Medical Mysteries and Rare Diseases: William Gahl at TEDxCMU 2011

imagine what it's like to be asked to find a cure for a fatal disease first you have to find the cause and then you have to fix it I'm gonna tell you today some stories about patients for whom that was true a cure for a human disease was obtained and about a couple of patients who at least have a chance for that and then I'm gonna tell you about a couple of kids who never had a chance I'm gonna tell you about what's possible and what's impossible and I'm gonna ask you to help me to change the impossible into the possible just as doc said this begins with a story that was really traditionally handled by medicine about cystinosis a rare disease in which the amino acid cysteine is stored within the compartments of cells so it can't get out because of a genetic defect consequently crystals form and those crystals destroy the tissue destroys the kidneys by 10 years of age destroys other organs of the body a fatal disease in the 50s and 60s you never wanted to make this diagnosis but there is a treatment for this and it's called sustaining a small molecule that promotes normal growth and the way it does this is by getting into those compartments of the cells called the lysosome and lowering the cysteine content there and then making the cells live and be fruitful so to speak the preserves the kidneys of these individuals and it prevents the non-real of complications which are often fatal it turns out that if you put these Sustainment into eyedrops it further more will dissolve those crystals and clarify the cornea and reduce the photophobia or pain in the eyes of these individuals you can see this here to the haziness has been clarified in a 20 year old with cystinosis as a consequence this disorder has turned around has been turned around by this treatment and this young fellow who's from Central Texas his name is Mason he's a good student takes his medicine plays baseball is expected to grow up to be a normal citizen of the United States contributing comes from a wonderful family and with any luck will turn out to be a cowboy now that's a case of the traditional handling of a disease in which genetics did not play a huge role and in fact it took decades to handle this but it turns out that Mason had a great advantage he had a diagnosis and there are tens of thousands of individuals around the country who do not have that advantage he don't have a diagnosis so the National Institutes of Health in Bethesda Maryland established an undiagnosed diseases program mmm and this program has added as its goal to try to find the diagnosis in patients who've long sought one and have been unable to have one and also to find out new diseases so that we can make new discoveries it turns out that there are over five thousand applicants to this and eighteen hundred individual charts that are this big and we've accepted over four hundred individuals and seen over three hundred of them and made fifty or sixty diagnosis of really rare diseases we have the advantage in this of having access to the experts at the NIH Clinical Center which is the largest Clinical Research Hospital in the world in addition we're able to use the Human Genome Project which annotates the 3.2 billion bases that we have and tells us where genes are and we have very modern genetic techniques so let me tell you something about some of these individuals there was a family of five and they're adults they have trouble walking it hurts them when they walk and it hurts them because they're not getting enough blood supply this is a normal knee and this is a knee of an individual in this family in addition to the bones this person has calcification of the arteries and that's what impedes the movement of blood down into the feet so we were able to use our sophisticated techniques in this case so it's called a million snip or single nucleotide polymorphism array to determine where along that entire 3.2 billion bases there's a region difference in these five siblings compared who are affected with this compared to their adult parents who are not affected and this was the only region it contained 92 genes and one of those genes was mutated we were able to find that and that gene encoded a protein which was an enzyme that produced a molecule called adenosine within the vascular cells and what this demonstrated to us was that adenosine is important for the prevention of calcification of those vessels in addition it allowed us to develop a treatment for these individuals which in this case involves bisphosphonates which you may remember if Sally Field has ever entered your home as boniva and this none of this would have happened without the undiagnosed disease programs in these diagnoses now here's another example a 52 year old woman who has this musculature that developed over the last four or five years she's weak though it it it doesn't feel good she has not only no strength but it's here at irritating and so we were able to do a muscle biopsy at the NIH she's part of the undiagnosed disease program and found that within the vessels of her muscle she has amyloid the accumulation of a protein we next did a bone marrow to determine what where the protein might be coming from and it turns out it was coming from plasma cells she had multiple myeloma which you may remember has just recently taken the life of Geraldine Ferraro and because of this diagnosis we were able to refer her to the Mayo Clinic where she had a stem cell bone-marrow transplant and she's now doing extremely well and she writes me every few months so let me read to you what she wrote me a few months ago today is buddy's birthday that's her husband I'm making his cake I can stand long enough and my arms are strong enough that I can this year after a while I'm going to run out to the mall and pick up a few more things I'm confident that no matter what the parking situation is I can walk in from the parking lot walk through the stores long enough to get some things and pay for them and walk back out and exercise and be strong enough to fix dinner enjoy the family while we celebrate this evening last night I held Ellie and Alanna my granddaughter's on my lap and read them a story I'm able to do those things words can't express how grateful I am we also have a five year old boy who has problems with his feet and with his thumbs genetically but he also has a bleeding problem when he bruises those bruises don't heal and so we used our sophisticated genetic techniques to determine that he has a problem with the formation of a certain modified sugar called Dermot and sulfate it's really a soulful transferase and what this means and it turns out that the dermaTend sulfate that he fails to make is important for this healing process and so we are now interested in trying to provide for him dermaTend sulfate well these are all examples of rare diseases just three of them but it turns out that there are over 6,000 rare diseases and these affect up to 25 million Americans they are defined by law as disorders that affect fewer than 200,000 each but together they affect a whole large number and it turns out that they're only a few hundred treatments for these rare disease treatments are difficult to come by why because it's not profitable for pharmaceutical companies and to invest in a disorder that involves only 20 people or 50 people or even 500 people so it falls upon the National Institutes of Health and upon physician investigators to pursue treatments for this and now I'm going to tell you something that you might find impossible to believe we have potential treatments that makes sense that have presumably very few side effects and yet we're not allowed to use them and why is that it turns out that the Food and Drug Administration ensures the safety of our foods and of our of the drugs that come to us and they do a wonderful job of this but there is one issue for rare diseases they apply the same criteria for the use of an investigational drug as they do for common diseases in fact the dictum of the Food and Drug Administration when investigational new drugs come before them is that people with rare diseases deserve the same protection as other human subjects now when you apply to the Food and Drug Administration to use an investigational drug it's called an IND investigational new drug application and the FDA requires that animal studies be done a lot of toxicity studies etc etc and this is very expensive so much so that the drug companies don't really pursue it now I would propose that instead one should use the paradigm of risk versus benefit especially since the risk of not treating some individuals with rare diseases is sometimes a certain death and this is an accepted ethical principle so let me tell you about some examples of how the system used to work when sustained mean remember that drug for cystinosis was approved in 1994 there were no animal studies required of it in other words the FDA used its discretion and look at his scores of individuals who are whose lives were saved by that and they're positively affected by that on the other hand here's Canavan disease this is a neurodegenerative disorder which the central nervous system does not function and that kids die in usually in the first three or four years of life and what I'm showing you here is an ERV and if you think of a nerve as a copper wire that's supposed to transmit impulses it has its elation on the outside and if you cut that in cross-section you'll see the insulation here and then the nerve in the center the insulation is made up of myelin and milan is made up of acetate and these individuals have a genetic defect and the inability the inability to produce acetate so they can't make myelin they have a lack of myelination and that's why they have neurological deficits so we wanted to give glycerol triacetate as a source of acetate and we had a little girl who was born in July of 2007 we thought we had a window of about 12 weeks or so to treat this little girl we got the glyceryl triacetate from a company called Cognos the donated a 50 gallon drum we got the nurses ready for this we submitted an investigational new drug exemption to the FDA and we got institutional review board approval for this protocol and in the end the FDA wrote to us you need to conduct the following chronic toxicity studies and provide full reports for our review and evaluation six-month oral toxicity study in a rodent species nine-month oral toxicity study and anon rodent species these studies should be conducted in neonatal animals to match the age groups of the patients to be enrolled in the proposed clinical study and there were three pages of other requirements we could request a single patient exemption but at one-tenth of the dose previously used in humans we didn't have those data so we told the mother and she thanked us for our attempt and the disease took its course now let me tell you about a piper Piper has Lai's encephalopathy another neurodegenerative disorder due to many different genetic defects pyruvate dehydrogenase deficiency pyruvate carboxylase deficiency cytochrome C oxidase deficiency etcetera there was a protocol to treat individuals with Lai's encephalopathy with a particular drug made by edison pharmaceuticals but that protocol required that there be a genetic cause known for anyone who had Lai's encephalopathy and wanted to use the drug in this case piper didn't have that and but there was a physician named dr. Greg Ann's in Stanford who submitted an emergency IND to the FDA and in addition the drug company asked for a special exemption for piper the result was in the words of Piper's mom there were no exceptions and we just had to watch her die so at the memorial service which was two weeks ago today the mom sent an invitation and at in the invitation she wrote God saw you getting tired when the cure was not to be so he put his arms around you and he whispered come to me so keep your arms around her Lord and give her special care make up for all the moments when life seems so unfair so many times I needed you so many times I cried if love could have saved you you would have never died well what's the solution to this it turns out that the Food and Drug Administration has the opportunity to use discretion in these regards they actually did so recently with respect to the drug Makena or whatever it was for premature pregnancy they have that capacity we we need for them to use it and we need to for the Food and Drug Administration regulators to look at this as a risk to benefit ratio which again is an ethical principle that we've all adhere to for the last like 50 years or so and the risk for these individuals is sometimes certain death you know people in the rare disease community want to be protected but they don't want to be protected to death and who can address this well it turns out that there are officials within the government that are addressing this issue in particular the NIH FDA Leadership Council with dr. Francis Collins and dr. Peggy Hamburg know that this is an issue and are addressing it the Society for inherited metabolic disorders is the group of experts in rare diseases who care for these patients and they have offered expertise to the Food and Drug Administration over these particular investigational new drug applications the health resources and services administration is going to have a hearing on this in May and there's a URL here to which you can really address your comments and finally I would ask all of you and why do I ask all of you because all of you are really affected by this every one of you must have a friend or an acquaintance or a family member who has a rare disease when the Bell Tolls for Piper it tolls for all of us so so I would ask you today to do some certain things one if you can write your newspapers over this another if you are in health care policy consider pursuing this as a project you can submit your comments to the hersa website but most of all help us with this I don't have the answer but you're all smart people you might have answers I'd ask you to offer your suggestions so that so that when you're asked the question what would you do if you are asked to find a cure for a fatal disease just think about the patients that I've mentioned today thank you you


  1. The comment about what pipers mom said broke my heart. No mother should ever watch their daughter, because they could get treatment ๐Ÿ˜ข๐Ÿ˜ญ

  2. Exceptional medical science Challenges exceptional patients cases/ emergency operations and emergency medications Instant resolving Many rare cases Methods at institute of medicos open Google doc Rajendra sheregar See videos images discriptions Medical science institute

  3. Primary Scerlosing Cholangitis will be my personal murder weapon and indifference to the disease my murderer. When I was told that I had this, on top of the Crohn's disease and Fibromyalgia which gives me PTSD episodes and depression with suicidal ideation… I was calm. I asked the transplant surgeon, my GI, my pain specialist, & my primary physician for their honest opinion about my chances of simply getting on the UNOS list when I need it… and after MUCH hemming and hawing with plenty of blah blah thrown in; the opinions were not a chance in hell.

    I have a teenage suicide attempt, a psychiatric ward stay about a year after my mom died during a PTSD depression, I'm on Suboxone and its been a long term thing for the Crohn's and Fibromyalgia pain, etc.

  4. I just canโ€™t understand why there is a problem with trying anything when the alternative is certain death. It makes no sense. They will let these people die without trying and yet, assisted suicide is forbidden when you are painfully dying. Why let children and babies die who are begging for life and force painfully dying patients to live. America is great. HOWEVER, when it comes to social issues, America is way, way, way behind. Americans do not like change and are extremely scared of anything new. Why? Why is this? Even when we see positive factual results in a different country we still we stick to the failing old ways. One thing we can do is clear the senate and house of reps of almost everyone over 35 yrs old. Mid to late twenties would be great. They have the latest education, new ideas, sharper minds, fearless, and will change the country for the good. If something doesnโ€™t work they will come up with a different plan. They have a vested interest in our country so they arenโ€™t going to mess it up and they arenโ€™t too young. I am 49.

  5. I was fortunate to be accepted into the National Institute of Health Undiagnosed Diseases Program. I was also fortunate to be featured on 60 minutes with Dr. Gaul. Dr. Gaul I would like to tell you that I am paralyzed from the neck down now. Upon returning from NIH I had to hire a lawyer to stay in my home. Department of Social and Health Services would only offer me 10 hours a day for caregiving. I won the case and I now received 17 hours per day. In 2013 I was dropped on my head by an untrained caregiver. It took me 5 months just to receive a case manager. I work from home so I received Medicare and Medicaid benefits. I was shocked to know DSHS would not give me total care of 17 hours per day. I would not be speaking with you today if I remained in a nursing facility. I am leading up to a very important point. I have Trained 200 caregiver's. Because of my best rehab experience with the University of Washington I had to train brand-new people with no training. This is against the law. I was shocked to know this and I have been a advocate for vulnerable adults ever since. I have worked with people with no training straight from Taco Bell or homelessness or drug addiction and immigrants Which I have to teach English Comprehension at the same time as rehab therapy. I trained today and I am exhausted. I had help for a few hours only. The topic of discussion is how is my life going to end living with a terrible disease that causes paralysis/blindness/spasticity/lung problems/brain and spinal cord injuries. People are living longer and in about 10 years they talk about the silver synonymy that will be hitting Aging People suffering from neurological diseasesbaby boomers. I want to die in my home just like most people. I do not believe in human suffering. I have been told by the manager of rehab therapy at the University of Washington I should go on Ted talks. They have modified my wheelchair so I can drive with my chin. I am getting tired Dr. Gaul. I will not survive in a nursing home at this point. Anyway you look at it it is going to be a horrible death. I am scared. I am thinking about voluntary stopping eating and drinking. Social workers have told me that this is the only legal way for me to end my life. I cannot do a end-of-life because I cannot pick up a cocktail. People suffering from neurological diseases will never get 6 months or less to live. All stammers patients as well. I do not want to be a hypocrite. I have seen my boyfriend die from stopping life support. It took 5 days. I have never seen somebody so scared in my life. They treat animals better than Michi people. People are going to see nursing homes screaming and crying because they cannot receive the care. Even if the caregiver's wanted to they have no time to many rooms. Someday this will come to light. I have had conversations with CBS. Lara Logan still keeps in touch with me. Unfortunately the medical correspondent could not direct this vast problem. 60 minutes me immensely do a follow-up on me. I keep trying. I am tired. I was blessed to go to NIH and I was blessed to be on 60 minutes and I was blessed with so many people helping me. I feel there is a purpose for my life my voice. Christine Davidson

  6. The risk versus benefit should be taken into consideration more seriously in cases such as the ones Dr. Gahl described. I find it very hard to fathom the number of people that are dying because their potential cure must go through a long list of trials that can take much longer than they are expected to live. If we want to find cures for rare diseases why take so long for the medication to be used? I believe that if someone has a rare disease and they have exhausted all other options then they have nothing to loose by trying the medication. The risk of something happening wouldn't be as substantial especially if they are expected to die anyhow. It could potentially be a benefit to that person if the drug works for them. You have to remember these cases are rare, so when someone is on their death bed with one of these rare disease we should jump on that opportunity to try and find a cure and possibly even save their life.

  7. The lady who had Multiple Myeloma should have been diagnosed by local specialists. The fact that she made it all the way to NIH before it was found is just an example of how shitty many doctors' diagnostic skills are.

  8. Eating healthy is not going to stop genetic mutations. Though it certainly won't hurt, and may help in some cases, these diseases are still going to happen even if people eat the right foods. So no, what people eat will not stop these diseases. Only science can stop them by what this guy said. Find the cause, which then helps lead to a treatment, and probably even a cure.

  9. This man is a Godsend! His abilities are long overdue to say the very least. As a person who suffers from a medical mystery, I can appreciate this fully. I am beyond frustrated with this illness and all that it has stolen from me.

  10. @ludlloy Tell me, how a "raw food" diet will help to cure diseases like Tay-Sachs or Erdheim-Chester. A lot of what Dr. Gahl deals with is purely genetic– your lifestyle has almost no bearing on why you have the disease. So calling us scientists and physicians "stupid" is quite offending and I'd love to see a scientific study (which of course, is carried out by us stupid people) where your claims are sanctioned.

  11. @ludlloy well, I do see your point about a good diet and maybe all these anti-bio-tics, additives and hormones in our foods,etc. is what is making us sick. I was talking about illnesses that are not diet-related like a heart condition such as aortic stenosis, where the aorta is narrow by nature; however so much of the health problems in the world could be helped by a much better diet; like we need any more greasy double fried chicken wings and 8-topping pizzas! Sorry if I sounded mean!

  12. @ludmilalloyd Yes, I do agree that prevention is important when a disease can be prevented by a good diet, exercise and avoided substances like alcohol and drugs; however, would you say that a person with William's Syndrome is stupid to look for help for her heart problems, calcium problems, and other issues? Medicine is a gift from God and people like you just blame the victim for their illness and spread lies about doctors. I would not be alive if not for the medical profession!

  13. Full support for such an initiative. I havea rare disease, and only people like me can relate to this problem. Good luck to Dr Gahl and his team. I got to know of his NIH group through a recent Scientific American article. This is as close you get to a real-life 'Dr House' setting.

  14. Those of us with Hermansky-Pudlak Syndrome know Dr. Gahl well. He's such a brilliant and caring physician. We love him. As people with an ultra rare disorder, we hope and pray that some of these issues are solved. We pray and cheer for our researchers daily. When they make a breakthrough, it would be such a tragedy to have it tied up in red tape while we pass away from our disease.

Leave a Reply

(*) Required, Your email will not be published