Modelling haematocrit distribution in vessel networks
Lead Research Organisation:
University of Oxford
Department Name: SABS CDT
Abstract
Hypoxia (lower than normal oxygen levels) in tumours is a common phenomenon with implications for pa- tient prognosis and treatment. Hypoxic regions within tumours have proven to be less susceptible to chemo- and radiation therapies, stimulate tumour cell migration, select for tumour cells with aggressive phenotypes, and promote angiogenesis leading to irregular vasculature [15, 22, 33, 34, 35]. These problems provide major obstacles to clinicians seeking to treat cancer patients. In intensely proliferating tumours, the tumour cells' de- mand for oxygen and nutrient surpasses their availability within the tumour micro-environment. These newly forming cancerous cells also increase the distance between healthy cells and their local vascular networks by growing in locations between the two. As a result, these healthy cells go beyond the diffusion distance of oxygen. This abrupt change from normoxic (normal levels of oxygen) tissue to hypoxic tissue promotes the formation of irregular vasculature which can result in uneven oxygen distribution and brief short-term periods of hypoxia, known as cycling-hypoxia [22].
Several important side affects of cycling hypoxia have been observed experimentally and in patients. These can include increased metastatis [2, 9], increased plasticity and mobility of tumour cells [22], increased tumour resistance to chemo- and radiotherapy [22] and immune resistance and suppression [21, 23], to name but a few. These side effects make cancerous cells more aggressive and more resistant to treatments.
It is therefore important to understand the mechanisms which result in hypoxia and how such factors can be managed. The use of anti-angiogenic factors have been proposed as a treatment for hypoxia. Counter- intuitively, anti-angiogenic treatments have been shown to improve the prognosis of patients in certain cancers [5, 10, 12, 19]. Despite this knowledge, an exact mechanism as to why these treatments are effective remains elusive. One approach to understanding why these treatments are so effective is to simulate the effect of different vascular networks on the oxygen distribution in tissue. Tumour vascular networks are often irregular and chaotic and can lead to uneven distributions of red blood cells (RBCs) in a network. Simulating this distribution allows predictions to be made on how uniformly oxygen diffuses into the tissue. Furthermore, this oxygen distribution can be further incorporated into a model for delivery of oxygen dependant therapeutics. Progress towards this goal has been made using Microvessel Chaste, an open-source library that has proven effective in modelling the distribution of RBCs in vessel networks and the resulting levels of oxygen in the surrounding tissue. [17].
Several important side affects of cycling hypoxia have been observed experimentally and in patients. These can include increased metastatis [2, 9], increased plasticity and mobility of tumour cells [22], increased tumour resistance to chemo- and radiotherapy [22] and immune resistance and suppression [21, 23], to name but a few. These side effects make cancerous cells more aggressive and more resistant to treatments.
It is therefore important to understand the mechanisms which result in hypoxia and how such factors can be managed. The use of anti-angiogenic factors have been proposed as a treatment for hypoxia. Counter- intuitively, anti-angiogenic treatments have been shown to improve the prognosis of patients in certain cancers [5, 10, 12, 19]. Despite this knowledge, an exact mechanism as to why these treatments are effective remains elusive. One approach to understanding why these treatments are so effective is to simulate the effect of different vascular networks on the oxygen distribution in tissue. Tumour vascular networks are often irregular and chaotic and can lead to uneven distributions of red blood cells (RBCs) in a network. Simulating this distribution allows predictions to be made on how uniformly oxygen diffuses into the tissue. Furthermore, this oxygen distribution can be further incorporated into a model for delivery of oxygen dependant therapeutics. Progress towards this goal has been made using Microvessel Chaste, an open-source library that has proven effective in modelling the distribution of RBCs in vessel networks and the resulting levels of oxygen in the surrounding tissue. [17].
Planned Impact
The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
