Dr Stephen Land and Gloria
I started out in laboratories in the UK, Canada and the US that followed an idea known as the “August Krogh Principle” which states that most medical problems have a naturally evolved solution that can be found in the natural world. For example, we studied how Amazonian fish tolerate the very low oxygen levels in the Amazon River through to freeze tolerance and hibernation in freshwater frogs and turtles. This work was (and still is) relevant to several areas of medicine such as the action of anesthetics, the preservation of organs for transplant, understanding why organs fail during heart-attack or stroke and how cancerous tumours grow despite little access to nutrients or oxygen.
Many of the same processes that enable survival of harsh conditions are, surprisingly, also at work during fetal development in the womb because low oxygen levels are a major and constant feature of this environment until birth. Low oxygen is particularly important when it comes to the growth of the fetal lung since it promotes the formation of the tubes which come together to make the network of respiratory airways and blood vessels. We noticed that if fetal lungs from mice were exposed to abnormally high oxygen concentrations, cysts would form along the length of the airway. This effect was reversed by returning the lungs to low oxygen suggesting that the cells of the airway can recover their proper organisation. A collaboration with Andrew Tee at Cardiff University, UK, introduced me to the striking similarities between our fetal lung cysts and those that form in the BHD lung and so we began a series of studies to investigate how folliculin might be involved in this process.
We’re researching the process of lung cyst formation in BHD and, since it’s neither safe nor practical to obtain cells from the lung directly, we’re using cells brushed from the back of the nose. It’s a little uncomfortable (makes your eyes water!) but because these cells are actually part of the airway system and can be grown in the lab, they give us several new exciting ways to study how folliculin mutations trigger cyst formation further down in the lung. Since we’re able to collect these brushings from different BHD patients, we can refine our studies to investigate how “real world” folliculin mutations affect lung cell biology rather than, say, crudely blocking folliculin expression or introducing engineered genes that mimic patient mutations. The cells can be grown either as flat sheets or as miniature tubes enabling us to address important questions, such as how they organise themselves to form the lining of the lung, how they protect the lung from pathogen attack (viruses, bacteria and airborne particles), how they keep the lung moist and regenerate themselves when they become too old to function normally.
Once we understand the answers to these questions, we aim to use these cells as a model for testing new drugs that prevent or reverse cyst formation in the BHD lung. We also believe that some of the cells obtained from nasal brushings have stem cell properties raising the possibility that gene repair technology could be used to fix the folliculin mutation before re-seeding these cells back into cystic regions of the lung. This might appear far-fetched but the technology already exists to repair DNA mutations inside these cells and several groups around the world are using this approach to develop similar treatments for other lung diseases such as Cystic Fibrosis.
Above all, financial investment, curiosity and free exchange of ideas between different groups since relevant equipment and techniques are only as good as the people that use them. I also believe that safe and effective cures for BHD crucially depend upon a solid understanding of the natural history of folliculin and its protein partners and so fundamental research into the biology of this gene/protein is just as important as applied research into the clinical aspects of BHD syndrome.
There is a long standing issue in biology that has its origins in ancient marine sponges that asks how cells “know” where they are, how they find one another and how they perceive top from bottom. If you crush a marine sponge through a sieve, for example, the cells that are loosened will find one another and then re-assemble as a new sponge. It’s the same if you cut your finger. Immune cells move to the wound to clear away infection before the cells at the edge of the cut grow towards one another to repair the wound. If this kind of orientated or “polarised” movement is disrupted, cells lose the ability to interact with one another and so cannot form proper tissue structures. Research presented by different groups at the 2012 BHD symposium in Cincinnati suggested that folliculin drives this process by associating with structures inside the cell that orientate the direction of growth and which hold neighbouring cells together. We have since collaborated with some of these groups to show that folliculin interacts with the same structures in cells of the human reproductive system raising the possibility that it may have an important role to play in controlling cell orientation right from the first moments of life.
Inside the BHD field: Although I wouldn’t like to single out any single publication, the research that has come from Japan on BHD lung cyst formation has established an important foundation for studies in this area and represents the point of departure for the work that we are doing now.
Outside the BHD Field: Robin, ED. The evolutionary advantages of being stupid. Perspect. Biol. Med. 16(3):369-80, 1973. Intelligence, in the end, may not be the solution to anything!
Short term: To develop the nasal brushing model to the point where we can use it to test drugs that prevent cyst formation in the BHD lung.
Long term: To develop an inhaler-like delivery system for drugs that target lung cyst development and pneumothorax in BHD syndrome. Also, to see if we can apply this method to deliver some of the new technologies for gene repair that are being developed in animal models at the moment.
It is becoming ever more clear that folliculin plays a fundamental role in the biology of cell behaviour and, as our understanding of this increases, I can see this field taking off in much the same way as cystic fibrosis research did in the 1980’s and ‘90’s. That is not to say that treatments for BHD will remain elusive. Far from it. Technologies that are now being developed to treat other conditions are ripe for translation into BHD and I very much hope that our patient-orientated nasal brushing model will be at the heart of this process.
Book: Wuthering Heights. How on Earth did Emily Brontë – a closeted nineteenth century Minister’s daughter – come up with such as disturbed vision of life? The book is relentlessly grim but brilliant.
Film: The Blues Brothers – “It’s 106 miles to Chicago, we got a full tank of gas, half a pack of cigarettes, it’s dark… and we’re wearing sunglasses. Hit it!”.
Music: Pink Floyd. My 13 year old daughter is, however, actively trying to re—educate me into the ways of Snoop-Dog and M&M.
I like Art too – The Tate Modern in London is always worth a visit if you’re prepared for your ideas about art/life to be challenged.
A Sea Captain like my Dad.
My hope is that, by then, I will have achieved something that has made a difference to someone.
My Dad used to say, “For when the one great scorer comes to write against your name, he writes, not whether you won or lost, but how you played the game”. I’m also mindful of the Harvard Professor that had the motto “Illegitimi non carborundum” above his door. I aspire to the first bit of advice and tend to live by the second!
I have two. D’Arcy Wentworth Thomson -19th Century biologist who was the first to describe how geometric shapes, like the spiral of a snail shell, the proportions of your face or the buttress-like hip-joint, are formed in nature. His famous book “On Growth and Form” was first published in 1915 and still endures nearly 100 years later as a classic work in the field of biology. Its influence extends well beyond science having inspired modern artists, designers and architects and I am sure he would have had an opinion on the processes that contribute to lung cyst formation in BHD.
My second hero is my late mentor, P.W. Hochachka, one of the most generous, enthusiastic and far-sighted scientists I have ever known. He showed me how to put the idea that “nothing is impossible” into practice.
BHD Personal Story: Gloria is from the USA and was diagnosed with BHD earlier this year.
I went to a Dermatologist in February 2012 because of the little whitish bumps on my chest, neck and jaw line. I’d had them for years but they were getting worse. It was pure vanity that made me go. I wasn’t worried about anything serious.
My Dermatologist did a biopsy of one and it came back as a fibrofolliculoma. She called a few days later and explained BHD to me and that I might have it. I later had a blood test at the genetics department, and a CT scan, which showed many lung blebs/cysts, and some very small benign-looking tumors on my kidneys.
I was very preoccupied with it and stressed out, ever since learning about BHD and that I might have it. I told one of my 2 sisters about it and we Googled it over and over. It was very strange to hear of something so bizarre and to imagine that I could really have this. We worried about our children and grandchildren.
Yes. Two sisters, a daughter and a son.
Confusion, stress, worry, guilt. So far one sister has tested negative and others are waiting to be tested. It was a huge relief to hear she is negative as she has 5 kids and 4 grandchildren who now don’t have to worry about it, since it does not skip a generation. We can only assume it came from my father. He always had “bumpy skin” and my mother’s was smooth and pretty. We have nothing else to go on. I wish we knew more. He died in 1995 at age 75; with heart issues and she died in 1999, at age 77, of a heart attack also. Neither had any known lung or kidney issues. My father had colon cancer when he was 60, which was found during an appendectomy. It was removed at that time and he had no problems or reoccurrences. My father had one brother who has also passed. I’m trying to find my cousins from his side, to ask if they have symptoms, but have not been able to locate them yet. I don’t recall my uncle having the same type of skin as my father.
The Internet. The genetics counsellor here at UVA also explained some things. My sister was given a thick folder of info from her medical clinic. They researched it upon her request.
Start with a Dermatologist. They seem to be aware of it and most other professionals do not. If you have no skin lesions, get a CT scan and/or a bloodtest from a genetics clinic.
There is an element of guilt even though I realize it is no more my fault than it was my father’s. It’s hard. My son and his wife want to start a family so naturally he has concerns and much the same feelings as I do. He has an appointment where he lives, for a genetics test.
Listen to patients and research it. Be aware of the initial signs of skin lesions, and any history of a collapsed lung.
Increased skin lesions. I fear ever having a collapsed lung but so far have not had any symptoms of that. A CT scan revealed a 9mm nodule in my right lower lobe, tucked inside of a bleb. I had it removed in June. It was cancer. Everyone is wondering if this was incidental or caused by BHD. I have an appointment at NCI/NIH in Bethesda MD in November because of it. My kidneys are not worrisome for now but need to be watched, as do my lungs of course.
No treatments, just semi-annual scans in my future.
My Family Nurse Practitioner referred me to the Dermatologist who sent me to the genetics dept at the UVA Medical Center. They referred me to a Pulmonologist here at UVA. My NP had never heard of it; I just wanted to know if the bumps on my face could be removed.
So far only the Dermatologist and Genetics Dept have ever heard of it. They have all shown an interest in it though.
Yes. I ended up going above and beyond my very high deductible and am sure I will be paying on medical bills the rest of my life. I’m on a payment plan with them, which helps. It is always on my mind. I am grateful to have insurance albeit not a great plan.
Try not to worry or let it consume my thoughts. BHD does not have to be life threatening. I know there are many worse things to have and I feel fortunate. My thoughts are mostly financial at this point.
Don’t panic. There is a lot of really good information out there. Join bhdsyndrome.org and stay connected. You aren’t alone. Have regular check ups and scans. Try to focus on helping others with more serious problems rather than dwelling on this; it helps keep things in perspective.