Strategies in fighting AIDS

Few days ago, I blogged about how Perez et al made use of zinc finger nucleases as DNA scissors to get rid of the CCR5 allele within the CD4 T cell, which would confer resistance to the HIV virus. Yet another method exists, which allows gene editing to be made to the CCR5 gene. This is achieved using single-stranded oligonucleotides. These single-stranded oligonucleotides were shown to induce site-specific alterations by activation of DNA repair pathways.

Oligonucleotide-based gene editing has been suggested as an approach to correct genes resulting in neuro-muscular disorders (Bertoni, 2005). Other than single stranded DNA oligonucleotides, DNA/RNA hybrid molecules and double stranded DNA molecules of 100 - 1000 base pairs can be used. The use of microinjection technology allow for the introduction of these genome-altering molecules into the stem cell (Davis).

Unlike current therapeutic approach to correct the defective gene, the trick is to make the CCR5 gene defective which is the opposite, and in doing so, generate a population of HIV-resistant CD4 T cells.

Citations
1) Bertoni C. Oligonucleotide-mediated gene editing for neuromuscular disorders. Acta Myol. 2005 Dec;24(3):194-201.

2) David BR. Genome editing - Its promise and limitations for gene therap. At: http://www.pasteur.fr/applications/euroconf/geneandcelltherapy/22_Davis_abstract.pdf

Cure for AIDS

The successful transplant of bone marrow by Dr Gero Huetter and followed by the patient's showing no signs of HIV infection might provide some insights into the road to eradicating HIV.

In 2002, it was reported that the Great Ormond Street Hospital successfully attempted gene therapy of a 'bubble' child, who is obviously suffering from SCID. Earlier in June this year, Perez et al demonstrated HIV resistance in CD4 T cells by transciently expressing CCR5 zinc finger nuclease to induce genetic disruption of the CCR5, which provides stable and heritable resistance to HIV virus (Perez et al, 2008). CCR5 is known to be a mediator in the entry of a HIV virus to a T cell. Those with a mutation in the CCR5 are known to be resistant to HIV. The CCR5 zinc finger nuclease provides permanent disruption of the CCR5 allele. Advances have also been made in "gene editing" techniques, which uses zinc finger nucleases.

Perhaps, a possible approach to curing AIDS would be to introduce the zinc finger nucleases to bone marrow cells via gene therapy techniques, transciently expressing these nucleases in order to disrupt the CCR5 alleles. Without the functional CCR5, these altered cells which will be transplanted back into the bone marrow would generate new generations of HIV resistant CD4 T cells.

Citations

1) Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008 Jul;26(7):808-16. Epub 2008 Jun 29

Benefits of cooperate charity

In a bid to promote industrialization, tax benefits, discounted operating costs and freely available land are being dangled as carrots to entice companies. Companies also participate in charity drives, which provide them with a form of tax relief.





From a public policy planning perspective, it might be worthwhile to consider the benefits of attacting the cooperate sector to partake in charity drives or relief programs through tax reliefs and forms of benefits. Thus, the policy planner can identify a particular area which requires monetary resources, and solicit for the participation of various companies. Monetary resources are not required all the time. Even donated office space, land, equipment, stores and other peripherals can be done in the name of charity towards the community.

The companies will naturally benefit from tax relief and other benefits in exchange for their charity. They will also benefit from the positive image the community has of them, which itself is a form of advertorial.

In the past, charity organisations have always borne the mantle of charitable or relief works. Perhaps, the cooperate segments of the society should also be roped as well.

A possible cancer immunotherapy approach - Inducing the formation of granulomas

Granulomas are formed when the immune system encounters an antigen it cannot destroy, and as a result, it attempts to isolate the antigen, leading to the formation of a granuloma. A granuloma consists of macrophages, immune cells and a extracellular matrix. T cells are the perpetuator of granuloma formation, secreting cytokines and expressing adhesion molecules.

Non-resectable tumours have always posed problems for cancer patients. Standard treatment of non-resectable tumours include radiotherapy and chemotherapy. Perhaps, it is possible if the immune system can be tweaked to form a granuloma around the tumour mass, isolating it from the rest of the body. More work into the cellular processes of granuloma formation will give us an idea of the physiological mechanisms behind it. A greater understanding behind the mechanisms will perhaps allow us to consider this part of our immune process a weapon in the fight against cancer.

Citations
Sacco RE, Jensen RJ, Thoen CO, Sandor M, Weinstock J, Lynch RG, Dailey MO. Cytokine secretion and adhesion molecule expression by granuloma T lymphocytes in Mycobacterium avium infection. Am J Pathol. 1996 Jun;148(6):1935-48.

Alternative approach to tackling cancer: B cell therapy

The work of Brendjens et al in retrovirally infecting peripheral T cells thereby transforming them into 19z1+ cells (capable of targeting CD19+ Burkitt lymphoma cell line) marked another approach in cancer therapy. This work demonstrates the possibility of genetically engineering large populations of patient T cells with reactivity towards tumour antigens. Some of the challenges to these approach are the long-term survivalability of the genetically engineered T cells, their ability to home in on tumour sites and establishing a tumour-specific immune response.

Another approach will be to harness the potential of B cells. Like what Brendjens et al did with T cells, the B cells can be virally infected and transformed into cells that are capable of expressing the tumour specific antibodies. Biologics have become notably used in the war against cancer, with avastin, an anti-VEGF antibody, making the headlines in recent times. Thus, the ability to produce anti-cancer antibodies, our body's natural biologics seem to be an attractive proposition. What is so attractive about the use of B cell therapy comes from another intrinsic property of B cells - their ability to present antigens, i.e. they are antigen presenting cells. This means that the B cells are able to augment the adaptive arm of immune response, presenting antigens and co-stimulating T cells in order to direct immune response against the cancer cells. Thus, the possible approach maybe to genetically-engineer the B cells and expose them to tumour antigens. Some of the challenges may be similar to that experienced in T cells, i.e. the ability of the populations of B cells to survive in the body.

Citations

1) Brian Becknell & Michael A. Caligiuri. Cancer T cell therapy expands. Nature Medicine 9, 257 - 258 (2003)

2) Brentjens, R. et al. Eradication of systemic B cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).

3) Maher, J., Brentjens, R.J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

Top civil servant versus private sector executive - an argument from the standpoint of competitivieness

Earlier on, the Singapore government tabled a motion to peg the salaries of ministers and civil servants to that of the private sector. To peg the salaries against earners in the private sector, there must be some basis to show that a civil servant is indeed comparable to someone who is employed in the private sector.

One of the questions that arises is if there is any basis of comparison in the first place. If there is no basis of comparison, the argument for the need to raise salaries of civil servants and ministers by pegging them to the salaries of executives in the private sector is untenable. This is simply because there is little basis for comparison with their counterparts in the private sector.

In fact, in reality, there is little basis of comparison between someone working in the private sector and a civil servant. In the private sector, the raison d'etre for an employee or executive is simply to generate revenue or profits for the firms they are working for. A top executive in a firm is ultimately answerable to the shareholders, in as far as profits are concerned. Thus, more often than not, the worth of an employee or executive for that matter in the private sector is based on his ability to generate revenue. Therefore, his salary is justified by his ability to generate revenue or level of competitiveness, one way or another. (in the context of this article, competitiveness means the ability to generate profits or revenue in the financial sense).

How about a civil servant or even a top grade civil servant for that matter? His raison d'etre is public administration. Barring exceptions of civil servants occupying certain positions in the Economic Development Board or the Ministry of Trade and Industry, majority of civil servants are not in the position to generate revenue, so to speak. It follows that the working philosophy is not competitive in the sense. This can be illustrated with a simple comparative example. A superscale civil servant working at the headquarters of the Education Ministry makes decisions on the education system in Singapore in a public administrative capacity. However, a top executive in an educational provider company would be tasked with steering the company with the goal of generating more profits in mind. There is a world of difference between the two and the nature and aims of their work. It follows that the argument of using the private sector as a basis to justify the revisions in salary is not tenable.

There is another argument from the basis of lost opportunities, i.e. what talents in the civil service would have gained if they worked in the private sector instead. I am not denying that there are people formerly in the civil service who will eventually do well in the private sector, BUT again, to assert that a top executive within a civil service would go on to be a high flyer in the private sector may not sound convincing. The reason is the argument that I highlight earlier. The civil servant may have been brilliant at public administration, but we do not know if he is brilliant at generating revenue. An extrapolation of such a nature would be problematic.

The main thrust of my argument is that if one wants to peg salaries against a benchmark, there must be some basis of comparison with the benchmark. Thus, it is important to compare a civil servant with a someone working in the private sector. If there is no basis of comparison, then it follows that there is no basis for pegging salaries against that certain benchmark.

A critical look at the current electoral system's problem and a possible solution

Abstract

The current system of elections in Singapore has this unique feature - the Group Representation Constituency (GRC), whose purported existence is to allow minority representation. That aside, parliamentary elections have seen large percentages in walkovers , i.e. in more than 40% of the seats especially in the years after the GRC was introduced . In the event of a walkover, the political party facing a no-contest automatically gains seat (s) in the parliament. Walkovers occur due to the fact that the current opposition could not field that many candidates to contest all the seats. This paper critically examines the current electoral system's ruling of a walkover, and suggests a possible solution.

The problem with the current electoral system's ruling of a walkover is based on the flawed assumption that the party with the default victory has the mandate of the people living in the ward. This may not necessarily be the case. It could be possible that majority of the people in the uncontested ward desire another political party to represent them. Thus, from the representative democrat viewpoint, the current system is problematic since the wishes of the majority in the ward may not be reflected in the outcome of the elections.

Thus, the solution is to subject the entire "uncontested ward" to a vote. The residents will vote on whether they want the uncontested party to represent them in parliament. If it turns out that majority of the residents wants the uncontested party to represent them, the uncontested party candidates will naturally win their parliamentary seats. If it turns out that the majority of the residents do not want the uncontested party to represent them, the party is out of the running. A subsequent poll will be designated for a later date. In this subsequent poll, the uncontested party is excluded from contesting, given the fact that the majority of the residents do not desire their representation in an earlier vote. The seats at the constituency will then be contested by the other remaining parties. Candidates of other political parties who were unsuccessful in their wards may also contest in this subsequent poll.

Introduction

The parliamentary General Elections is held once every five years. On polling day, voters will vote for their desired representatives, who upon winning the contest in the ward, will serve as Members of Parliament. In the 1991 General Elections, the People's Action Party was returned to power on nomination day, as a result of 10 walkovers in 15 GRCs, and 1 walkover in a Single Member Constituency (SMC), gaining a total of 41 seats out of 81 seats. During the 1997 General Elections, the number of seats in some of the GRCs was increased to 5 seats in some and 6 seats in the others. The People's Action Party was returned to power on nomination day as a result of walkovers in 9 out of 15 GRCs, gaining a total of 47 out of 83 seats. During the 2001 General Elections, the People's Action Party was returned to power on nomination day as a result of walkovers in 10 out of 14 GRCs, gaining a total of 55 out of 84 seats. During the 2006 General Elections, the People's Action Party was not returned to power on nomination day, but it had walkover victories in 7 out of 14 GRCs, gaining a total of 37 out of 84 seats (Singapore Elections). Thus, an interesting observation is that most of the walkovers take place in the GRCs. In the current electoral system, the uncontested party automatically gains the seats in parliament. The question arises whether the residents of the walkover ward supports the uncontested party. From the democratic viewpoint, the current electoral system fails to address the voices of residents in the walkover ward as victory is given to the uncontested party by default, with the possibility that the uncontested party never had the residents' support (majority support) in the first place.

What then are the suggested changes to the current system of electoral contest to address the voices of the residents in the uncontested ward? A two-phase electoral contest is suggested herein as a possible solution. The first phase is known as the "Gatekeeping" phase, which ensures that the uncontested party has the mandate of the people living in the ward. In this "gatekeeping" phase, people will vote on whether or not they want the uncontested party to represent them. If the uncontested party has the approval of the majority in the ward, the "gate" is opened for its entry into parliament. However, if majority votes against the uncontested party, then it is out of the running of the elections. A subsequent poll is carried out at a later date involving the other political parties to determine the representatives of the ward. If the other political parties have enough candidates, they can take part in this subsequent poll. Candidates of the other political parties who are unsuccessful in their contested wards during the earlier election may participate in this subsequent poll too.

Discussion

The suggested approach has its strengths and weak points. Touching on the weak points, one of its criticisms will be from the standpoint of proportional representation (Proportional Representation Library). For example, if in a particular ward, 30,000 voters support the uncontested party, and they are likely to vote for the uncontested party at the "Gatekeeper" polls. However, 20,000 voters support a second political party, while 20,000 voters support a third political party. Thus, the end result is that the 30,000 "majority" out of this 70,000 do not "have their voices heard". In the winner-takes-all nature of the "First Past The Post" system, the uncontested party rightly deserves victory since it has the 30,000 majority. If you have 40,000 voters voting against the uncontested party, will it even be democratic to suggest that the uncontested party deserves to represent the entire ward (Ace Project)? In any sense, current polls at every single ward under the current system is based on the majority-wins-all First Past the Post system. The same criticism of proportional representation can be leveled at the current First Past the Post system. The nature of the contest in each ward under the current electoral system is that of majority is the winner-takes-all, and is by no means based on proportional representation.

Another weak point is perhaps the longer than usual polling period in the event that the "Gatekeeper" poll has eliminated the uncontested party. A later date for the poll has to be set aside for the residents of the uncontested ward to determine their representatives. The drawback is that the formation of the parliament is being delayed.

Moving on to the strength of this approach, first and foremost, it addresses the question of whether or not the uncontested party has the mandate of the people in the ward. It goes that if majority of the people do not desire its representation as reflected in the polls, it's only right that the "gate" to its entry into parliament is closed.

Another strength of this approach is that it preserves the fundamental values of meritocracy. Suppose in a situation whereby the other parties encounter mishaps, be it administrative mishaps or otherwise, and a group of individuals or a single individual apply to contest in this ward. It follows that this group of individuals or individual for that matter are applying for the sake of contesting per se, and are not interested in representing the interests of the voters. Will it wise to give this group of individuals or individual a walkover victory? The answer is an obvious no. The "gatekeeper" poll will be able to easily eliminate such individuals from the contest. In essence, candidates who merit the voter's support will be rewarded accordingly and those who do not deserve the support will be eliminated.

Yet another strength of this approach is that it will further encourage more pro-active participation from the political parties in improving the lives of the voters. Under the current system, the uncontested party is automatically given default victory. If the uncontested party has to win the approval of the voters at the "Gatekeeper" polls, it will have greater impetus to be more pro-active in winning the hearts and minds of voters. All the more the voters will benefit.

The thrust of this paper is to critically examine the current drawbacks of electoral contests in the event of a walkover. There is not much literature out there addressing the event of a walkover, especially from the standpoint of the voters' desires in a walkover ward. Although, it is not without its drawbacks, the benefits outweighs the drawbacks. Thus, it will be a positive move from a democratic perspective that the relevant authorities do try to take steps to allow voters in "walkover wards" to decide who should represent them, either through wholesale changes or revision in the current electoral system.

Citations

1) Ace Project. Electing a President using FPTP. accessible at http://www.aceproject.org/ace-en/topics/es/ese/ese01/ese01a/

2) Proportional Representation Library. Mount Holyoke College accessible at http://www.mtholyoke.edu/acad/polit/damy/prlib.htm

3) Singapore Elections Results accessible at http://www.singapore-elections.com/