Twin disorders

Twin Disorders What can two little girls teach us about Alzheimer's disease? By Alison McCook hen you meet identical four-year old twins Addi and Cassi Hempel, you might notice something about the way they walk. They used to run around like other toddlers, but now they are more wobbly, more uncertain, and walk with their legs somewhat wide apart, as if aboard a boat. They can sway in any direction, losing their balance. They fall more often than they should.

By | November 1, 2008

Twin Disorders

What can two little girls teach us about Alzheimer's disease?

By Alison McCook

hen you meet identical four-year old twins Addi and Cassi Hempel, you might notice something about the way they walk. They used to run around like other toddlers, but now they are more wobbly, more uncertain, and walk with their legs somewhat wide apart, as if aboard a boat. They can sway in any direction, losing their balance. They fall more often than they should.

They will notice you, and smile. They don't say words but they talk, a rhythmic, nonsensical babble from which a crystal-clear sound occasionally escapes: "ice cream," "paddycake," "four." Their heads have a slight bobble, and they sometimes can't angle their eyes downward, so they fall again.

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1 Neurons affected by both diseases experience dramatic accumulations of autophagic vacuoles and lysosomes, and cells affected by both disorders have enlarged endosomes, a feature seen in only a small number of disorders, says Nixon.

The similarities are strong enough that some researchers study NPC because of its link to Alzheimer's. "It is certainly one of the reasons we chose to get into Niemann Pick ourselves," Nixon says. "We are finding more and more reasons to draw similarities between lysosomal storage diseases [like NPC] in general and Alzheimer's."

When Goldstein chose to follow suit, however, he realized he knew little about the rare disease. In jumped Chris Hempel, who helped arrange one-on-one and conference phone calls between Goldstein and the NPC scientists she knows to educate him about its molecular underpinnings. "Parents were very helpful in facilitating that and moving me into this new area," Goldstein says.

He is now building an NPC neuron using human embryonic stem cell lines, which no longer express the NPC gene. "We're differentiating them now." The goal, Goldstein says, is to use the neurons to screen drug candidates. The technology doesn't exist to perform a high throughput screen using neurons, but he says that "it's not outside the realm of possibility" to use NPC neurons to test compounds flagged during HTP screens of non-neuronal cells. "We don't know how useful [an NPC neuron] will be," he says. "Personally, I think it will be incredibly useful."

In a kitchen with large windows that sometimes cloud over with smoke from nearby California wildfires, an island contains a tray piled with the plastic syringes, droppers, powders, and capsules the Hempels are using to try to arrest the girls' disease. The high-ceilinged kitchen is the center of life in the house, where Chris keeps her computer so she can check E-mail and correspond with scientists while staying connected to her household. This includes her mom and dad, who divorced decades ago but now sleep in separate rooms at the Hempels' to help out with the kids.

Mouse sympathetic neurons with two functional copies of NPC1 (upper panels) and two mutated versions (lower panels). The green represents stains from antibodies raised against NPC1. The cells were also incubated with the cholesterol binding compound, filipin (blue). In healthy cells, cholesterol is largely on the cell surface; in diseased cells, cholesterol is more widely distributed.
Used with permission of Elsevier, image supplied by Jean Vance, U of Alberta.

Sitting at the kitchen island, Chris reaches for the tray, picks up a white, plastic sheet of pills, and points to one capsule: "Each of these is roughly $200," she says, adding up to $160,000 per year for both girls to take the drug (thankfully, it's covered by insurance). The drug is the only prescription that comes with some evidence it may help NPC: Zavesca (miglustat), an inhibitor of glycosphingolipid synthesis, normally used to treat another lysosomal storage disorder, Gaucher disease.2

Chris's palms, knuckles and fingers are frequently stained orange from the curry spice curcumin. Her decision to try curcumin as a treatment for her kids came out of experiments by University of Oxford researcher Frances Platt, who Chris found through the Internet. Platt has been investigating NPC for years, and suspects that the dysfunctional NPC1 protein disrupts the regulation of calcium in the cell, and pharmacological agents that cause calcium to increase in the cytoplasm could correct this disruption. Platt and her colleagues found that curcumin could elevate cytosolic calcium; she tested it in NPC mice, and found it improved their disease. But Hempel didn't know this when she contacted Platt - she simply saw Platt was working on curcumin and NPC, and tried "begging for information" about whether curcumin could help her girls. Platt cautioned her that her research was preliminary, performed in mice, etc. But, yes, Platt conceded, maybe curcumin could help her girls.

Currently, the girls swallow twice-daily doses of powdered curcumin, which stains anything they put their mouths on, such as the nose of Cassi's favorite stuffed dog. The daily amount is 3,000 mg of curcumin and other ingredients added by the company that manufactures the supplement. It's hard to tell if anything is slowing the girls' inevitable deterioration, but there are hopeful signs: Months after her diagnosis, Cassi didn't even make eye contact, but on a sunny afternoon in July, she smiles at other people, even laughing when her sister farts. "I know how well they're walking because of the bruises," Chris Hempel says, and she believes the girls are doing better. Early evidence also suggests curcumin could help treat Alzheimer's disease.3

Platt is part of a group of researchers known as SOAR-NPC, or Support of Accelerated Research for Niemann-Pick disease type C. SOAR-NPC is managed by Collabrx, a new "virtual" biotech that facilitates collaborations between researchers. The purpose, says Smruti Vidwans, a molecular biologist-turned-drug development strategist who oversees the NPC group at Collabrx, is to find therapies faster by getting scientists to develop a targeted strategy for doing so, share ideas and data, and making sure no one doubles another's efforts. In exchange, researchers receive professional consulting and management services (such as Vidwans and Collabrx's software platform, which lets them share data and ideas remotely). They also receive funding from the Hide & Seek Foundation (which funds lysosomal diseases) and, primarily, Dana's Angels Research Trust, an NPC foundation.

Besides regular conference calls with each other and Vidwans, scientists have to be up for "real time peer review" in which they are constantly asking each other if they're doing the right studies, looking for the right outcomes, and so forth, says Jonathan Jacoby, COO of Collabrx, adding he is in "daily" contact with NPC scientists. "You discuss things as they happen within the group of researchers involved, which is actually quite different" from the normal process, says Platt.

"We are finding more and more reasons to draw similarities between lysosomal storage diseases like NPC in general and Alzheimer's." - Ralph Nixon

The Hempels, who are using some of the money they raised to fund Collabrx scientists, met at software company Netscape, a company known for publicly releasing the code of its software, and they were initially shocked to learn that scientists traditionally restrict access to their data until it's published, or meet their colleagues only at yearly conferences. Scientists "don't act like Internet startups," says Chris Hempel. "They're like, 'We'll call you in two weeks.' And we're like: No, you need to call us tomorrow!" She says she hopes the SOAR-NPC system becomes a model for other diseases.

The gait of mice with NPC (left), relative to wild-type (right). When paws are dipped in red and green paint, and mice walk along paper, affected mice show a shorter stride, and struggle to lift their paws between steps.
Source: PLOS Genetics / Matthew Scott

Last year, SOAR scientists identified more than 10 therapies to test in mice, and as of this summer, nearly all were being tested. They are already starting to think about the right combination therapy, Vidwans says. "This is probably something that wouldn't have happened without SOAR."

Twice now, Addi and Cassi Hempel have flown across the country to Bethesda, Md., to meet with Forbes (Denny) Porter, at the National Institute of Child Health and Human Development. They are part of his longitudinal trial of NPC, designed to define biomarkers researchers could use as part of a clinical trial and diagnostic test for NPC.

Chris Hempel also helped with this project. Once her kids were enrolled in Porter's trial, she asked him if there was anything she could do. Actually, there was: "I'm at the NIH, so we don't see many control kids," Porter told her. The study needed to compare blood and urine samples from NPC kids to those from healthy kids, and most kids who come through the NIH have some sort of a disease. She and another NPC parent immediately got to work on a urine and blood drive, and once Porter obtained approval from his IRB, "it took a couple of weeks" for the parents to send between 30 and 40 blood samples, and the same number of urine samples, he says. "It saved months of work and difficulty," Porter says.

NPC "is of enormous basic science interest." - Lawrence Goldstein

Ideally, any discovery that comes from the labs of Porter, Austin, Goldstein, or any of the Collabrx researchers would benefit more than the handful of NPC patients. "Our fondest hope" is that insights into how NPC works will yield insights into other disorders of cholesterol metabolism, such as Alzheimer's, and even cholesterol disorders in general, says Austin. (Nobel laureates Michael Brown and Joseph Goldstein studied severe hereditary familial hypercholesterolemia and discovered LDL receptors, which led to new ways of treating atherosclerosis.) "I think it's perfectly possible that what we discover [in NPC] will be useful to Alzheimer's disease and other neurodegenerative diseases," says Austin. "There's a long history of rare diseases shedding light on more common ones. This wouldn't be the first."

But for the most part, the only patients on Chris and Hugh Hempel's minds are Addi and Cassi. Standing in the kitchen making a quesadilla for himself and Chris, Hugh raises the idea of feeding tubes, for when the girls have trouble swallowing and could aspirate small particles of food or liquid into their lungs, putting them at risk of pneumonia. Parents obviously have to make the decision of whether or not to do it, but the responsibility of it is daunting, he says. "We're not going to get there," Chris asserts, resisting the possibility of her girls getting that sick.

Later on that day, Chris sits in front of her computer and quietly watches a video clip of a little boy with an advanced form of NPC, who doesn't move and makes no eye contact with his mother, who is talking to him off-camera. "It's heartbreaking," Chris says as the movie ends. It's impossible to imagine that her kids, who can still walk and talk, will one day be bedridden too. "That thought of kids losing their mind - I don't know," she says. "It's got to be one of the cruelest diseases on the planet for kids. And for parents, if they can't remember who you are."

Have a comment? E-mail us at References

1. J.V. Reddy et al., "Clues to neuro-degeneration in Niemann-Pick Type C disease from global gene expression profiling," PLoS ONE 1(1):e19, 2006.
2. S.D. Woodlhouse et al., "Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells," Lancet Neurol, 6:765-72, 2007.
3. N. Aynun et al., "Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease,"J Pharmacol Exp Ther, 326:196-208, 2008.


Avatar of: Heidi Chokeir

Heidi Chokeir

Posts: 1

November 10, 2008

I just finished reading your cover story in The Scientist this month. As a scientist and a mother I am totally blown away. As a mother of a healthy sever year old, I can't even begin to imagine the agony that the Hempels must be feeling as they watch their daughters slowly waste away. I was inspired by their drive to find a way to help them. As a scientist I was impressed to see scientists working together outside the peer review system to solve a daunting problem more quickly using true translational research. This really embodies what the ideals of science are all about, but are often forgotten in the race to making the discovery first. Finally I see a new paradigm in patient care that gets patients and their advocates directly involved with the scientists working on a most basic level in order to speed discovery. What a profound, beautiful and hopeful story on so many levels. It gave me goosebumps.
Avatar of: Gopal Bulusu

Gopal Bulusu

Posts: 1

November 24, 2008

One of the best reports by The Scientist in recent times! Hats Off to you! \nThis is the Real War: the war on debilitating new diseases of the brave but also callous new world. A world that is shrinking, not just in terms of communication, but also in resources and patience.\nIt is heartening to note that Scientists across the globe are cooperating with each other in a hope to give back normal childhood to thousands of children. One wonders how many under privileged infants in strife-torn third world and developing countries who can ill-afford nutritious meals, leave alone health care and diagnosis, have died and dying. \nMay the efforts of all the parents and scientists succeed.

December 1, 2008

palm print analysis may give clue for magneticcephalogram applications:\nMirror image hologram in understanding genetic reversals-reg [Incident: 081201-000032]\nOxford astro physics/astrobiology/Hubble-NASA-Knsk Engineering college\nResearch team Chairman:Hon.Roger Daviesand Dr.John wheater and Richard Greiffet Hon.Kevin Yates On Royal astronomical side Hon.Marteen Reeves ,cantab.\nand S.Nandakumar,Knsk Engineering college,Anna University\nIntroduction to acoustic mirror image for possible mirror symmetry in nano tech applications:\nCitation: Possible SQUID vitro research magnetocephalogram could be used in case of people genetic abnormalities:\nSpace domains has been observed with mirror image holgrams out of which there is definite energy flow which could be applied in genetic aging to bring forth the young genetic stage along time reversal planes.\nHigh field high-speed magnetic resonance imaging generates high level of acoustic noise that really generates a mirror symmetry has been evaluated by Oxford astrobiological investigation for genetic application to ward of mental discease.The acoustic effect effects have second negative impact and a possibility that acoustic energy to magnetic structures contributing mirror image . \n In real space time three symmetries are discrete operations and the one is mirror symmetry or parity which can called a Jesus mirror hologram. If there is mirror symmetry all events in the mirror world should occur in reflected in exactly in the same world. Charge symmetry implies that a particle and its anti particle behave and and interact identically. Similarly time symmetry requires that an event forwards in time should be identical to the backwards in time.\nThis theory though opposed by the theory of Lee and Yang ,according to Russian physicist Lev Landue is not lost in the event of weak interaction rather be brought along the real image from the negative mirror image as there is a definite link in between them. All is not lost in the combination of C and P restored in the symmetry still exists and not violated. \n The important application may be to erase the bad memories of mental diseases and transferring into the corresponding mirror image. Particular application in neuron memory transfer may be possible by in the case of aggressive criminal tendencies inherited by clubbed thumb as well as for people having the heart line and head line joined together with their heart line starting from Saturn mount. A possibility is that the mirror symmetry will be a link in thinking computers.\nConclusion: Mirror image symmetry out of blue mirror or equivalent SQUID biological circuits may be used to ward off mental diseases. According to Okada and Wu physiological basis of magnetic field consists of as voltage sensitive wave conductance as synchronized population spikes super imposed in a brief wave and possible SQUID vitro research magnetocephalogram could be used in mirror symmetry dynamics in case of people genetic abnormalities.(refer Dr.Meyer from Newyork arrested)\nRef;Nobel prize works done by Japanese physicists 2008.\n
Avatar of: Steven Brenner

Steven Brenner

Posts: 14

December 2, 2008

I read the story on Twin Disorders by Alison McCook in the Nov 2008 issue of The Scientist with interest, especially with reference to hyperphosphorylated forms of tau protein being present in virtually identical form in both Nieman Pick type C in children and neurofibrillary tangles in brains of patients with Alzheimer?s disease.\nApparently the neurofibrillary tangles are instrumental in development of dementia. \n There has been some excitement in the Alzheimer?s disease community recently with the discovery methyl thionium chloride, better known as methylene blue apparently targets tau in Alzheimer?s disease, and inhibits or at least delays progression of the disease with more effect than currently available drugs. \n Information was presented at the International Conference on Alzheimer?s Disease July 26-31 July, 2008 in Chicago by Claude Wischek. \n Although a preliminary study of 321 patients, the results were encouraging.\n Methylene blue is used as a urinary tract antiseptic in clinical medicine and was identified as a treatment for malaria by Paul Ehrlich about 1891. It fell out of use due to a side effect of turning the urine green, but there has been some recent interest again in its use as an anti-malarial medicine. \n Methylene blue is quite inexpensive and has widespread use as a laboratory stain, I had used it extensively staining neurons in cell death experiments some years ago. \n Methylene blue might be a consideration for treatment of children with Nieman Pick type C, since it seems to inhibit tau protein from forming neurofibrillary tangles, prominently seen in Nieman Pick type C and seems to be relatively safe as well as bei ng widely available and cheap. Otherwise there doesn?t seem to be much hope for children with the disease. Hopefully it can also arrest the progression of Alzheimer?s disease, since there has been little meaningful progress in treatment of Alzheimer?s disease either. \nThanks\nSteven Brenner\nSt Louis, MO\n
Avatar of: jeremiah davis

jeremiah davis

Posts: 3

June 21, 2010

is there any evidence that, where curcumin is commonly used as a spice, such as india, these diseases, e.g. npC and Alzheimer's, are less common or, at least, less pronounced?
Avatar of: Alison McCook

Alison McCook

Posts: 68

June 21, 2010

I haven't seen any evidence that NPC is less common in countries where people consume a lot of tumeric (curcumin), but that may just be because NPC is so uncommon in general, that it's hard to spot trends. It's a good question, however!\n\nAlison McCook\nDeputy Editor

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