist who confirmed the BHD diagnosis

3.   What impact did the diagnosis have on you?

It was a shock initially, especially reading about the increased risk of renal cancer. On the positive side, it was actually good to know why my family were having lung collapses when so many of us did not fit the usual profile for pneumothorax at all.

4.   Have you explained BHD to family members?

Yes, I explained the BHD to my immediate family, I have done online research, so I also sent copies of the information to my family. Spreading the information hasn’t been easy, my mother’s siblings were told and some did not want to inform their children until their own diagnosis was confirmed. This meant some family members knew and some didn’t. It was very difficult to manage and caused some ill feelings at the time. With all seven of them receiving positive test results, this is no longer an issue.

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

The full implications to my family are still uncertain as we have not all been screened yet. Those of us who have been diagnosed are undergoing renal and lung scans. Most of us are concerned about how widespread the syndrome is within our family. Of the nine screened so far we have had no negative results.

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

I have obtained most of my information from the internet. BHD is not well known within the general medical profession in New Zealand, and I have often found myself taking the educator role when speaking with doctors. I now go to BHD appointments armed with fact sheets.

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

I think if you are concerned that you have BHD it is best to seek diagnosis as quickly as possible. Although not a lot can be done about preventing symptoms, it is reassuring to have regular screening, then any treatment can be undertaken quickly.

8.   Has it affected you as a parent?  E.g. telling your children, starting a family, genetic counselling.

I have children in their early twenties, they have not yet sought diagnosis. I do worry about how it will affect them if they have BHD, will they consider the options when starting a family, will they experience collapsed lungs, will my beautiful daughter end up with fibrofolliculomas. There is a degree of guilt attached to passing something like this on to your children, and that is difficult.

9.   Do you have tips and advice for caregivers?

Be open and honest with your children, don’t over dramatise the syndrome, and help them work towards informed choices for their own health.

10. What are your current symptoms?

I have fibrofolliculomas on my face and upper torso. I also have lung cysts.

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

I am not being treated currently. I have had pleurodesis and partial pleurectomies on both lungs.

12.  How did you find a doctor?

I do not have a doctor that looks after my BHD conditions, the general medical section of the local hospital has ensured that I have seen any specialist needed, and they are responsible for arranging regular renal screening for me.

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

One of the difficulties for me has been that in New Zealand the healthcare system is quite departmentalised with different specialists treating each aspect of the syndrome. But because BHD affects an unusual group of specialtities, renal, cardiothoracic and dermatology, there hasn’t been what I would see as a holistic approach to managing my health.

As I said earlier, BHD is not well known among healthcare professionals, however there is a greater awareness among younger professionals.

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

New Zealand has a public healthcare system, so I am able to get all the treatment I need free. However we can also top up our medical cover with private health insurance, this would no longer an option for me as my premiums would be loaded. The New Zealand public health system is renowned for having long waiting lists, but I have always had immediate treatment when I needed it.

15.   What are your thoughts for the future?

I am optimistic that my family will continue to have no incidence of renal tumours.

I am resigned to the fact that my face lumps will continue to get worse, but hopeful that in the future a way will be found to stop the symptoms of BHD.

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

It probably isn’t as bad as you think at first. Find out everything you can about BHD and take good care of your general health and well being.

BHD Researcher Interview: Dr Laura S. Schmidt

Biography: Dr. Schmidt obtained her Ph.D. degree in biochemistry from Vanderbilt University in Nashville. She held postdoctoral fellowships at Indiana University under Dr. Howard Guest, and at Boston College under Dr. Joseph Orlando. She was a Medical Foundation scholar at Tufts University Medical School in Boston in the laboratory of Dr. James T. Park. Dr. Schmidt was employed at the NCI as a member of the Laboratory of Immunobiology from 1990 to 2005, and recently joined the Urologic Oncology Branch, NCI, NIH. Her research is aimed at the identification of renal cancer susceptibility genes through the study of families with inherited renal cell carcinoma.

1. How did you get interested in BHD research?

For the past 20 years my research interests have been focused on the identification of genes that predispose individuals to the development of kidney tumors through the study of families in which kidney cancer is inherited. I have been part of the NCI team that discovered the VHL gene, which causes clear cell kidney cancer associated with the von Hippel Lindau disease, and identified mutations in the MET oncogene that predispose to papillary renal tumors in Hereditary Papillary Renal Carcinoma. In the late 1990’s we described 5 families with a rare inherited renal neoplasm, renal oncocytoma, for which the causative gene was unknown. When a careful dermatologic examination revealed fibrofolliculomas, the cutaneous hallmark lesion of Birt-Hogg-Dube´ syndrome, on the faces of some of these patients, we were able to make a clear connection between this rare dermatologic disorder and a risk for developing kidney neoplasms. We recruited additional BHD families with fibrofolliculomas and kidney tumors, which enabled us to localize the BHD locus by linkage to chromosome 17 and identify causative mutations in the FLCN gene.

2. What are you currently working on?

Now that the FLCN gene has been identified and the mutation spectrum well documented, our laboratory is focused on understanding the function of the encoded protein, folliculin, in normal cell pathways and how mutations in FLCN can lead to the development of kidney cancer in BHD patients. We have developed a number of mouse models of BHD as well as cell-based systems to help us in our research.

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

The discovery of a biomarker specifically linked to the types of kidney tumors that develop in BHD patients would be useful for diagnostic purposes and for the development of therapeutic treatments. When the function of the FLCN protein is elucidated, the development of a functional assay will be immensely helpful to our research.

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

Emerging data from several labs have supported an interaction of FLCN with the converging PI3K-AKT-mTOR and AMPK-TSC1/2-mTOR pathways that regulate cell growth through nutrient and energy sensing.  This is most significant because it links FLCN with other tumor suppressor genes that have been shown to regulate these pathways and which, when mutated, give rise to hamartoma “overgrowth” syndromes   like BHD syndrome. Our goal as researchers is to uncover and clarify the details of this most interesting connection.

5. Do you have a favourite research paper?

The two papers describing kidney-targeted FLCN inactivation in the mouse [Baba et al., (2008) J Natl Cancer Inst.100:140-54; Chen et al.,(2008) PLoS One. 3:e3581] have provided exciting in vivo models with which to elucidate FLCN function and for testing therapeutic drug treatments.

6. What are your short/long term goals?

In the short term, we are following up on data from protein-protein interaction studies and gene expression analyses that suggest novel pathways in which FLCN interaction may be important.  Our long-range goal is to develop therapeutic treatments for BHD-associated kidney cancer based upon the results of FLCN functional studies.

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

Ultimately BHD researchers are united in a common goal to develop therapeutic treatments for the cutaneous lesions and kidney tumors that develop in BHD patients.  Our concerted effort to elucidate FLCN function and to understand how loss of FLCN dysregulates the biochemical pathway(s) with which it interacts will provide the basis for targeted therapies to improve the prognosis and quality of life of BHD patients.

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

I love all musical theater, but I guess my favorite is “West Side Story”.

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

As long as I can remember, I loved science and wanted to be a “scientist”. I credit my father for fostering my interest in science by showing me as a young child how magnets work, pointing out the constellations in the night sky, and helping me find interesting creatures and plants along the trails we hiked together.

10. Where do you see yourself in 10 years?

I will probably continue the study of families with inherited kidney cancer syndromes at the NCI, but I also hope to do some traveling and look forward to playing with my grandchildren!

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

We are only here for a short time so try to make a positive contribution to the world every day, strive to keep your work life and your home life in a healthy balance, and don’t forget to stop and “smell the roses”!

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

Dr. Berton Zbar, lab chief of the Laboratory of Immunobiology at the NCI, was my mentor and scientific adviser for nearly 15 years until his retirement in 2004. My approach to scientific research has been greatly influenced by his advice and counsel. He has been my role model throughout my scientific career and I am indebted to him for the many valuable lessons learned under his scientific guidance.

BHD personal story: Mark, New Zealand

Mark is a registered user of www.BHDSyndrome.org and has previously contributed to the forum.

1. When did you first get diagnosed?

A surgeon first suggested I might have BHD in late-2006.  It took about 3 months to get an appointment with the genetics clinic, have some blood drawn, and then get the results back.

2. What symptoms prompted the BHD diagnosis?

I’d just been in for surgery to sort out a recurring pneumothorax.  My surgeon was puzzled by the family history of pneumothoraxes.  A few months later he had some down time and spent the day digging around looking for conditions that could explain that family history.  He suggested my family might have BHD.

3. What impact did the diagnosis have on you?

It was actually quite nice to have an explanation for my family’s long-standing problems with collapsed lungs.  We didn’t know too much about the other BHD symptoms at that stage.

4. Have you explained BHD to family members?

Yes.

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

Nearly all of that side of my family have now had the genetic testing and we’ve discovered several family members who have BHD but who haven’t (to date) had any manifestation of it.

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

All the usual sources … eMedicine, Wikipedia etc … and then more recently I discovered the bhdsyndrome site.

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

No special advice really … just that it’s better to know what your medical situation is rather than to be in the dark.

8. Has it affected you as a parent?  E.g. telling your children, starting a family, genetic counselling.

Not yet, because my children are 1 and 3 years old.  But it does make me watch them a little more closely to see if they get any skin bumps etc etc.

9. Do you have tips and advice for caregivers?

No.

10. What are your current symptoms?

None.  I’ve had operations on both my lungs now and I don’t imagine they can collapse again.  I have a CAT scan or an ultrasound on my kidney in alternate years, but I don’t seem to have any problems there so far.

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

No current treatment

12. Do you have advice for people living with the BHD?

Stay fit.  Both times I’ve had pneumothoraxes I’ve been very fit, and I believe it does make a big difference to how badly it affects you and how quickly you bounce back.

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

Very good

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

Not really.  I live in New Zealand and we have a public funded health system here.  I do have private health insurance too, but that’s really focused on just non-essential elective surgery.

15. What are your thoughts for the future?

Just to keep having regular annual checkups on my kidneys.

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

It seems that with good medical care then BHD isn’t anywhere near as serious as many other medical conditions.  Sure, it’s not great, but there are a lot of things that are worse.