The genomic medicine

A section of DNA; the sequence of the plate-li...

Image via Wikipedia

Hi guys,

check this video out. The general scientific director of National Human Genome Research Institute is showing how to purify DNA from Strawberry by using everyday household items. It is absolutely a fantastic idea that clarifies also the basic chemical principle of the DNA. After all purifying DNA is not so complicate!

Dr. Erik D. Green started his pioneering studies for whole genome analysis during his post-doc at the Washington University School of Medicine genetics department. His complete biography can be found here. Dr. Green has recently published a very interesting review on the achievement of scientific community in the field of genomic with the title: “Charting a course for genomic medicine from base to bedside”. He summarizes 5 principal achievements: understanding the structure of the genome, understanding the biology of the genome, understanding the biology of the disease, advancing the science of medicine and finally improving the effectiveness of health care (by the 2020!). Very interesting review full of very usefull link. Enjoy the reading.

The treatments of Crohn’s disease

struktura infliximabu

Image via Wikipedia

The treatment of Crohn’s disease is depending on the specific symptoms and clinical history of each patient. In addition the use of some drugs is still controversial. However, it is possible to outline a general scheme of action (also called algorithm) for the treatment of Crohn’s disease. The treatment is organized in two steps: 1) Induction of remission; 2) Maintenance of remission. Below I will quickly describe some drugs used and their target. Using as reference the paper of Dr. Baumart and Dr. Sandborn published on Lancet, I will also mention some of the new therapies that are tested in Clinical trial.

Scheme of Action for Crohn’s Disease treatment.

1) Induction of remission: is achieved by the use of medications that reduce the inflammation, the main manifestation of the diseases.

  • The 5-aminosalicylates (5-ASA), such as Sulfasalazine, are often used as a first-line therapy for intermediate/moderate disease. Sulfasalazine successfully interferes with the synthesis of eicosanoids (local mediators of inflammation which are responsible for the warmth, swelling, dolor and redness typical of inflamed area) and some local pro-inflammatory cytokines. Sulfasalazine does not act systematically (reducing in this way its toxicity) but as a pro-drugs: when ingested it is not active in the stomach but it is broken down by the bacterial flora in the colon into 5-aminosalicylic acid (5-ASA) and sulfapyridine, which then inhibit the enzymes like cyclooxygenase and lipoxygenase reducing the production of eicosanoids and prostaglandins.
  • The corticosteroids, such as budesonide and prednisone, are used for first-line therapy for more severe disease. The corticosteroids can act by blocking cell mediated immunity: they inhibit the intracellular signaling (activation of NFkB) which promotes production of pro-inflammatory molecules such as IL-2 and INFg. Corticosteroids also inhibit synthesis of eicosanoids by blocking phospholipase A2 through the promotion of lipocorting 1 expression (for more detail check this NEJM paper). The potent therapeutic effect is followed by adverse side effects: the strong immune-suppression induced may allow opportunistic infections, osteoporosis, diabetes, skin fragility and others.  Although budesonide is less potent as immune-suppression agent than prednisone, it has much less adverse side effect because its action is not systemic. This is due to its rapid hepatic conversion to well-tolerated metabolites and its strong affinity for corticosteroid receptor (for more details check Greenberg et al.).
  • The tumour necrosis factor (TNFa) inhibitors, such as the Infliximab, have been shown to be very effective in treating moderate/severe pathology. Infliximab is a chimeric-antibody (murine and human antibody) that irreversibly binds and blocks the TNFa, a cytokines involved in the inflammation process. Due to the presence of murine sequences in Infliximab that may induce rejection, a fully human antibody is used instead: Adalimumab.
  • Surgery is usually used to treat Crohn’s disease complications such as fistulae, strictures, bowel obstruction or intense inflammation. The surgery aim to remove the inflamed part of the intestine.

2) Induction of remission: although many of the previous listed medicaments can be used, the one with less adverse side-effect are normally preferred. Budesonide is normally used instead of prednisone because it doesn’t affect bone density (and cause osteoporosis). Infliximab or Adalimumab, can be used when the disease is particularly severe.

The most common therapy uses Mercaptopurine immune suppressive drugs such as azathioprine. The azathioprine is a pro-drug that is activated in the body and converted into purine analogue (adenine and guanine) blocking DNA synthesis. Fast growing cells such as white blood cells during an inflammation, are particularly sensible to that inhibition. It has got few adverse side effects in the short time but in a long term it has been shown to be a carcinogen.

The algorithm of Crohn’s disease medical menagement (from Baumgart and Sandborn, Lancet)

Investigated treatments for Crohn’s disease

The medications used in clinic (listed above) are not always specific for Crohn’s disease. Corticosteroid, for example, can be used to induce a generalized immune-suppression for many different diseases as they act systemically. But the ability to act so strongly and so systematically, make them responsible for many adverse side effects. Therefore, it is necessary to develop new therapies that specifically target the tissues where the inflammation goes on. Below I report a list of experimental drugs that are being tested in clinical trial to determine their efficacy and possible toxicity (taken from Baumgart and Sandborn, Lancet):

The causes of Crohn’s disease

Schematic of NOD2/CARD15 gene.

Image via Wikipedia

The Causes of Crohn’s disease are still unknown. However, statistical studies (that do not give causative explanations but only strong suggestions) indicate that Crohn’s disease may be caused by both genetic and environmental factors (in other words a genetic predisposition may enhance the effects of an environmental factor). Today, I don’t want to just list the causes but I want also try to explain the scientific method used to achieve this knowledge.

Genetic Cause:

1)    To determine whether a disease has genetic causes the first thing to do is to statistically study the frequency of a disease first in a population (as shown in the previous post) and subsequently compare with the frequency in a specific family whose members show the pathology. If the frequency of the disease within the family members is higher than the average frequency of the general population, a genetic cause of the disease is highly probable (because the genetic errors are transmitted from parents to the offsprings).

Þ   As reported  by Satsangi and colleagues (see the paper here), statistical studies from clinical data show that 5-10% of Crohn’s disease patients have a first-degree relatives with the same pathology with a concordance for disease type (see previous post) of about 70-80%.  Therefore, the risk of developing Crohn’s disease for a person with a first-degree relative with the disease is about 15 times higher than the average risk in the population. Particularly important studies involve twins: a much higher correlation of Crohn’s disease is calculated in monozygotic twins (37%; twins with identical genome) than in dizygotic twins (7%; twins with non-identical genome).

2)    The second step is to find the gene or the genes responsible for the pathology that have been transmitted from parents to their children. One of the most common strategies used by scientist is the Genome Wide Scan to identify susceptibility loci (or region) in the Chromosomes. This approach consists in sequencing small regions (marker sequences such as micro-satellites, SNPs, RFLPs, etc…) throughout genome of all the members of an affected family in order to identify chromosomal loci transmitted with high frequency to the sick members of the family and with less frequency to the healthly members. The analysis of those frequencies using dedicated algorithms is called genetic linkage (for more technical information check here) and allow to find susceptibility loci where it is possible to identify and subsequently study several genes.

Þ   Using this approach, no single locus has been found but many susceptibility loci have been described on chromosomes 1, 3, 5, 6, 12, 14, 16 and 19 (for references see Baumgart and Carding). This result implicates that Crohn’s disease is a polygenic disease making even more difficult the challenge to describe the causes. More detailed studies have linked specific genes to the diseases: Nod2/Card15 a pattern recognition receptor involved in immune response against microbes present in the intestinal tract and its mutations have been associated with Crohn’s disease in white population; Mhc (major hystocompatibility complex) receptor responsible for the presentation of intracellular proteins to lymphocytes.

3)    Once the responsible genes are identify by statistical analysis, the scientists start studying the function of the proteins (codify by the genes) within the cell and how its disruption may affect the cell and the immune-response as whole. The possible experiments to be performed are in such a big number (depending also from the function of the protein its-self) that it is not possible to list them all. However, some common approaches are often very informative. One example is the disruption of the homologue gene (gene with the same function in a different specie) in a mouse model called “knockout” that allows to subsequently study the phenotype of the animal and the molecular outcome.

Þ   Structural studies of NOD2 have shown that it consists of 3 domains: a CARD domain responsible for activation of a signaling protein NFkB, a NOD domain responsible for the oligomerisation of the protein and a Leucine-rich region responsible for bacterial recognition (typical example of the modular structure of the proteins).

Þ   The knockout mouse model for NOD2 do not fully fit the human Crohn’s disease (further suggesting the multi-factorial causes for this disease) but it gives important notions. The absence of a functional NOD2 alter normal signaling within the intestinal cells leading to abnormal activation of NFkB and production of pro-inflammatory cytokines (which may be one cause of the chronic inflammation). It will be interesting also understand if and how a deregulation of NOD2 in intestinal cells may influence the activity of so called T helper 1 lymphocytes.

 

Environmental causes:

The evidences for environmental factors rely entirely on statistical analysis and therefore have to be intended only as suggestion of causes (for references see Baumgart and Carding).

The LIFE STYLE may be one of the major factors:

  • Smoking drastically aggravates the course of Crohn’s disease accelerating the need for surgical intervention.
  • Bacterial or viral infection may trigger an excessive immune-reaction
  • Excessive sanitation may reduce the exposure of children and adults to microbial and other environmental antigen limiting the fully maturation of mucosal immune system that subsequently may over-react to safe bacteria or antigen.
  • Stress seems to increase the incidence of relapse in patient with quiescent disease.
  • Diet may play a role although weak data are presented so far.

 

Many other studies will be required for a fully understanding of the molecular mechanism involved and the cells interaction. Remained tuned on E-ducereX to be updated!

 

A funny parody of a real lab problem!!!!

Hi guys!

Here is a very funny video to start your day with a smile!!!!  Scientists are really crazy, sometimes…

The Crohn’s Disease

diagram of a human digestive system

Image via Wikipedia

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.

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

A thin-film Giemsa stained micrograph of ring-...

Image via Wikipedia

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.

Malaria: new strategies against the deadliest pathogen on hearth.

Countries which have regions where malaria is ...

Image via Wikipedia

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

Vaccination: the success over infectious diseases

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

Image via Wikipedia

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.

Stem Cells: treatment for Leukaemia

Diseases and conditions where stem cell treatm...

Image via Wikipedia

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)