Connect with us

Uncategorized

Superluminal Medicines Launches to Drug Protein Conformations in a Flash

A few days after the launch of Superluminal Medicines was announced on August 28, CEO Cony D’Cruz told GEN about the company’s journey, which started as…

Published

on

Whenever I interview the founders of a new biotech company, I typically inquire about the origin of the company’s name. There is an astonishingly wide range of responses to this question.

A few days after the launch of Superluminal Medicines was announced on August 28, as I was getting ready to speak with CEO Cony D’Cruz, I started trying to connect the company name with G protein-coupled receptors (GPCRs), the targets of their emerging small-molecule drug discovery programs. Everything that sprang to mind was predicated on the idea that a lumen is “the inside space,” be it inside an organ or cell. It turns out that my biologically based assumption was entirely incorrect.

Cony D’Cruz, co-founder and CEO at Superluminal Medicines.

According to D’Cruz, the company’s journey started in January 2022, when RA Capital Management’s principal Nathaniel Brooks Horowitz and senior associate Soumya Ray suggested the name superluminal—it means “faster than the speed of light”—for a top-secret project aimed at tackling drug discovery on a never-before-seen timeline. They considered using a range of computational technologies to expedite each stage of the drug discovery process to accomplish this.

As a result of that idea, Superluminal Medicines has received $33 million in seed funding, with significant contributions from Insight Partners, NVIDIA, and Gaingels, to fuel its drug discovery engine and pipeline of small molecule therapeutics.

A computational crystal ball

In early 2022, the team working on the top-secret “superluminal” project started looking at the landscape of available computational technologies. They brought in tools for protein structure prediction like AlphaFold2 and molecular dynamics simulations based on free energy perturbation methods, which D’Cruz considered useful only with high-quality crystal structures to build a computational model on.

However, D’Cruz said that crystal structures (but not really cryo-EM) have some limitations in the resulting protein construct because the crystal structure is modified to some degree, which can be quite significant when talking about membrane proteins.

“It creates an artificial structure, which is great for getting the crystal structure but not so great for the representation of how it actually behaves in a cell,” said D’Cruz.

They then began to do something that, at face value, seems quite counterintuitive: reduce the sequence homology parameters in AlphaFold2, which essentially works by finding similar sequences to the input, extracting the information using an especially neural network architecture, and then passing that information to another neural network that produces a structure.

“If you give AlphaFold2 a sequence, it goes out into the ether and picks everything that’s structurally available that looks like that sequence,” said D’Cruz. “If you start reducing the sequence homology constraints, you basically draw a wider set of structures and start seeing something very interesting—protein flexibility. You get this dynamic movement of the proteins computationally because you can stitch together all the various conformations.”

Cryo-EM at scale is challenging, expensive, and time-consuming, but D’Cruz and his team are trying to do just that with computation to optimize drug discovery cycles.

With this as their starting point, the top-secret project morphed into the stealth company Superluminal Medicines and a team began predicting complex protein structures.

By using these protein structure prediction tools, biologist-turned-co-founder and head of discovery Ajay Yekkirala, PhD, began considering what would happen if you could target particular conformations of a complex protein, like GPCRs, to elicit specific downstream signaling. A year ago, they started to see some encouraging indications that they could predict conformations of a specific GPCR.

Protein nonconformists

The next piece of the computation pipeline puzzle was to connect different GPCR conformations to different signaling pathways. This gave them a place to start their virtual screening for small molecules that work only with certain GPCR conformations.

According to D’Cruz, the fact that so many drugs fail in the preclinical and clinical testing stages due to toxicity events has a significant impact on this step. Superluminal has tried to get ahead of toxicity events by trying to understand as much as possible in terms of Absorption, Distribution, Metabolism, and Excretion (ADME) liabilities, spending significant resources on building a predictive tool specifically for this.

While D’Cruz said it’s too early to say how well this toxicity prediction tool works, at least it provides their medicinal chemists with a line of sight of what’s possible in terms of an issue downstream that they can then start thinking about and avoiding by design.

D’Cruz, who spent more than nine years at Schrödinger, says that there is no way that Superluminal can or will skip any testing that’s traditionally involved in drug development and discovery. Where these tools will have a major impact is in minimizing animal testing by making predictions upfront and only testing limited sets of compounds to ultimately speed up and optimize the drug discovery cycle.

I pressed D’Cruz on the limits of their computational approach, asking if there was any value in getting their own crystal structure and CryoEM data. For this, Superluminal initially teamed up with Thermo Fisher and The Cambridge Pharmaceutical Cryo-EM Consortium. Now, Thermo Fisher has put out quite a few CryoEM microscopes, allowing Superluminal to expand the number of sources of structural protein data.

“We’re always going to need structural validation to finally get to the ground truth,” said D’Cruz. “However, we don’t wait for it in order to progress a program. So the definitive go-or-no-go is actually in the cell. Can we elicit the appropriate biological response we want? If that’s the case, then we move forward. We always try and get a structure, but we don’t wait for it.”

Hypothetical pudding

The targeting of GPCRs has been at the heart of several recent company launches in the past few years, notably Septerna, which was launched with the backing of Nobel laureate Robert Lefkowitz, MD. Earlier this month, Solu Therapeutics launched behind its CyTaC (Cytotoxicity Targeting Chimera) platform to drug cell surface receptors, including GPCRs.

Superluminal’s strategy is more akin to that at Solu Therapeutics. D’Cruz said that while this funding round will help Superluminal develop a proof of concept that creates value through targeting GPCRs, their computation is by no means limited to working with GPCRs.

After all, the initial top-secret superluminal project started off focusing on not only GPCRs but also enzymes. D’Cruz said that one of the first proof-of-concept examples of their computation focuses on an enzyme that has evaded crystallographers for years.

“It is an enzyme that we chose to go after because, for years, we couldn’t get the crystal structure appropriately because the five-prime end was capped,” said D’Cruz. “We predicted the structure without the cap and docked compounds, and then we got a crystal structure without the cap, proving that we got the prediction correct. So, we know we can do enzymes.”

According to D’Cruz, Superluminal’s choice to target GPCRs was purely a “business decision.” In the future, D’Cruz hopes that they will be able to partner and expand the domain of applicability of the platform beyond GPCRs.

What D’Cruz thinks will help Superluminal Medicines stand out from the rest of the pack pursuing GPCRs is the quality of his team. The team currently consists of ten people, which includes experimental biology scientists in Yekkirala, who was a postdoc at Harvard Medical School and Boston Children’s Hospital before co-founding Blue Therapeutics and then ending up as a VP and the head of biology at RA Capital Management. Another key figure is Yamina Berchiche, PhD, who previously was at the Institute for Protein Innovation and goes by the name “Dr. GPCR.”

Additionally, they have brought in experienced computational scientists, such as head of engineering Yang-Ming Zhu, PhD. Zhu spent almost two decades with Philips, reconstructing 2D positron emission tomography (PET) scans into 3D images for diagnostics, and is, according to D’Cruz, Superluminal’s “machine learning guy who is used to dealing with complex and difficult data sets and brings a different way of thinking to drug discovery and development.”

To impress upon me the importance of out-of-the-box thinking when it comes to computation, D’Cruz gives an anecdote from last year, in which shortly after joining, Zhu asked if there was any money for IP. Zhu had already developed several proprietary machine learning algorithms by taking algorithms from different applications and industries like manufacturing and transportation, which have high-data complexity, and applying them to their drug discovery pipeline.

“We like to fool ourselves in biology, but the data is actually not that deep—we don’t have a lot of data,” said D’Cruz. “That’s one of the limitations of using machine learning in drug discovery and development. There are far more pictures and data for cats than there are drug discovery programs or even compounds. So, [Zhu] managed to bring in new ways of thinking to our industry, which is what we’re looking for.”

With this initial team and funding round, D’Cruz emphasized that Superluminal is focused on developing assets.

“Obviously, we spend money developing the platform, but in service of the assets,” said D’Cruz. “We try and understand the biology problems, the fundamental things that we’re trying to do once we identify the targets, and then the tool sets we need with either what’s currently available or what we need to develop to get to that point. At the end of the day, it’s the value of what we create that anyone’s going to judge us by. It’s really hard to value an algorithm.”

In the growing space of AI-based drug discovery, no one says that their algorithms are average—they say that they’re the next best thing. While confidence, to some degree, is necessary to move a project forward, the field is not at the stage where there is an answer for the best approach or for the ones that may be wildly wrong—even dangerous. With such a fast-growing space, the only way to judge a company’s value will be through robust and validated assets. The proof of the pudding is in the eating, not the dreaming.

The post Superluminal Medicines Launches to Drug Protein Conformations in a Flash appeared first on GEN - Genetic Engineering and Biotechnology News.

Read More

Continue Reading

Uncategorized

Macro Briefing: 19 February 2024

* ‘Soft landing’ debate for US economy in focus again after latest reports * New signs emerge that America’s shale-oil boom is peaking * US says…

Published

on

* ‘Soft landing’ debate for US economy in focus again after latest reports
* New signs emerge that America’s shale-oil boom is peaking
* US says it will react if China dumps goods on global markets
* China reports record upsurge in travel, which may presage stronger growth
* China’s central bank leaves key policy rate unchanged
* Regional banks are vulnerable to risk tied to commercial real estate lending
* US natural gas prices plunge amid warm winter weather
* US producer price inflation rose more than expected in January:

Younger adults grew their wealth at a sharply faster pace than older Americans in the wake of the pandemic, due primarily to holdings in stocks, according to a new study published by the New York Fed. “We examine wealth dynamics from 2019:Q1 through 2023:Q3 for three age groups: 18-39, 40-54, and 55 and over,” the report explains. “eal wealth has increased for all three age groups since 2019, but the change has been most dramatic for younger adults (see chart below). For individuals 39 and younger, wealth increased by 80 percent. In contrast, it grew by only 10 percent for those aged 40-54 and by 30 percent for those 55 and over.”

Read More

Continue Reading

Uncategorized

Taxing Billionaires Won’t Reduce Taxes For The Middle Class

Taxing Billionaires Won’t Reduce Taxes For The Middle Class

Authored by Daniel Lacalle,

In a world of populist policies, the notion of taxing…

Published

on

Taxing Billionaires Won't Reduce Taxes For The Middle Class

Authored by Daniel Lacalle,

In a world of populist policies, the notion of taxing billionaires to alleviate the financial burdens of the middle class stands as a tempting narrative. Advocates tout it as the quintessential solution to income inequality, promising a redistribution of wealth that lifts the masses from their fiscal woes. However, this narrative, so alluring in its simplicity, crumbles upon closer examination, revealing a multitude of complexities and pitfalls that belie its benefits.

Central to the fallacy of taxing billionaires lies a fundamental misunderstanding of the dynamics of government spending and deficits. Proponents of this approach often overlook the inconvenient truth that as most governments increase spending even when tax receipts rise, deficits soar to unprecedented heights, burdening future generations with a mountain of debt and always increasing taxes for the middle class.

Taxing the rich is the door that leads to more taxes for all of us. The case of the United States is evident. No tax revenue measure is going to wipe out an annual two trillion dollar deficit. Therefore, the government announces a large tax hike for the wealthy and disguises it with more taxes for everybody and higher inflation, which is a hidden tax.

The notion that taxing billionaires will miraculously alleviate this fiscal strain is akin to applying plaster to a gaping wound—it does not even provide temporary relief, and it fails to address the underlying malaise.

A seminal paper by Alesina, Favero, and Giavazzi (2015) delves into the implications of government deficits on economic growth. The authors argue that persistent deficits not only crowd out private investment but also lead to higher interest rates, reduced confidence, and ultimately diminished economic growth. This underscores the importance of fiscal prudence in addressing long-term fiscal challenges and the evidence that tax hikes are not neutral.

Billionaires mostly hold their wealth in shares of their own companies. This is what is called “paper wealth.” However, they cannot sell those shares and if they lost them, their value would decline immediately.

The redistribution fallacy comes from three false ideas:

  • The first is the notion that billionaires do not pay taxes to begin with. The top one percent of income earners in the United States earned 22 percent of all income and paid 42 percent of all federal income.

  • The second error is believing that wealth is static—like a pie—and can be redistributed at will. Wealth is either created or destroyed. Confiscating the wealth of billionaires does not make the middle class or the poor richer. We should have learned that lesson from the numerous examples in history, from the French Revolution to the Soviet Union.

  • The third mistake is to believe that the economy is a sum-zero game where the wealth of one person is the loss of another. That is simply false because wealth is not “there.” It must be created through an exercise where all parties win in exchange for cooperation.

The world must strive to create more wealth, not limit those who generate it.

Consider the recent clamour for increased government intervention and spending, particularly in the wake of global crises. For instance, the COVID-19 pandemic prompted governments all over the world to enact a flurry of fiscal stimuli, ostensibly intended to soften the blow of the economic fallout. Yet, as the dust settles, we find ourselves grappling not only with the immediate ramifications of increased government spending but also with the long-term consequences of ballooning deficits as well as persistent inflation.

Who came out as the loser of the redistribution and stimulus frenzy of the past decade? The middle class. It has been destroyed by persistent inflation created by printing money without control, rising debt and deficits and constantly bloating government size in the economy, which in turn creates two taxes for the middle class and the poor: inflation and rising indirect taxes.

Critics of this approach have long warned of the dangers of irresponsible government spending. Taxing billionaires will not stop this trend of excessive bureaucracy and irresponsible administration of public services; in fact, it may accelerate it, as we have seen in so many countries, and certainly will not reduce the tax wedge on ordinary citizens.

History is replete with cautionary tales of nations brought to their knees by unchecked fiscal excesses. From hyperinflation to sovereign debt crises, the ramifications of fiscal irresponsibility are manifold and far-reaching. And yet, in the face of mounting pressure to “tax the rich,” policymakers seem intent on repeating the mistakes of the past, heedless of the inevitable consequences.

But the fallacy of taxing billionaires extends beyond the realm of fiscal policy—it strikes at the very heart of economic prosperity. At its core, capitalism depends on investment, entrepreneurship, and innovation—all of which are at risk from excessive taxation. The narrative that vilifies billionaires as greedy hoarders of wealth overlooks their crucial role in driving economic growth and prosperity.

By focusing solely on redistributive measures, policymakers risk undermining the very foundations of prosperity upon which our economic system rests.

Moreover, the notion that taxing billionaires will somehow level the playing field and uplift the middle class is predicated on a flawed understanding of economic reality. In truth, the global mobility of capital renders such measures largely ineffective, as the ultra-wealthy can easily relocate to jurisdictions with more favourable tax regimes. This not only undermines the efficacy of taxing billionaires as a revenue-generating mechanism but also exacerbates the very inequalities it seeks to redress.

Indeed, the unintended consequences of excessively taxing the rich are manifold and far-reaching. From reduced investment and job creation to economic stagnation and decline, the repercussions of such policies are felt across society. And while the rhetoric of wealth redistribution may sound appealing in theory, the reality is far more sobering—a stagnant economy, diminished opportunities, and a dwindling standard of living for all.

So, where does this leave us? If taxing billionaires is not the panacea it purports to be, what alternatives exist to address income inequality and alleviate the burdens of the middle class? The answer lies not in punitive taxation but in prudent fiscal policy, targeted policies, and a renewed focus on fostering economic growth and prosperity for all.

Primarily, we must recognize that fiscal responsibility is not a luxury but a necessity. Governments must exercise restraint in their spending, prioritize efficiency and accountability, and resist the temptation to paper over fiscal deficits with ill-conceived tax hikes and money printing. Only through disciplined fiscal management can we hope to secure a prosperous future for generations to come.

Second, we must recognize the vital role that entrepreneurship and investment play in driving economic growth and prosperity. Rather than demonizing billionaires as the root of all evil, we should celebrate their contributions to society and create an environment that fosters innovation, entrepreneurship, and wealth creation. This means reducing regulatory barriers, incentivizing investment, and empowering individuals to pursue their entrepreneurial ambitions.

Finally, we must understand that opportunities provided to citizens, not the size of the government, are what define true progress. Rather than relying on the state to solve all our problems, we should empower individuals and communities to chart their own course to prosperity. This means investing in education, healthcare, and infrastructure, providing a safety net for those in need, and fostering a culture of self-reliance and personal responsibility.

In conclusion, the fallacy of taxing billionaires lies not in its intentions but in its execution. While the notion of redistributing wealth may sound appealing in theory, the reality is far more complex. By succumbing to the allure of punitive taxation, we risk stifling economic growth, undermining prosperity, and perpetuating the very inequalities we seek to redress. Only through prudent fiscal management, targeted interventions, and a renewed focus on fostering economic growth can we hope to build a future that is truly prosperous for all.

Socialism does not redistribute from the rich to the poor, but from the middle class to politicians.

The fallacy of massively taxing billionaires is another trick to promote socialism, which has never been about the redistribution of wealth from the rich to the poor, but the redistribution of wealth from the middle class to politicians.

Tyler Durden Sun, 02/18/2024 - 17:30

Read More

Continue Reading

Uncategorized

Taxing Billionaires Won’t Reduce Taxes For The Middle Class

Taxing Billionaires Won’t Reduce Taxes For The Middle Class

Authored by Daniel Lacalle,

In a world of populist policies, the notion of taxing…

Published

on

Taxing Billionaires Won't Reduce Taxes For The Middle Class

Authored by Daniel Lacalle,

In a world of populist policies, the notion of taxing billionaires to alleviate the financial burdens of the middle class stands as a tempting narrative. Advocates tout it as the quintessential solution to income inequality, promising a redistribution of wealth that lifts the masses from their fiscal woes. However, this narrative, so alluring in its simplicity, crumbles upon closer examination, revealing a multitude of complexities and pitfalls that belie its benefits.

Central to the fallacy of taxing billionaires lies a fundamental misunderstanding of the dynamics of government spending and deficits. Proponents of this approach often overlook the inconvenient truth that as most governments increase spending even when tax receipts rise, deficits soar to unprecedented heights, burdening future generations with a mountain of debt and always increasing taxes for the middle class.

Taxing the rich is the door that leads to more taxes for all of us. The case of the United States is evident. No tax revenue measure is going to wipe out an annual two trillion dollar deficit. Therefore, the government announces a large tax hike for the wealthy and disguises it with more taxes for everybody and higher inflation, which is a hidden tax.

The notion that taxing billionaires will miraculously alleviate this fiscal strain is akin to applying plaster to a gaping wound—it does not even provide temporary relief, and it fails to address the underlying malaise.

A seminal paper by Alesina, Favero, and Giavazzi (2015) delves into the implications of government deficits on economic growth. The authors argue that persistent deficits not only crowd out private investment but also lead to higher interest rates, reduced confidence, and ultimately diminished economic growth. This underscores the importance of fiscal prudence in addressing long-term fiscal challenges and the evidence that tax hikes are not neutral.

Billionaires mostly hold their wealth in shares of their own companies. This is what is called “paper wealth.” However, they cannot sell those shares and if they lost them, their value would decline immediately.

The redistribution fallacy comes from three false ideas:

  • The first is the notion that billionaires do not pay taxes to begin with. The top one percent of income earners in the United States earned 22 percent of all income and paid 42 percent of all federal income.

  • The second error is believing that wealth is static—like a pie—and can be redistributed at will. Wealth is either created or destroyed. Confiscating the wealth of billionaires does not make the middle class or the poor richer. We should have learned that lesson from the numerous examples in history, from the French Revolution to the Soviet Union.

  • The third mistake is to believe that the economy is a sum-zero game where the wealth of one person is the loss of another. That is simply false because wealth is not “there.” It must be created through an exercise where all parties win in exchange for cooperation.

The world must strive to create more wealth, not limit those who generate it.

Consider the recent clamour for increased government intervention and spending, particularly in the wake of global crises. For instance, the COVID-19 pandemic prompted governments all over the world to enact a flurry of fiscal stimuli, ostensibly intended to soften the blow of the economic fallout. Yet, as the dust settles, we find ourselves grappling not only with the immediate ramifications of increased government spending but also with the long-term consequences of ballooning deficits as well as persistent inflation.

Who came out as the loser of the redistribution and stimulus frenzy of the past decade? The middle class. It has been destroyed by persistent inflation created by printing money without control, rising debt and deficits and constantly bloating government size in the economy, which in turn creates two taxes for the middle class and the poor: inflation and rising indirect taxes.

Critics of this approach have long warned of the dangers of irresponsible government spending. Taxing billionaires will not stop this trend of excessive bureaucracy and irresponsible administration of public services; in fact, it may accelerate it, as we have seen in so many countries, and certainly will not reduce the tax wedge on ordinary citizens.

History is replete with cautionary tales of nations brought to their knees by unchecked fiscal excesses. From hyperinflation to sovereign debt crises, the ramifications of fiscal irresponsibility are manifold and far-reaching. And yet, in the face of mounting pressure to “tax the rich,” policymakers seem intent on repeating the mistakes of the past, heedless of the inevitable consequences.

But the fallacy of taxing billionaires extends beyond the realm of fiscal policy—it strikes at the very heart of economic prosperity. At its core, capitalism depends on investment, entrepreneurship, and innovation—all of which are at risk from excessive taxation. The narrative that vilifies billionaires as greedy hoarders of wealth overlooks their crucial role in driving economic growth and prosperity.

By focusing solely on redistributive measures, policymakers risk undermining the very foundations of prosperity upon which our economic system rests.

Moreover, the notion that taxing billionaires will somehow level the playing field and uplift the middle class is predicated on a flawed understanding of economic reality. In truth, the global mobility of capital renders such measures largely ineffective, as the ultra-wealthy can easily relocate to jurisdictions with more favourable tax regimes. This not only undermines the efficacy of taxing billionaires as a revenue-generating mechanism but also exacerbates the very inequalities it seeks to redress.

Indeed, the unintended consequences of excessively taxing the rich are manifold and far-reaching. From reduced investment and job creation to economic stagnation and decline, the repercussions of such policies are felt across society. And while the rhetoric of wealth redistribution may sound appealing in theory, the reality is far more sobering—a stagnant economy, diminished opportunities, and a dwindling standard of living for all.

So, where does this leave us? If taxing billionaires is not the panacea it purports to be, what alternatives exist to address income inequality and alleviate the burdens of the middle class? The answer lies not in punitive taxation but in prudent fiscal policy, targeted policies, and a renewed focus on fostering economic growth and prosperity for all.

Primarily, we must recognize that fiscal responsibility is not a luxury but a necessity. Governments must exercise restraint in their spending, prioritize efficiency and accountability, and resist the temptation to paper over fiscal deficits with ill-conceived tax hikes and money printing. Only through disciplined fiscal management can we hope to secure a prosperous future for generations to come.

Second, we must recognize the vital role that entrepreneurship and investment play in driving economic growth and prosperity. Rather than demonizing billionaires as the root of all evil, we should celebrate their contributions to society and create an environment that fosters innovation, entrepreneurship, and wealth creation. This means reducing regulatory barriers, incentivizing investment, and empowering individuals to pursue their entrepreneurial ambitions.

Finally, we must understand that opportunities provided to citizens, not the size of the government, are what define true progress. Rather than relying on the state to solve all our problems, we should empower individuals and communities to chart their own course to prosperity. This means investing in education, healthcare, and infrastructure, providing a safety net for those in need, and fostering a culture of self-reliance and personal responsibility.

In conclusion, the fallacy of taxing billionaires lies not in its intentions but in its execution. While the notion of redistributing wealth may sound appealing in theory, the reality is far more complex. By succumbing to the allure of punitive taxation, we risk stifling economic growth, undermining prosperity, and perpetuating the very inequalities we seek to redress. Only through prudent fiscal management, targeted interventions, and a renewed focus on fostering economic growth can we hope to build a future that is truly prosperous for all.

Socialism does not redistribute from the rich to the poor, but from the middle class to politicians.

The fallacy of massively taxing billionaires is another trick to promote socialism, which has never been about the redistribution of wealth from the rich to the poor, but the redistribution of wealth from the middle class to politicians.

Tyler Durden Sun, 02/18/2024 - 17:30

Read More

Continue Reading

Trending