The Crohn’s Disease

diagram of a human digestive system

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Hi Guys!

As the beginning of my first post-doc at the Harvard Medical School is coming closer, I decided to focus many of my future posts (although I won’t stop talking about the more important discoveries in science and their consequences in understanding reality and society) on the specific topic of my studies: the Crohn’s disease.  I will explore how molecular biology strongly improve our knowledge of this disease (and more generally of immunology), I will comment on new discoveries and their importance, I will discuss new therapies and I will provide plenty of resources to be updated on this unknown and painful disease. Whoever wants to share their pathological and human experience or the experimental discoveries will be welcome to write on the BLOG. So guys, if you want to understand Crohn’s disease do not miss to read EducereX!!!!

Introduction to Crohn’s Disease

The Crohn’s disease is chronic inflammation that may affect any part of gastro-intestinal tract (from mouth to anus). The Vienna classification (1998) classified Crohn’s disease based on the anatomical location and occurrence of complication.

With respect to anatomical location at diagnosis the classification is:

1.          ILEOCOLIC Crohn’s disease which affects both Ileum (last part of small intestine connected to the large one) and large intestine (21% of cases)

2.              Crohn’s ILEITIS which affects only the Ileum (47% of cases)

3.          Crohn’s COLITIS which affects the large intestine (28% of cases) and it is difficult to distinguish from ulcerative colitis (another idiopathic IBD).

4.          Crohn’s disease of the upper gastrointestinal tract (3%).

With respect to behavior of Crohn’s disease and occurrence of complications:

1.   stricturing: the intestine wall gets thicker and the bowel narrow until eventually completely obstruct the passageways of food: bowel obstruction (which is a main complication). This is mainly due to swollen of intestine wall (due to the inflammation) and scar tissue that reduce the bowel diameter (17%).

2. penetrating: the inflammation creates fistulae (abnormal passageways) that connect intestine to other epithelial tissues such as skin (explaining the skin rush). The frequency is 13%.

3. inflammatory: the most common pathology that causes inflammation without other complication such as stricturing and fistulae with a frequency of 70%.

The clinical symptoms can be summarize as follow:

  • Abdominal Pain
  • Diarrhea (bloody diarrhea if inflammation is at its worse)
  • Fever (in the worse case)
  • Vomiting
  • Weight loss
  • Ulcer (in some cases)

Epdemiology of Crohn’s disease.

This previously unknown disease is becoming very popular and important in the western world (with highest rate in Northern Europe, North America and UK) as is where, worldwide, the pathology is more common. The Crohn’s & Colitis American Foundation estimates that around 1.4 million of Americans suffer of Inflammatory Bowel Disease (IBD). The IBD is a terminology which groups a series of chronic inflammation of gastro-intestinal tract of which Crohn’ disease and ulcerative colitis represent the 2 more frequent conditions.

As reported by Lancet (Baumgart at al., The Lancet, 2007), in North America Crohn’s disease affects white individual with a frequency of 43.6 per 100,000 persons, a much higher frequency when compare with other ethnical group: Hispanic with 4.1 individuals per 100,000, Asian with 5.6 individuals per 100,000 and African-American people with 29.8 individuals per 100,000. These epidemiology data strongly suggest an hereditary cause of Crohn’s disease: in the next post I will comment on the genetic and other causes of the Crohn’s disease discovered so far by scientists.

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Interview Dr Robert D. Newman: How to tackle Malaria.

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In the post of last week, we discussed generally what Malaria is, where is more frequent and in particular we commented a couple of very innovative approaches giving an example of the importance of imagination to successfully tackle difficult scientific problems. Today, I would like to report the more important hits taken from an interview of Dr Robert D. Newman (director of the World Health Organization’s Global Malaria Programme since July 2009) published on WHO website.

In this interview, it is immediately clear that Malaria cannot be approached as WHO previously did with Small Pox or it is doing now for other diseases (look to this post). First of all, all the strategies adopted so far to control Malaria  failed.

Q: There is a long history of efforts to control malaria, from the League of Nations’ Malaria Commission of the 1920s to the abandoned eradication campaign of the 1950s and 1960s. What is different today?

A: First, the tool kit is broader. People know that it’s not going to happen with a single wonder drug or insecticide, but a complicated mix of insecticide-treated nets, indoor residual spraying, better diagnostic testing, better antimalarials and new tools on the horizon. Also, we have realized that no one organization can do this alone. It needs to be a global partnership, as with Roll Back Malaria. The WHO Global Malaria Programme plays a key role in that partnership by setting evidence-based policies, independently tracking progress, designing approaches for capacity building and health systems strengthening, and identifying threats to success and new opportunities for action. But you also need bilateral programmes, nongovernmental organizations and academic institutions. At the centre of everything you have national malaria control programmes, which are much more sophisticated than 20 years ago. So you have a different landscape today.

In second instance, an efficient vaccination strategy is not yet available.

Q: Is there any progress in terms of a vaccine?

A: There is a vaccine called “RTS,S” that is now in a very large phase III trial in 11 sites in seven African countries and will have enrolled approximately 16 000 infants and young children by the trial’s end. We have never had a malaria vaccine get that far. The phase II studies in the target age groups in Africa have shown anywhere from 40–60% protection against malaria in the follow-up period for the trials. It’s very exciting progress, but the efficacy to date is not that of, say, a measles vaccine, which is expected to be at least 90%. If licensed, it would be the first vaccine for a parasitic disease. The WHO Global Malaria Programme and the Department of Immunization, Vaccines and Biologicals have convened a joint technical expert group that regularly reviews progress on the RTS,S trial, scheduled to finish in 2014. So by 2015 the group will have enough evidence to advise WHO as to whether it should recommend this vaccine for public health use.

In addition, another limitation of Malaria vaccines “RTS,S” is the specificity for the parasite common in Africa but not for the parasite common in other part of the world such as in the sud-east Asia, where Malaria is very common (look at this post). Probably for those reasons WHO change their strategy:

Q: In March 2010 WHO changed its policy and now recommends diagnostic testing for malaria in all suspected cases before initiating treatment. Given the limited availability of quality microscopy, especially in Africa, how will countries achieve this?

A: Over the past few years a constellation of changes has compelled our technical expert group to recommend we move to universal access to diagnostic testing for malaria. Microscopy remains a reliable diagnostic tool but is seldom available. In the past 10 years, we have seen an increase in the availability of rapid diagnostic tests for malaria. Their cost has come down and their accuracy is reported through a product testing programme. In recent years, malaria transmission has dropped, so that in many places we are also saving money, as a typical rapid diagnostic test costs about US$ 0.50 while the average course of an artemisinin-based combination therapy (ACT) costs just under US$ 1. About a decade ago in Africa fewer than 5% of suspected cases in the public sector were given a diagnostic test, whereas in 2009 diagnostic testing was performed on 35% of such cases.

Therefore, the most efficient therapy we have now to tackle Malaria is the ACT. But, it is actually well know the phenomena of “drug resistance” when a single therapy is use for long time (the same happen for the anti-biotic). Dr. Robert D. Newman explains that this is partially also the case of Malaria.

Q: Your report alerts us to resistance to artemisinins particularly on the Thai–Cambodian border, but also spreading to other parts of the Mekong region. Does that mean that ACTs – the most effective antimalarials to date – will soon be rendered useless?

A: While we have seen the emergence of resistance to artemisinins, we have not seen resistance to ACTs. That’s a very important distinction. When administered as part of an ACT regimen, the partner drug “covers for” the artemisinin by killing the parasites that were not killed by the artemisinin. We have seen problems only in cases where the partner drug was previously used on its own and is no longer effective due to resistance. Right now we have five ACT regimens that are recommended by WHO for treating falciparum malaria. We don’t have ACT resistance per se, so the good news is that the combination, if chosen well, is still working.

Q: Why is there more drug resistance in south-eastern Asia than in Africa and Latin America?

A: Why is the Mekong area known as “the cradle of drug resistance”? Often resistance arises where the drugs were used first and the longest. The Mekong also has a very large private sector and a lot of the market for these drugs is unregulated. In the case of ACTs, artemisinins were marketed alone, and so people might buy a seven-day course but only take the drug for two days, or they may have gone to a shop that sold them a couple of doses. I ascribe most of the problem to early adoption and inappropriate use.

Q: Will resistance to artemisinins spread to Africa?

A: If history is any guide, yes. The global plan I mentioned looks at these scenarios and classifies countries. A tier-one country has confirmed resistance; a tier-two country is one that neighbours or has a significant migrant flow from a tier-one country. Tier three includes everywhere else, including Africa. We are asking tier-three countries to test four to six sites for efficacy and resistance to medicines that are in use there. If every country follows this recommendation, we can respond quickly and mobilize all the resources needed to face the emergency should resistance to artemisinins emerge.

Therefore, more efficient therapies are needed before the drug resistance of Malaria parasites became so strong that we cannot treat anymore people with the disease. And science, responsible to improve human condition, has an important goal to achieve.

Comment on “Arsenic instead of Phosphorus: the extreme adaptation of living creatures.”

Despite the heavy critique the authors of a paper that one of Mario’s most recent blog entries referred to currently face (see http://www.sciencemag.org/content/330/6012/1734.summary) and irrespective of the public attention this discovery receives (I usually mistrust what the public’s attention attracts most), I really enjoyed hearing about this new paper and the way the authors carried out science. It encouraged me in my notion that considerate findings can still be revealed by having clear and uncomplicated ideas and by doing basic and (relatively) simple experiments. Usually when people hear the word “science”, they think of formula, extremely complicated theories, statistics and the like which only experts or nerds can understand. And I have to admit: very often when I scan through the scientific literature, I find it hard not to be intimidated by the often strangely sounding titles. And yes, very often you just have to be a specialized specialist to understand the sub-specificities of a tiny speciality that constitutes a small part of a certain discipline to take the most out of a discovery and to understand its consequences. But the biggest attention is usually paid to discoveries that are more generally comprehensible (even if it is only because of mentioning the possibility of extraterrestial life….). And not rarely, they are also the ones that have the power to initiate so called paradigm changes (a term introduced by the American philosopher Thomas S. Kuhn).

Another reason why I liked that paper was the methodology behind, it seems to follow the logics of the “creative leap” article, brilliantly brought forward by Davide: someone had an idea by challenging the concept of a limited amounts of elements constituting all living things on earth and decided to confront it with reality. After having found a bacterial strain that could survive in the presence of high concentrations of Arsen, they had a closer look to see if it actually used this chemical compound to integrate it into its cellular constituents. And when they found some evidence that it did, they further tried to explain the fact why a bacterium would rather use Arsenate than phosphate since the former is much less stable than the latter by referring to the environmental conditions these bacteria were found in and in which a less stable chemical molecule might be more advantageous to drive fundamental cellular reactions (see the video Mario put in). Of course, since this discovery is so new and comes so surprisingly, many questions still remain: were the techniques used the right ones? Were the questions the authors asked fully answered by the experiments they carried out? What other tests need to be included? Etc. etc. I think it’s absolutely right to ask these questions, in the end that’s what science is all about. And maybe future tests will prove the authors wrong. Having said that, I still think this paper was interesting in so many ways, for me the most attractive aspect was the methodology and the way science was done and lived! Just look into the eyes of the passionate first author (see video) and the way she promotes her discovery and you know that everything they have done was right, despite the possibility that they were completely wrong!

Malaria: new strategies against the deadliest pathogen on hearth.

Countries which have regions where malaria is ...

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As stated by the 2008 Malaria report of WTO “In 2004, Plasmodium falciparum –the most common strain in Africawas among the leading causes of death worldwide from a single infectious agent. They estimated that “3 billion people at risk of infection in 109 malarious countries and territories and around 250 million cases annually, leading to approximately 1 million deaths”.

The map on the side shows the countries (in yellow) at risk of Malaria. It is immediately clear that the Malaria is present mainly in the poor countries, too much poor to be treated with the medicines available (Chloroquine, Artemisinin and Malarone) for the western world populations that can successful cure this disease. To defeat this disease it is therefore necessary to develop new and less expensive strategies such as Vaccines.

Before exploring some new exiting vaccination approaches that promise to successfully treat (at least in part) Malaria, it is important to summarized the more recent achievements of basic biological research that describe the whole life cycle of the parasites that cause Malaria giving potent means for therapy design. (the image below has been taken from Parasite Image Library)

The malaria parasite life cycle occurs in two hosts: mosquito and men. When a plasmodium-infected female mosquito (of the species Anopheles) that has been previously infected with the Plasmodium has a blood meal, the Sporozoites (the stage of the parasite life that can infect human host) are inoculated in the blood stream of the human host (1) to reach and infect liver cells (2) where they mature in merozoites (4) that are released in the bloodstream. After the exo-erythrocytic cycle (A) that can contain the dormant parasites for long time, merozoites can infect human blood cells (5) starting the erythrocytic cycle (B) which consist in infection of erythrocytes, proliferation and release by lysis of the parasites (6). This is the stage in which the main clinical manifestations occur: cyclical fever, anemia, etc…When an Anopheles mosquito takes a blood meal from the malaria infected human host (8), it is infected by the parasites that starts its sporongonic cycle (C, sexual reproduction) in the digestive apparatus of the Mosquito (9,10,11,12). The sporozoites so created migrate to the salivary glands of the mosquito to be inoculated into human host and start again the life cycle.

After more than 20 years of attempts, the GlaxoSmithKline (GSK) has produced a vaccine formulation, composed of the surface protein CS, that has finally reached an advance clinical test. Using this vaccine, it’s ongoing a study on 16.000 children in Africa. The limitation of this vaccination is that shows an efficacy of 50%, too low respect usual vaccines that have an efficacy of at least 80%.

 

Another exciting approach (although it seems fantasy-science) is the “vaccination” of the Anopheles mosquitoes to interrupt the parasite cycle. It is a proposal coming from the biologist Dinglasan and his group who showed that blocking by specific antibodies a protein present in the mosquito digestive apparatus disrupts the proliferation of the Plasmodium (see paper here). They are also showing (in a mosquito-mouse malaria model) that vaccinating the mice against the mosquito protein makes mice to produce an amount of specific antibody ables, once ingested by mosquito, to inhibit Plasmodium reproduction.

Here, I gave quick example of how imagination and fantasy are important in science and how importantly they can change positively our life.

 

2010 in review

Hi Guys! Below is the summary of how our blog is doing. Considering that it is a science blog we did great: 1100 visitors in 3 months and many comments by blog and  by e-mails. This very good result stimulates me in continuing writing and discussing with you all about science, biology and philosophy.

I would like to thank you all for your interest and your participation. So let’s keep discussing about science in our path to the reality!

Summary of Blog Activity

The stats helper monkeys at WordPress.com mulled over how this blog did in 2010, and here’s a high level summary of its overall blog health:

Healthy blog!

The Blog-Health-o-Meter™ reads This blog is on fire!.

Crunchy numbers

Featured image

The Leaning Tower of Pisa has 296 steps to reach the top. This blog was viewed about 1,100 times in 2010. If those were steps, it would have climbed the Leaning Tower of Pisa 4 times.

In 2010, there were 13 new posts, not bad for the first year! There were 31 pictures uploaded.

The busiest day of the year was November 23rd with 86 views. The most popular post that day was Lista di cosa piacerebbe ai ricercatori/List of what (Italians) researchers would like.

 

Attractions in 2010

These are the posts and pages that got the most views in 2010.

1

Lista di cosa piacerebbe ai ricercatori/List of what (Italians) researchers would like November 2010
7 comments and 1 Like on WordPress.com,

2

The idea behind EducereX November 2010
9 comments

3

Vaccination: the success over infectious diseases December 2010
8 comments and 1 Like on WordPress.com,

4

About October 2010

5

I Wish Everyone Could Experience a Creative Leap November 2010
3 comments

Arsenic instead of Phosphorus: the extreme adaptation of living creatures.

The structure of deoxyribonucleic acid (DNA), ...

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Since the discovery of the DNA structure by Watson and Crick in 1953, molecular biology has revealed most of the secrets of life. Biologists discovered that any living organisms, from plants to bacteria and from algae to men, are made of cells that use DNA with the same structure and composition as information database for the production of proteins constituted with the same 20 Aa. All the basic mechanism of DNA replication and protein assembling is highly chemically (mostly carbon, hydrogen, nitrogen, oxygen, sulfur, and phosphorus) and functionally conserved.

The work of Wolfe-Simon and colleagues subvert completely this view. With a selection procedure using a medium inoculated with Mono lake sediments rich in arsenic, they purified a bacterial clone  (called GFAJ-1)  that is not only able to growth in presence of arsenic (probably by expressing proteins that reduces his toxicity) but also to use AsO4-3 (that correspond to physiological composition of phosphorus: PO4-3) as a building brick for DNA and other basic molecules.

 

In the figures, it is possible compare the bacteria grown in phosphorus (left) and the ones grown in arsenic (right). The latter show a swollen shape probably due to large vacuole-like regions, structures not explained by the authors.

They further analyzed the bacteria ability to proliferate (although very slowly, 1 duplication every 10 days) in presence of arsenate showing that is slower than in presence of phosphorus but quicker than in absence of both arsenate and phosphorus. In addition they performed a detailed analysis of bio-molecule composition with particular interest in DNA molecule using mass spectrometry techniques. In the authors point of view, their results demonstrate that arsenic participate to DNA formation, replacing phosphorus.

Here is an interesting interview to the authors of this research:

Controversial issues

As expected, such important statement is strongly debated in the scientific community. The results of this paper may be in conflict with the chemical laws as we know them. Therefore strong experimental evidences are needed in order to support these findings. And this is maybe the weakest point of this work: the experimental evidences have strong limitations and many gaps that make biologists and chemists be skeptical of this high impact paper. Dr. Rosie Redfield exposes very well the limitations of the experimental work on her blog (http://rrresearch.blogspot.com/2010/12/arsenic-associated-bacteria-nasas.html)

The reasons for Flu Vaccines

3D model of an influenza virus.

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WHY: Why are the World Health Organisation and many countries so worry about the Pandemic Flu?

The influenza viruses are able to rapidly infect a high number of people and to rapidly spread around the world, nowadays helped by the globalization. Pandemics of influenza are present since our ancestors, with different rate of death in the population. The most lethal recorded pandemic flu was after the First World War (’18-’19). The “Spanish” flu hit worldwide causing between 50 to 100 million deaths. Below you can see the kinetics of deaths (as the weekly number of deaths per 1000 persons): the “Spanish” flu hit in 3 waves (spring ‘18, winter ’18-‘19, spring ’19).

Figure taken from Jeffery K. Taubenberger and David M. Morens, Emerging Infectious Disease, 2006. The figure shows weekly combined influenza and pneumonia mortality in the United Kingdom, 1918–1919.

Since then, biological research made a lot of improvements: in 1933 the influenza virus was isolated (Smith et al. Lancet 1933;2:66-68), strong antibiotics have been discovered to treat opportunistic infections, hygiene conditions and containment measures have been improved, antiviral drugs have been developed.

However, the WHO estimates that every year the influenza hits up to 1 billion people worldwide of which 3 to 5 million cases result in severe disease and between 300,000 and 500,000 deaths annually.

How: how do we design flu vaccines?

The Influenza virus is a RNA virus with 8 chromosomes. These features make Flu virus highly susceptible to spontaneous mutations and rearrangement between strains eluding the immunological response. This explains why an individual can be infected multiple times during his life. Lambert and Fauci, on New England Journal of Medicine, summarize life cycle of influenza virus, highlighting the step where immune response act to stop infection.

Vaccines can be used to control influenza infections. However, the high mutagenesis rate of influenza deny the possibility of eradicating flu virus with one vaccine. That means that seasonal flu vaccines, in contrast to other vaccines, are used as prophylactic treatment and not to prevent the pathology in general. “Universal” vaccines, which protect against a wide range of flu strains, are needed.  Wei and colleagues published in Science (Vol. 329 no. 5995 pp. 1060-1064) how a two step vaccination strategy can elicit production of antibody-reactive against multiple influenza virus strains. The tab below shows the flu-reactive antibody titer following vaccination strategies.

Who: who shall we vaccinate?

The pathology cause by influenza virus is usually quite mild. It is therefore usually useless to get vaccinated as the pathology itself elicits a more potent immune response and consequentially immune “memory”. The statistics indicate that the majority of death due to influenza, occur in the elderly population, hitting in particular persons with chronic pathologies that compromise their health. It is therefore important to use the seasonal flu vaccines as prophylactic treatment to protect those weak people. To reach optimal results, vaccination treatment on a wider scale should be used once a “universal” vaccine will be completely developed, in the attempt to eradicate also this disease from hearth as for smallpox.

Vaccination: the success over infectious diseases

None - This image is in the public domain and ...

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As I mentioned in “The idea behind Educere X” , studying science helps to demolished wrong prejudices that negatively impact on human life. Today I want to demolish the prejudice against Vaccination and to demonstrate instead that vaccines are one of the main cause for improvement of world health.

Historically, vaccination has been seen as an invasive treatment associated with subsequently pains and in some cases the transmission of the disease it was aimed to protect from. In addition, most of the vaccination campaigns were imposed by governments that can be easily corrupted by the giant pharmaceutical companies, which look for increasing their business. These elements may explain why vaccines are still considered suspiciously nowadays, although vaccination has reached such impressive results (like eliminating the small pox virus as a epidemic pathogen) and many incredible advances has been achieved in vaccine design and safety. The concern for vaccines is also expressed by many blog where they describe a conspiracy for reducing world population. So let’s apply the scientific method to answer the question:

Are the vaccines useful for human health and survival?

  • We can split the question above in 2 easier questions: Are the vaccines able to protect against pathogens?

Here I report a typical experiment performed in mouse model to determined that vaccination protect from disease caused by a pathogens:

The experiment is performed in parallel by treating a mouse with a vaccine consisting of attenuated pathogens emulsionated into adjuvant (that help to stimulate the immune response) and a mouse treated only with emulsionated adjuvant in a physiologic solution. If later (a month or so) the mice are infected by the living pathogens, the vaccinated one will remain completely healthy while the non-vaccinated one will develop the symptoms of the disease. This evidence is further sustained by the mechanistic correlation between protection and the systemic antibody level as shown by the plot on the right. It is easy to observe that while non-vaccinated mouse does not produce any antibody against the pathogen, the vaccinated one has a pick of antibody production some days after vaccination (usually around 7 days). The antibody level drops after pathogen clearing but didn’t go back to zero. The residual amount of antibody in mouse system (indicating the presence of long- living lymphocyte B memory cells that produce antibody) represents the “memory” of the immune system that is able to promptly protect against an infection of the same pathogen keeping healthy the vaccinated mouse. This process occurring during a vaccination can be repeated many times obtaining always the same result: protection of vaccinated mouse from the pathogens.

  • Is this true also for human being?

That’s is definitely the case. The biggest success of vaccination is the world eradication of the smallpox virus. After being firstly described by Edward Jenner in 1796 with an unethical experiment on a 8 years old boy (a kind of experiment as shown above), the smallpox vaccines protect millions of people in Europe. As described in the 1996 annual report, a project of the World Health Organization (WHO) aimed to use the vaccination to prevent the 10-15 million people per year getting sick with 2 million people per year dieing in the poor countries. After 10 year of vaccination the small pox was eradicated from hearth. Nobody is infected by small pox anymore, since 30 years (1980 is the official declaration of smallpox eradication http://globalhealthchronicles.org/smallpox). They also proof the economical convenience of the vaccination campaign: they spent 313 million $ that have been largely repaid by saving on international surveillance activity and medical treatments, without considering the invaluable saving in human life.

Strengthened by this success, the WHO is now aiming to eradicates many other diseases of the third word countries by vaccinations: typhoid diarrhea, diarrheal disease caused by rotavirus, Streptococcus pneumoniae, Haemophilus influenzae and others. The GAVI association (http://www.gavialliance.org/index.php) strongly contribute in fund rising.

However new infectious disease are becoming predominant as killing agent such as West Nile virus, Dengue Virus and some old infection agent are still predominant such as malaria and AIDS because of lack in efficient treatments.

The research community is challenged to find treatment for these diseases. To reach this aim, money shouldn’t be the priority of government and pharmaceutical companies that deliberately don’t invest in this kind of research because the poor countries cannot buy the vaccines.

An Odd Question

Doctors had told his parents the chances of finding

an exact match for the desperately sick infant were about 1 in 20,000.

“I said, ‘Well then, I’ll add 20,000 people to the bone marrow registry’”, his father remembered.

“They looked at me like I was crazy.”

Michael Guglielmo

 

A very brief post this week – I apologize for that but these’re busy days in the lab. Anyway I want you think about a few numbers I found on the internet. So, consider the following odds related to the chances one person has to die from a specific cause (based on series relative to year 2001; http://www.livescience.com/environment/050106_odds_of_dying.html):

 

  1. 1 in 100 is the chance you have to die in a motor vehicle accident (I don’t drive motor vehicles!);
  2. 1 in 5,000 refers to the probability to die for electrocution (impressive!);
  3. 1 in 20,000 is the probability to die in a air travel accident – air travel companies spend a huge amount of money to reduce chances to make mistakes (in each procedure) very close to zero, but it still remain numerically considerable;
  4. 1 in 60,000 is the chance you have to be in the midst of a tornado and (likely) to pass away;
  5. 1 in 100,000 is the estimated probability to die after snake, bee or other venomous bite or sting (probably following untreated anaphilaxis);

 

Well, 1 in 100,000 is also the chance one person has to find a (allogeneic) matched donor if diagnosed with an haematologic disease which eventually requires Bone Marrow Transplantation (BMT) from an unrelated donor as the preferred (and often life saving) treatment modality. This is an odd question.

 

Becoming a donor will transform chances into favorable outcomes. Here you can find one blog regarding a personal experience of hematopoietic stem cells (HSC) donation and the astonishing story of Giovanni Guglielmo. See you next week with related stuff.

 

Emma Caitlin’s “The Bone Marrow” Blog:

http://caitlinzemma.wordpress.com/author/czemma/

 

Giovanni Guglielmo’s story:

http://helpgiovanniguglielmo.org/default.aspx

Stem Cells: treatment for Leukaemia

Diseases and conditions where stem cell treatm...

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Let’s talk with the specialist

Last week we defined what the Stem Cells are (“Something about stem cells”), their biological properties (“The plasticity of Stem Cells”) and the ethical issues they rise  (“Ethical issues related to stem cell research”). Today I report an interview to Doctor Benjamin Uttenthal a Clinical Research Training Fellow at the University College London. He explains how Haematopoietic Stem Cells that reside in the bone marrow can be used to treat patients affected by Leukaemia. He also introduces some of the more advanced immunological treatments for Leukaemia studied in his laboratory.

Which are the most common types of leukaemia and how do they differ from each others?

Leukaemias are cancers of the blood or bone marrow, and all result in an abnormal proliferation of white cells in the blood. The commonest leukaemias can be divided into four categories: acute or chronic, and lymphoid or myeloid.

Acute leukaemias cause a rapid increase in immature white cells in the bone marrow. These immature cells crowd out the production of normal blood cells, and spill out into the peripheral blood. Because the abnormal cells in acute leukaemias are proliferating rapidly, acute leukaemias need to be treated quickly and with more aggressive chemotherapy. However, rapidly dividing cells are more easily killed by chemotherapy, and acute leukaemias can often be cured. Acute lymphoblastic leukaemia is the commonest leukaemia in childhood, and with better treatments the cure rate has increased to over 80% in recent years. Acute myeloid leukaemia is more often seen in adults.

Chronic leukaemias cause proliferation of more mature, but still abnormal, white cells. They progress less rapidly than acute leukaemias, and in the commonest leukaemia of all, chronic lymphocytic leukaemia, a period of observation is often required to decide whether treatment is needed at all. Chronic leukaemias can affect people of any age, but are most frequently seen in adults.

Which are the treatment approaches generally used?

The mainstay of treatment for leukaemias remains chemotherapy. Traditional chemotherapy drugs preferentially target rapidly dividing cells, and hence often affect normal cells in the body as well as cancer cells. This causes many of the side-effects of chemotherapy. For instance, the normal bone marrow contains many cells which divide rapidly to replenish red cells, white cells and platelets in the blood. Traditional chemotherapy will affect these cells as well as any cancer cells, and so patients undergoing chemotherapy frequently have low numbers of these normal blood cells.

As our understanding of the biology of specific cancers has improved, more targeted treatments have been developed. These are exemplified by imatinib (Glivec), a molecule which specifically targets an enzyme (tyrosine kinase) that is abnormally switched on in chronic myeloid leukaemia cells and drives their proliferation. Imatinib, the first tyrosine kinase inhibitor, is available in tablet form and has revolutionized treatment for chronic myeloid leukaemia, with 95% of patients achieving a complete haematologic response (normal blood counts) after a year of treatment.

Can you tell us something about immunotherapy of leukaemia?

Immunotherapy is an umbrella term for all treatments which harness the body’s immune system to treat disease. A form of immunotherapy which has been used for a long time to treat leukaemia is the transplantation of bone marrow or peripheral blood stem cells from a separate donor to a patient (allogeneic bone marrow/stem cell transplantation). For many years it was thought that the beneficial effects of bone marrow transplantation arose from the chemotherapy or radiotherapy given to the patient, and that bone marrow transplantation simply allowed high doses of chemotherapy to be used to treat the leukaemia, followed by ‘rescue’ of the patient’s bone marrow by transplantation from a donor. However, more recently it has been recognized that immune cells within the transplanted bone marrow themselves play an important part in clearing leukaemia cells that remain, recognizing them as ‘foreign’ and attacking them in a response known as ‘graft-versus-leukaemia’ or GVL. However, this response against ‘foreign’ cells may also be directed against the normal tissues of the bone marrow recipient, causing a potentially severe complication of bone marrow transplantation called ‘graft-versus-host disease’ or GvHD. For this reason, research aimed at improving immunotherapy in leukaemia has often focused on ways of improving the GVL response while limiting any GvHD. One way of doing this is to develop immune cells which specifically recognise and attack leukaemic cells but not the normal cells of the patient. In our research group we have done this by using gene therapy to target the immune cells against a molecule called WT-1, which is found at high levels on acute myeloid leukaemia cells. The aim is to give these cells to patients with acute myeloid leukaemia, a process known as adoptive cellular immunotherapy. A similar approach has already met with some success in patients with metastatic melanoma, a skin cancer, and we are optimistic that we will soon be able to start clinical trials in a small and selected number of patients.

To know more check: Uttenthal BJ et al. “Adoptive therapy with redirected antigen-specific primary regulatory T cells is a potential novel cellular therapy for graft-versus-host disease” Human Gene Therapy 21:507-525 (2010)