PTH1R mutations are associated with Blomstrand lethal chondrodysplasia, which can include aortic coarctation. Research in zebrafish found that knocking down PTH1R directly disrupted aortic formation, causing a localized loss of the aorta. Further research showed this effect was mediated by Notch signaling, and activating Notch signaling rescued the aortic defect. This provides insight into why some cases of Blomstrand's syndrome involve the aorta and suggests Notch signaling may be a potential therapeutic target.

1. Medicine and medical research in the
sustainable community
Tim Chico
Senior Clinical Lecturer/Consultant Cardiologist

2. Medicine and medical research in the
sustainable community
Tim Chico
Senior Clinical Lecturer/Consultant Cardiologist

3. At some point in my life I expect to need medical
treatment
A: yes
B: no

4. From what you know of the NHS;
A: I think it represents a sustainable model of
healthcare
B: I think it is an unsustainable model of healthcare
C: Don’t know

6. How many deaths in UK hospitals are
“avoidable”?
A: 1 in 10
B: 1 in 20
C: 1 in 50
D: 1 in 100

7. What I would like you to think about
• The place of medicine in society; static, changing,
improving? Whose responsibility is health?
• What is the right relationship between patient and
doctor?
• Do we need more medical research?
• Is use of animals justified for medical research?

8. I am studying a subject in;
A: Humanities
B: Science
C: Other

10. Have you read a work of Shakespeare's?
A: yes
B: no

11. Can you describe the Second Law of
Thermodynamics?
A: yes
B: no

12. Have you read a work of Shakespeare's AND can
describe the Second Law of Thermodynamics?
A: yes
B: no

15. 1959: Scientists versus
Humanities
2013: Medics versus non-
medics

16. What is a heart attack?

17. What is a heart attack?
A) Sudden death or life-threatening event due to
cardiac rhythm disturbance
B) Acute interruption of myocardial blood flow by
rupture of an atherosclerotic plaque causing
myocyte necrosis that can cause no symptoms

18. Human coronary angiograms of normal and occluded right
coronary arteries

19. Should non-medics know more about medicine?

20. Should non-medics know more about medicine?
Paternalistic, patronising: “I know
what’s best for you”

21. Should non-medics know more about medicine?
“No decision about me, without me”. Open
discussion of options, informed consent
Paternalistic, patronising: “I know
what’s best for you”

22. Which doctor would you prefer?
A) Paternalistic, patronising: “I know what’s best for
you”
B) “No decision about me, without me”. Open
discussion of options, informed consent

23. You’re admitted to hospital with a heart attack.
How long do you think it would take to properly
explain the diagnosis and treatment?
A) 10min
B) 30 min
C) 1hr
D) More than 1hr

24. You see a doctor who explains your illness and
treatment. How much information do you retain
immediately afterwards?
A) 100%
B) 75%
C) 25%
D) 10%

25. Imagine a disease that is fatal if untreated but
curable if found early. It affects 1 in 1000
students. Doctors invent a test that is correct
95% of the time. You test positive.
What is the chance you have the disease?
A) 95%
B) 50%
C) 2%
D) 0.01%

26. When a drug is prescribed for diabetes, what
proportion of patients take at least 80% of the
tablets they should?
A) 100%
B) 90%
C) 66%
D) 50%

27. How many years fewer do smokers live on
average
A) 20
B) 10
C) 7
D) 3
E) 1

28. Better understanding of medicine might help;
• Understand and evaluate care provided by medics
• Reduce personal risk of disease
• Influence public health in non-medical career paths
• Make informed political choices about health funding
and research

29. But how good is medicine anyway?

30. What is your current view of Medicine?
A) Extremely advanced; surely there isn’t much more we
can achieve?
B) Fairly advanced; we may be approaching a limit to what
we can do
C) Still quite a lot of room for improvements in treatment
and understanding
D) Primitive; people will look back on us in 20 years time
and be stunned by how little we could do

31. A patient consults a doctor because of a
symptom (for example pain). What percentage
of such cases can currently be medically
explained?
A) 100%
B) 90%
C) 66%
D) 50%

32. How do we know a treatment is effective?
Anecdote (not very useful)
Observational studies (lots of flaws)
Randomised Controlled Trials (RCT); the best of a bad
bunch, but still lots of problems

33. A GP gives you a treatment. What is the
likelihood that there is Randomised Controlled
Trial evidence the treatment works?
A) 100%
B) 75%
C) 50%
D) 25%

34. 1922

35. 1942
1949
1983
2005

36. The current state of Medicine
• Amazing advances in the last 50 years
• Extremely expensive
• Still limited in what we can achieve
• Huge health inequalities
• These factors drive the need for more research

37. But do we need research?

38. Do you agree with Chris Boardman?
• A) Yes
• B) No
• C) Not sure

39. But do we need research?

41. Does medical research need to use animals?
• Most does not; health services research, studies in
man, cell culture. Particularly good for observational
studies.
• Some cardiovascular studies require use of animals,
particularly those that change something (like a
gene)
• All medical therapies have passed through “pre-
clinical, i.e. animal studies

43. I would take a drug that had never been
administered to an animal previously
• Yes; preclinical studies didn’t pick up TGN1412
• No; preclinical studies are imperfect but better than
nothing

44. Regenerative medicine: growing new
organs

45. You have a heart attack, which kills 30% of the
working part of your heart. How much
improvement can current medical treatment
achieve?
A) 100%
B) 50%
C) 20%
D) 1%

46. Is it currently possible to grow a human heart
from a single cell?
• Yes
• No

47. It is currently possible to grow a human heart
from a single cell!
• We know this is possible; since we have all done it
once
• Regenerative medicine hopes to switch on and
control the existing pathways that made our organs
in the first place

49. How can zebrafish tell us anything about
ourselves?
• “Conservation”: higher organisms use/adapt existing
processes
• The same genes that make blood vessels in zebrafish
make blood vessels in humans

50. Developing embryo 0-16h

52. Aortic coarctation is a congenital abnormality in blood
vessel formation

53. PTH1R mutations cause Blomstrand lethal
chondrodysplasia
Blomstrand, Pediatric Radiology 1985

54. Blomstrand lethal chondrodysplasia is associated with
aortic coarctation
Reference Sex Aortic
Coarctation
Blomstrand, Pediatric Radiology 1985 F YES
Spranger, Advances in human genetics 1995 M Not known
Young, J Med Genet 1993 F YES
Leroy, Am J Med Genet 1996 F YES
Loshkajian, Am J Med Genet 1997 F YES
M YES
Den Hollander, Am J Med Genet 1997 F NO
F Not known
Oostra, Am J Med Genet 1998 F Not known
Galera, Pediatric Radiology 1999 M NO
Ooostra, Virchows Arch 2000 F NO
M YES
F NO
M NO
Hoogendam, Journal of Clin Endocrin & Met 2007 M YES

55. Research Questions

56. Research Questions
• Is PTHR1 needed for aortic formation?

57. Does PTHR1 directly contribute to aortic formation?
2d old control
morphant
embryo

58. Does PTHR1 directly contribute to aortic formation?
2d old control
morphant
embryo

59. Does PTHR1 directly contribute to aortic formation?
2d old PTHR1
morphant
embryo

60. Does PTHR1 directly contribute to aortic formation?
2d old PTHR1
morphant
Head embryo

61. Research Questions
• Does PTHR1 directly contribute to aortic
formation?

62. Research Questions
• Does PTHR1 directly contribute to aortic
formation? – yes

63. Research Questions
• What is the nature of the aortic defect?

64. • What is the nature of the aortic defect?

65. Research Questions
• Does PTHR1 directly contribute to aortic
formation? – yes
• What is the nature of the aortic defect caused
by switching off PTHR1? – a localised loss of
aorta

66. Research Questions
• How is this happening?

67. “Notch signalling” helps cells talk to each other

68. “Notch signalling” helps cells talk to each other

69. Green = Notch signalling
Normal
PTHR1 Site of future occlusion
switched off

70. If we switch on Notch signalling it “rescues” the aortic defect

71. What have we learned
• We know a little about why some babies with
Blomstrand’s chodrodysplasia have aortic
abnormalities
• We think this tells us that Notch is important in
aortic formation generally
• Switching on Notch signalling might be a useful
therapy if we can find a way to do this

72. Summary
• Biomedical research is maddeningly slow, and any
single study tells us hardly anything. However, if we
want to move forward, research is necessary
• If we discover, we understand. If we understand, we
can treat